1

A.V. Kuzin, Iu.G. Vasiliev, V.M. Tchuchkov, T.G. Shorokhova

ENSEMBLE CO-INTERACTIONS
IN THE CENTRAL NERVOUS SYSTEM

Izhevsk - Berlin
2004
 2
UDK 611.81.013 + 611.899.013]:612.824
BBK 28.866
К 89

Edited by Doctor of medical sciences,

corresponding member of the Russian Academy of Medical Sciences,
Professor L.L.Kolesnikov

Reviewers:
Yorg Schultz – Professor, Doctor of Medicine, Medical Head of Helios Clinic, Head of the scientific Counsel of the
European Academy of interdisciplinary medicine, Honorary president of the European union of Active anti-ageing;
V.N.Nikolenko – Professor, Doctor of medical sciences, Head of the department of the human anatomy of Saratov
State Medical University.

Recommended for edition by the consultative training counsel in anatomy and histology of the Ministry of Health of
Russian Federation
and by the Institute of Molecular and Systemic Medicine (Berlin)

A.V.Kuzin, Iu.G.Vasiliev, V.M.Chuchkov, T.G.Shorokhova. Ensemble co-interactions in the central nervous system:
Monograph. Izhevsk – Berlin: ANK – 2004. – 160 pp.

ISBN 5–9631–0005–4
The monograph contains the information concerning the structure and function of the neuroglio-vascular ensembles,
based on the authors’ investigations, as well as the available published results. While the early and sparse complex inves-
tigations of the analogical structures consider the presence of the macroglia as a factor allowing to isolate the functional
neuron groups, much attention is given to the function of such ensembles at the level of individual microvascular pools
around the bodies of the nervous cells, single or joined into the small groups; new data concerning the structure of the
neuro-glio-vascular co-interactions, their formation during the ontogenetic development are represented. The problems of
substances’ diffusion modeling in the central nervous system are discussed. The analysis of the correspondence of data,
recorded by means of the computer modeling, with the results of morphometric investigations, is represented.
The monograph may be of some interest for the neurobiologists, angiologists, physiologists and pathophysiologists.

УДК611.81.013 + 611.899.013]:612.824
ББК 28.866

© Collective of authors, 2004

© ANK Edition, 2004
 3
CONTENTS
LIST OF THE ABBREVIATIONS 4

INTRODUCTION 5

Chapter I. MATERIALS FOR THE MORPHOLOGICAL EXAMINATION AND THE PARTICULAR FEA- 7
TURES OF THEIR HISTOLOGICAL AND MORPHOMETRIC PROCESSING

I.1. Results of the authors’ investigations. Particularities of the sampling and histological processing of the ma- 7
terial

I.2. Characteristics of the morphometric analysis used 8

CHAPTER II. STRUCTURE OF THE NEUROGLIO-VASCULAR COMPLEXES 1

2

II.1. Structure of the neurons in the nucleus pontis and in the nuclei of the mesencephalon 1
2

II.2. Structure and function of neuroglia in the central nervous system 2

0

II.3. Relationship between the angioarchitectonic and structural-functional organization of the nuclear centers. 2
Ensemble organization of the nuclear centers 9

CHAPTER III. FORMATION OF THE NEUROGLIO-VASCULAR COMPLEXES DURING THE ONTO- 1

GENESIS 00

CHAPTER IV. BRAIN TRANSFER OF THE SUBSTANCES 1

22

CHAPTER V. MATHEMATICAL MODELLING OF THE TRANSPORTATION FLOW IN THE CEN- 1

TRAL NERVOUS SYSTEM 24

V.1. Mathematical analysis of the diffusion flows of the oxygen and carbon dioxide 1
24

V.2. Results obtained during the analysis of the oxygen diffusion flows using the mathematical model 1
27

V. 3. Carbon dioxide diffusion flows, obtained using the mathematical modeling 1

31

V. 4. Modeling of the glucose transportation flow in the nervous system 1

32

V. 5. Results obtained using the analysis of the mathematical model of the glucose transportation 1
36

V.6. Oxygen distribution modeling in the aniage of the posterior cerebral vesicle 1
41

CONCLUSION 1
44

REFERENCES 1
47
 4
LIST OF ABBREVIATIONS
A – Artery
Ast – Protoplasmatic asrocyte
Аrl – Arteriole
Fast – Fasciculated astrocyte
Ven – Vein
Gl – Gliocyte
V – Blood capillary
Vnl – Venule
N – Neuron
Nbl – Oligodendrocyte
Dk – Blood capillary diameter
Dm – Minimal diameter of the microvascular basin
Dpf – Pericapillary filtration diameter
Dpfpn – Pericapillary ultraphiltration diameter accounting for the neurons’ bodies
Dpfn – Pericapillary ultraphiltration diameter of the microvessels, situated within 20 μm from the nervous cell body
surface
Lv – Maximal diameter of the microvascular basin
Lm – Specific length of the microvessels
Lvn – Specific length situated within 20 μm from the nervous cell body surface
Ng – Number of the satellite cells – gliocytes of the pericarion of the unique neurons
Nn/a – Number of the neurons bodies, immediately surrounded with the processes of the unique protoplasmatical as-
trocyte
Nnkp – Number of the neuron’s bodies, situated within the unique microvascular basin
Ns – Number of the microvessels, situated within 20 μm from the nervous cell body surface
Ns/a – Number of the vessels on one section, around which one protoplasmatic astrocyte takes part in the formation of
the pericapillary “sleeves”
Max La – Maximal extent of the processes of the protoplasmatic astrocytes
Min La – Minimal extent of the processes of the protoplasmatical astrocytes
Sasn – Specific area of the microvessels’ internal surface, providing the most effective exchange with the neuron’s
body
Ss – Specific area of the exchange surface of the microvessels
Ssn – Specific area of the exchange surface of the microvessels, situated within 20 μm from the nervous cell body sur-
face
Vn – Volume of the pericarion vessels
Vvk – Volume of the microvessels
Vvn – Apparent density of the neurons’ pericarion.
 5
INTRODUCTION
The investigators of the nervous system have recently faced a challenge in the interpretation of the results obtained in studies of
the structure and activity of the nervous system. The abundant information concerning cerebral ultrastructural architecture does not
allow the authors to make a comprehensive clarification of the brain activities as an integral system (N.S. Kositsin, 1978; A.S. Ba-
tuyev, .P. Babmindra, 1993; I.G. Akmayev, 1996; K.K. Sudakov, 1996). The data concerning the neurophysiological processes in the
brain are often significantly abstracted of the investigation of morphologic substrate where these processes take place (O.S. Adrianov,
1995; N.N. Bogolepov, 1996). The growing specialization of actual neurological disciplines, one-dimensional interest to a certain line
of investigations determines the difficulties in the investigation of brain as a whole. The formation of the complex apprehension of the
cerebral processes appears essential. Histology and microanatomy per se, being the descriptive disciplines, are often considered by the
authors to be out of date, in many instances having the depleted capabilities (the position that we absolutely disagree with). This is
related to the impossibility of investigation of the physiological processes which take place in the examined morphological structure.
Until now the above mentioned sciences use insufficiently the methods of mathematical modeling of the biological processes. These
methods are limited either by the derivation of the generalizing formulas based upon the average values, or by the determination of
the most expressed correlations. Sometimes the researches are concerned with the entropy indicators, which are fairly promising.
Nevertheless the high degree of formalization does not allow specifying the concrete processes taking place in the diverse existence
conditions of the individual cellular and tissue body structures and those of the nervous system particularly. The number of interesting
phenomena existing in the real object, are lost, which results in the impossibility of the mathematical modeling of biological processes
as the near-real scientific cognition approach.

The proposed perspective of a more precise examination of the changes in the organism, particularly in the brain, consists in the
synthesis or combination of the opportunities of morphology, of mathematics and of physiology. This monograph does not pretend to
compose the global system, but here we attempt to propose the new approach to the solution of the problem of complex evaluation of
co-interacting structures in the organism, and in the central nervous system particularly. One of directions of the recent neuromor-
phology and neurophysiology consists in the investigation of the structural-functional correlations between the neuronal status and the
system of glial-trophic environment. The parameters are not developed which could allow performing an objective follow-up of the
intensity of blood supply not only in the entire anatomical structure (nerve centers), but in the individual neurons as well. The neural
cells can differ by their sizes, structure, mediators and structural rearrangements under the pathologic influences. In case of omission
of certain parameters the contradictory estimations of microcirculation state within different periods of ontogenetic development can
occur. The blood supply parameters of the nervous centers provided they are nominally considered as isomorphous structures having
the similar conditions of local blood circulation, do not allow establishing particular changes in the furnishment of separate compo-
nents and cannot take into account the relationship between the neuropil and the neuronal perikaryon. The significance of this investi-
gation is also determined by the focal nature of microcirculatory reactions in case of various vascular diseases, when the growth of the
microvessels is associated with the phenomena of their obliteration in the adjacent sections (N.V. Vereshchagin, 1999).

Thus far, the value of the large group of biologically active substances is clarified, secreted not only by neurons, but also by neu-
rogliocytes and by the endotheliocytes, that are known to exert the significant stabilizing influence on the functional activity and me-
tabolic processes in the nerve tissue (I.N. Bogolepova et al., 1995; P Hamilton Steven, 1994; T.J. Sims, S.A. Gilmore, 1994; A. Rizvi
Tilar, Ennis Methhav et al, 1994; Nakaya Yoshifumi, Kaneko Takashi et al, 1994; J Gehrmann, D.L. Yao, 1995; M.C. Jasek, W.H.
Griffith, 1998; T Ebendal, S Soderstrom et al, 1998). The importance of macroglia was demonstrated in the mechanisms of the so-
called volume signal transfer, of the impulse conversion, of accommodation and synchronization of the neuron ensembles, implicated
into the adaptive reactions (M.O. Samoilov, A.A. Mokrushin, 1999, B. Ranson, 1992; E.N. Benveniste, 1995; K.E. Bovenkamp, P.A.
Lapchac, et al, 1997; J.M. Conner, S Varon, M.S. Hoener 1998). At the same time, in the scientific publications the primary attention
is given to the structure of neuron ensembles (E.B. Arushanyan, 1979; T.I. Belova, E.L. Golubeva et al., 1980; S.N. Olenev, 1987;
V.P.Babmindra, T.A. Bragina et al., 1988; B Dalva Metthew, Grosh Anirvan, J Sharz Curla, 1994; K Seto, K Kamino et al, 1998;
N.N. Bogolepov, V.M. Chuchkov, 2003). The other research trends concern the vessels (T.V. Ryasina, 1977; A.D. Bekov, E.G. Aro-
nov et al., 1996), or the glial cells (Caviness Yerne S, Nission JenaPaul, 1991; A. Stendler Dennis, 1993; E. Nexdorf, Bergveiler Bar-
bara, Albrecht Dorotea, Heinemann Uwe, 1994). The comprehensive studies of neuron, glial and vascular structures have the sporadic
nature (A.M. Antonov, 1985; V.M. Chuchkov, 1991; L.K. Semenova, N.S.Shumeyko, 1994; O.Iu. Gurina, Iu.G.Vasil'yev, 1995;
Iu.G.Vasil'yev, 1995, 1998; V.M. Chuchkov, 2004).

The difficulty of discovering of all the components of the nervous system is explained by the morphological heterogeneity and
complexity of the micro-architectonics of neurons and neuroglia. The optico-electronic analysis, with all its sophistication and accura-
cy, cannot result in a comprehensive picture of the three-dimensional variability of these interrelations, since it is allows only studying
them merely in the small-volume zones, revealing the nature of neuro-glio-vascular co-interactions at limited sites, while the entire
range of such connections is lost.

In this context, the purpose of this monograph consisted in the attempt of summarization of our own study results and of other au-
thors opinions and in the analysis of special features of neuro-glio-vascular interrelations in some zones of mammalian central nerv-
ous system, along with the development of quantitative and qualitative methods of their assessment. In the course of this work we
developed the mathematical analysis approach to the assessment of the trophic supply at the level of microvascular capillary basins,
allowing performing the detailed analysis of blood supply at the level of individual populations of the neuronal perikarya and micro-
vascular basins.
 6
CHAPTER I. MATERIALS FOR THE MORPHOLOGICAL EXAMINATION AND
THE PARTICULAR FEATURES OF THEIR HISTOLOGICAL AND MORPHOME-
TRIC PROCESSING

I.1. Results of the authors’ investigations. Particularities of the sampling and histologi-
cal processing of the material
The study was performed in human, in rats, in mature rabbits and in dogs (Table 1). The investigation was executed in
compliance with the “Rules of performing investigations with the use of experimental animals”. These animals were se-
lected due to several reasons. First, the given species are the most frequently examined laboratory animals, and their study
can serve as a basis for further experimental trials. Secondly, we attach importance to the complication of cerebral struc-
tural organization from the rat and the rabbit to the dog and human. Thirdly, the species investigated belong to different
families and are characterized by special features of behavior, nourishment, by the unequal rate of ontogenetic develop-
ment. Fourthly, there are specific features of metabolism and sizes, number and diameters of the neuron bodies, the neu-
ropil level of development, and of neuroglial relations, according to the information, obtained from the preliminary study
of literature and of our studies. Thus, we attach a great relevance to the comparison of neuro-glio-vascular ensembles and
to the search for the most adequate model for experimental studies in these animal species.

The number of subjects of inquiry and the basic methods, employed in the study, are represented in Table 1. In rats the
time point 12 hours after mating was assumed as the beginning of pregnancy. The age of human embryos was determined
according to the clinical records and was compared with the dimensions of the embryo under investigation and its appear-
ance, in accordance with the recommendations of L.I. Falin (1976). The check of the periodization of human ontogenesis
with respect to the species examined was performed according to the recommendations of other authors (G.A. Schmidt,
1973; V.I. Makhinko, V.N. Nikitin, 1975; N.N. Tyatenkova, 2000).

The locus coeruleus, central gray substance of mesencephalon; the mesencephalic, the motor and the main sensitive
nuclei of trigeminal nerve on the both sides were investigated. The examination of the maximum variety of the versions
of neuro-glio-vascular ensembles along with the inclusion of minimum number of subjects of investigation served as a
base for the selection of those subjects. The structural-functional co-interactions in conditions of different functions of
individual nuclei were considered. The similarity of origin of ensemble organization in context of the divergent nature of
the development was taken into consideration.

The following structures were examined:

- the central gray substance of mesencephalon - small-cell, typically associative, bearing the locomotor function and
the function of conditioned response, having a reticular structure of neuropil, which lies periaqueductally (i.e. corres-
ponding to embryonic sub-ependymal zone);
- locus coeruleus – medium-cell and small-cell, associative, one of the upper center of autonomous (sympathetic)
innervation, that lies at the region corresponding to the sub-ependymal zones, with a reticular pattern of nerve fila-
ments. Furthermore, this nucleus is thought to exert the direct efferent control over the vascular structures of central
nervous system, probably in cooperation with the neck sympathetic nerve ganglia;
- nuclei of trigeminal complex, closely interrelated anatomically, ontogenetically and functionally, differing in the
structure and the function performed: a) the motor nucleus of trigeminal nerve, large-cell, originated from the mantle
zone of nervous tube, containing the multipolar neurons; b) mesencephalic nucleus, containing the primarily sensitive,
large, bipolar neurons (in evolutionary terms this nucleus is homologic to the sensitive craniocerebral ganglia); c) main
sensitive nucleus, typically sensitive, containing the medium-size multipolar neurons (originated from a zone near the
marginal veil).

For the purpose of detection of adrenergic mediators upon the injection of supravital dyes, the pieces of the brain were
sampled and frozen in liquid nitrogen after the decapitation of the narcotized animal. The sections 15 to 25 μm in thick-
ness were made using the freezing microtome, were then mounted to the object glasses, dehydrated and enclosed into the
Canada turpentine.

The special features of the diffusion of substances into the brain structures were determined using the supravital dyes
(Evans blue dye, trypan blue, methylene blue or neutral red). According to the studies results, the most representative data
were obtained upon injection of Evans blue dye and methylene blue. In this context, in the monograph not all groups of
animals were considered, but those injected with the mentioned tracers. Evans blue dye is known to bind nearly absolute-
ly to the proteins of plasma (C.A.Wioderhielm, M.L. Shaw et al, 1973; S Ooka Sauda, 1973).
 7
Table 1
Number of humans and animals investigated.
Methods of investigations, subjected to the statistical processing

Terms Golgi- Bilshovsky- Nissle Hematoxilin- Collargol Supravital

Bübenet Buquet eosine flood floods
Human embryo 5-6 weeks 11 9 14 10 10 -
Human embryo 7-8 weeks 10 6 8 7 8 -
Human 25-30 years 11 7 7
Rat embryo 12 days 15 14 12 10
Rat embryo 15 days 12 12 14 15 11
Newborn rats 14 10 12 8 15
Rat, 1 week 15 13 10 5 16
Rat, 1 month 16 10 11 5 11 20
Rat, 6 months 17 13 10 5 10 30
Mature rabbits 14 7 11 7 11 20
Dogs 2-3 years 9 6 9 9

According to the opinion of N.G. Zaytsev et al. (1984), in case of a relatively prolonged chemical fixation Evans blue
dye can escape from the venules and capillaries in the form of a “cloud” (N.G. Zaytsev, V.V.Banin, 1984). Our analysis
demonstrated the similar results with respect to the trypan blue, too. The infusion of specimens was performed according
to our earlier published procedure (Iu.G. Vasilyev et al., 1999). 2% dye in the normal saline solution was prepared ex
tempore and 0.3 to 0.5 ml were injected intracardially slowly, along with the simultaneous removal of the amount of
blood, equal to the injected volume. After the infusion the rats were decapitated under ether anesthesia and then subjected
to cold fixation. The slaughter was performed 1, 3, 5, 10, 30 and 60 minutes after the injection of preparation. The sec-
tions 10 to 30 μm in thickness were decolorized and enclosed into the Canada turpentine. In normal physiological condi-
tions virtually no diffusion of dye through the capillaries took place after the injection of Evans blue dye and of trypan
blue.

At the same time, the transient accumulation of the drug along the veins in the pericapillary space, in the structures
morphologically analogous to the astrocyte processes was observed. The conditions of artificial brain hypothermia were
created in the animals by means of the superimposition of the cooling plates with a temperature - 5ºC. The temperature of
the skin was set up at the level of 15 to 20ºC. The procedure continued 30 minutes. The injection of tracer was performed
one hour after the end of hypothermia, since according to the data of preliminary studies this period specifically is charac-
terized by the most explicit signs of the impairment of the barrier properties of endothelial lining. The slaughter was per-
formed 5, 10 and 30 minutes after the injection of drugs.

I.2. Characteristics of the morphometric analysis used

The sizes of neuronal perikarya were measured by the greatest and minimal diameters of processes. Only the cells hav-
ing a visible nucleus on the section were considered. The cell volume (V = μm3) was calculated according to the equa-
tions:

P
⋅ (L ⋅ D )
2
V= (1.1.),
6
for the structures with a ratio of diameters of 1.2 to 2 (Tashke K., 1980) (L and D = maximal and minimal diameters,
in μm); and
 8
4 a+b
V = ⋅ p ⋅a ⋅b⋅ (1.2.)
3 2
for the elongated structures (V Monesi, 1990). Where a and b are a maximum and minimum radii in μm. The true
number of cells (N) in the section with a thickness M was determined according to the formula of A.Abercrombie (1946):
M
N = A⋅ (1.3.),
M +d
where A = number of subjects per area unit, d - average diameter of the subject (μm). Then the average number of
neurons per unit of the surface being investigated was calculated. The calculation of cell number was performed in every
group individually, after having taken into account the nuclear sizes.
On the basis of the previous studies (Iu.G. Vasilyev et al., 1998), we suggest the investigation of the quantitative pa-
rameters of the trophic supply of the individual zones rather than of the nuclei and screen-type structures of the central
nervous system as a whole, would be more adequate. Particularly we imply the investigation of zones, being more active
and more energy-dependent in comparison with neuropil, i.e., the neuron bodies.
With the use of the proposed method of quantitative analysis presented in the previous publications (Iu.G. Vasilyev et
al., 2000), we attempted to give a more detailed evaluation of the state of trophic supply of individual items of heteromor-
phic structures (neuron perikarya) and of perineuronal zones, on the basis of the conventional morphometric parameters.
Many authors perform the calculation of the specific vessel length per a volume unit according to Blinkov and Moiseyev
equation (1961) (1).
n g ⎛ 4 n g − nb ⎞
Lv = nc ⋅ ⋅⎜2⋅ ⋅ ⎟ (1.4.),
nb ⎜⎝ 3 ng ⎟
⎠
where Lv – capillary length (mm/mm3).
In case the capillaries are situated at random fashion, i.e. ng= nb, the equation (1.4) acquires the following form:
n
Lv = (1.5.),
Svn
where n = number of the capillaries at the area under investigation, Svn = area of the individual vascularization zone
of the neuron (mm2).
The number of vessels, supplying one neuron, was calculated according to T Scherrer (1949) statement, confirming
that neuron individual vascularization zone, if the mean capillary pressure reaches 30 mm Hg, is limited to 25 μm, which
was shown by neurons’ demise upon occlusion of the afferent vessel within the distance specified. These data are con-
firmed by the investigations of diffusion through the vascular wall (C.A. Wioderhielm, M.L. Shaw, 1973; S Ooka-Sauda,
1973). Our own data agree with this, demonstrating the significant accumulation of the tracers employed is also limited to
this value. After the transplantation of the mature structures of the nerve tissue the neurons’ survival is observed within
the small, about 20 to 30 μm (D.M. Golub, R.V. Danilenko, N.M. Kovaleva, 1986). We attach a great importance to the
fact that upon maturation in all animal species investigated not less than one microvessel is located in the distance of 20 to
25 μm around any neuron, while in the distance less than 20 μm there are neurons without vascular environment. The
morphological data obtained are supported by the mathematical modeling of glucose diffusion. The significant glucose
absorption from the intercellular space may proceed at a distance not more than 25 to 30 μm from the microvessel to the
perikaryon of the neuron.
The area of capillary trophic supply is thus limited to 25 μm apart from the central region of a micro-vessel. Examin-
ing the rate of metabolism or destruction of the penetrating substance and its diffusion rate as the mutually balanced val-
ues, we found that the concentration of this substance depends inversely on the distance between the capillary wall and
the neuron, which was taken into account during the mathematical processing.
The area of neuron individual zone of vascularization in the section can be considered as the area of an oval, circle or
an irregular figure. Let us calculate this area by convention from the formula of an oval.
p
Svn = ⋅ Dl ⋅ Dd (1.6.),
4
where Dl = L+0,05 mm, and Dd = D+0,05 mm. The value of 0,05 mm was derived by means of addition of 0.025 mm
(radius of the individual vascularization zone of micro-vessels) to a radius of a neuron body.
The partial area of the surface of contact between the vessels and the body of a neuron can be determined based on the
equation:
n g ⎛ 4 n g − nb ⎞
Lv = nc ⋅ ⋅⎜2⋅ ⋅ ⎟ (1.7.),
nb ⎜⎝ 3 ng ⎟
⎠
where Dk = average capillary diameter in mm, Lv = specific length of the vessels per volume unit in mm/mm3.
 9
While reviewing this value it is necessary to take into account the following fact: if we consider the diffusion of sub-
stances as proximal to the normal line (normal line presumes the uniform diffusion in all directions), then the most effec-
tive exchange develops at the area of the capillary surface corresponding to the angle a, rather than on the whole surface.
The point that indicates the angle a in the micro-vessel was found from the average distance within 25 μm from the body
of neuron. The value of the angle a will account to the coefficient K, which determines the area of the contact surface of
capillary, the most effectively supplying the vessel - Sas. Thus, the formula for a partial area of the most efficient surface
of capillary will take the following form:
Sas = K ⋅ p ⋅ Dk ⋅ Lv (1.8.),
where,
a
K= (1.9.)
360°
a - the value of angle, which connects the lines not more than 25 μm in length from the central zone of blood capillary
to the marginal points of neuron bodies or boundaries of its surface.
The diameter of the partial zone of pericapillary filtration - Dpf is equal:
Dk
Dpf = (1.10.),
Vvk
where Vvk - the apparent packing density (in the relative units or mm3/mm3). It may be calculated using the direct
measurements according to the formula of A.A.Glagolev:
Vk Sk Pk
Vvk = = = (1.11.),
Vvn Svn Pvn
where Sk = area, occupied by the open sections of capillaries in the section (μm2), Svn = total area of the section (μm2)
being investigated, Pk = number of points over the vessels on the grid of eyepiece, Pvn - total number of points in the test
system. This formula was also used in the determination of the apparent density of the bodies of neurons (Vvn), but here
the value Pn (number of points, on the neurons) was examined (A.A. Gutsol, B.Iu. Kondratyev, 1988). The unknown val-
ue of the apparent packing density of capillaries may also be calculated from the equation:
p
Vvk = ⋅ Dk 2 ⋅ Lv (1.12.)
4
The concentration of substances, dissolved within one microvascular basin of the brain, depends directly upon several
factors.
The concentration directly depends on the time and volume velocity of the transport of substances through the vascular
membranes and their subsequent diffusion into the brain tissue. A correlation exists between the dilution and the volume
velocity of one minute blood flow, hydrostatic pressure and intravascular concentration of substances. The inverse depen-
dence is known to exist between the density from one part and the volume velocity of metabolism in cerebral tissue struc-
tures and the backward diffusion into the vessel – from the other. Duration of this process, volume of pericapillary filtra-
tion within the capillary, hydrostatic pressure and tissue concentration of substance are of great importance.
According to G.I. Mchedlishvali (1986), the blood flow in any peripheral organs is determined by the pressure change
and vessels’ resistance. Under normal physiological conditions these values are relatively constant, and the average capil-
lary pressure is equal to 20 to 30 mm Hg (D.W. Zwifact, 1974). Pressure gradient in the arterioles is limited within 0.1 to
0.3 N/m2 x μm, in the venules – within 0.07 to 0.4 N/m2 x μm, in the capillaries – within 0.7 to 1.0 N/m2 x μm (5 to 8 mm
Hg per 1 mm of the capillary length) (G.I. Mchedlishvali, 1986; D.W. Zwifact, 1974). Providing that the concentration of
a substance is uniform within the prolonged time, the level of substance under investigation is equalized within certain
limits. The volume velocity of one minute blood flow is in turn determined by the resistance to the blood flow in the ca-
pillary, by the pressure gradient, by the transverse diameter of a vessel. In the normal vital activity of the brain these val-
ues are similar in the analogous vessels. In this case the difference of the substances transfer effectiveness within the area
of the blood supply of one neuron per unit of time will depend upon several variable parameters: the specific capillary
density per one unit of pericapillary space; the relative volume occupied by the neuron bodies, having the maximal meta-
bolic activity, against their neuropiles and the other tissue elements of the central nervous system.
After summarization of the given parameters, the effectiveness of the transfer processes within the neuron may be
represented by the equation:
Dpf ⋅ Vvn
Dpfn = (1.13.)
Vn
Dpfn - diameter of the pericapillary ultrafiltration of the micro-vessel, which falls to the bodies of neurons (μm).
 10
Even with provision for a certain degree of the conventionality of this formula, it can serve as an indicator of meet-
ing of the neuron bodies’ trophic requirements in the central nervous system. While taking into account the metabolic ac-
tivity of the other components, this formula must acquire a more complex form. The coefficients must be included, which
show the degree of metabolism of the individual substances investigated and the specific volumes of each tissue compo-
nent of the nucleus analyzed.
Thus, the proposed modification of stereometric analysis allows to perform a detailed analysis of the trophic supply of
neurons with the use of comparatively simple and conventional methods of a morphometric analysis and to examine the
individual components of the nervous system rather than the assemblage of its heteromorphic structures.
The detection of satellite gliocytes around one neuron was carried out after the appropriate determination of the aver-
age length of the astrocytes processes. Then the average number of macroglial nuclei was calculated. As a result the num-
ber of gliocytes located in the perineuronal space was determined, which supply the neuron body and the elements of the
adjacent neuropil, including the initial segments of dendrites and axons. During the examination of the neuroglial co-
interactions we proceeded from the assumption demonstrated by the results of thorough optico-electronic investigations
of other authors.
According to this assumption, the glial layer, formed by the processes of the adjacent astrocytes, always exists be-
tween the bodies of neurons, their processes and the capillaries within the structures of the central nervous system having
well developed barrier properties. Its thickness can reach 20 to 30 nm, providing the selectivity of substances diffusion,
according to the debatable opinion of some investigators (N.S. Kositsin, 1978). The isolating properties of neuroglia with
respect to the synaptic contacts should be also taken into account. The role of the processes of gliocytes can consist in the
control of the transport flows, in the regulation of the ion spectrum in the intercellular substance. There is evidence for the
presence of zones of direct contact between the different parts of neurons and the external zones of the basal laminae of
capillaries (V.A. Pastukhov, 1974) in most regions of the brain, having the focal pattern.
The length of the astrocytes processes was determined via direct measurements from the central zone of its body. The
processes with a maximal and minimal remoteness from the body were measured. The number of vessels in contact with
the processes of a protoplasmic astrocyte was determined by means of the direct counting.
The further mathematical processing of morphometric information was performed in accordance with the conventional
methods (K.Tashke, 1980; M.B. Slavin, 1989; G.G. Avtandilov, 1990).
 11
CHAPTER II. STRUCTURE OF THE NEUROGLIO-VASCULAR COMPLEXES

II.1. Structure of the neurons of the pontis nucleus and in the nuclei of the mesencepha-
lon
In the opinion of O.S. Adrianov (1995, pp. 25-26): “it became obvious, that the analytical studies alone, no matter how
sophisticated they are, do not allow to examine the architectonics of the neurodynamic processes, which lie at the basis of
the forms of behavior differing in their degree of complexity and in their biological nature”. Therefore the complex inves-
tigations, including the morphological studies, must play an important role in understanding of the mechanisms of devel-
opment and functioning of the nervous system.
Among the voluminous amount of literature, dedicated to the stem and brain as a whole, the significant attention is
given to neurons and to the formation of their ensembles during phylogenesis and ontogenesis (A. Brodal, 1960; Ia. Szen-
tagothai, M. Abab, 1976; N.L. Lazriyev, 1981; S.N. Olenev, 1987; V.P. Babmindra, T.A. Bragina et al., 1988; A.S. Ba-
tuyev, V.P. Babmindra, 1993; L Rodella et al, 1994) and in the tissue cultures (O.S. Sotnikov, 1999). In the recent dec-
ades the studies were dedicated to the structure of individual neurons and to their co-interaction (K. S. Rayevskiy, 1988;
L.I. Spivak et al., 1988; V.V. Semchenko, S.S. Stepanov, 1999; J.E. Holden, H.K. Proudfit, 1996; D.F. Cechetto, V Ha-
chanshi, 1997). The neuron ensembles are demonstrated in some nuclei of the stem of brain in the form of operational
units (B.A. Zhigdalo, V.A. Polyakov, 1983; A.S. Batuyev, V.P. Babmindra, 1993).
Due to the opportunities provided by genetic replacement therapy the possibilities of investigation and control of cere-
bral processes have considerably expanded with the use of the introduction of transplants into the cerebral tissue (S Akli
et al, 1993; T Friedmann, 1989). A large body of the factors was revealed in different zones of the brain stem, playing an
important role in the formation and the functioning of the central nervous system. Thus, the motor and mesencephalic
nuclei of trigeminal nerve are characterized by the high concentration of fibroblast growth factor-9 (T.Todo et al, 1998).
Nitric oxide (cyclic 3', 5' – guanosine monophosphate) forms the signaling pathways acting as indicators at the critical
moments of the developing and mature brain. The activities of NO-sensitive guanylate cyclase is one of the factors, which
regulate the development in the central nervous system: it takes part in the determination of multiple nuclei and can be the
modulator of neural signaling.
The morphology of mesencephalic cholinergic nuclear complexes was examined in human. The high concentration of
cholinergic neurons was revealed in the mesencephalic nucleus of trigeminal nerve (up to 80 %). They are numerous in
the red nucleus and the black substance, but they are few in the central gray substance (P.A. Motavkina, V.E. Okhotin,
1984; S.N. Olenev, 1987; R.D. Huffman, R Davis, 1977; L Rodella Et Al, 1994; S.T. Sakai Et Al, 1998; M Palkovit Et
Al, 1998). The monoaminergic systems of the brain stem are described thoroughly enough (M.T. Ugryumov, 1997).
According to our data, the motor nucleus of trigeminal nerve in all species examined is located between the rostral and
the cranial zones of the pontis, immediately in front of the nucleus of facial nerve. It is heterogeneous, containing the dor-
sal and ventral zones. The dorsal zone is characterized by the presence of large, sparsely situated, multipolar neurons. The
ventral region is characterized by the presence of the nerve cells having smaller sizes, but compactly situated. The ventral
zone is smaller in dimensions. The immunopositivity for cholinacethyl transferase was revealed in the bodies and axons
of most neurons in every motor nucleus, including the neuropil of the trigeminal nerve. This nucleus contains a great
amount of terminals reacting positively to the cholinacethyl transferase.
The terminals form contacts with dendrites and bodies of neurons, and this indicates their cholinergic and cholinore-
ceptor nature (T Ishikawa, T Shimizu, 1998). The similar data are obtained with the use of dual immunohistochemical
detection of the specific acetylcholine transport protein and cholinacethyl transferase (A Roghani et al, 1998). In the mo-
tor nucleus of trigeminal nerve two types of afferent contacts are present, which go from the different muscle types and
reside non-homogeneously in different nuclear zones (H Kishimoto et al, 1998). In rats the direct projection of the axons
of the reticular zone in the black substance with the engine nucleus of trigeminal nerve is observed, which has been con-
firmed using the method of antegrade and retrograde transport (Y Yasui et al, 1997).
The groups of neurons of the motor nucleus of trigeminal nerve in a range of species (human, dog, rabbit, rat) are simi-
lar and represented by the following populations (Table 2, Figure 1):
1. Neurons having large and gigantic perikarya are situated one by one
 12

or in groups consisting of 2 to 3 cells. They differ in sizes, while having similar architectonics. They may be divided
into:
a) starlike cells having a distinct initial segment of axon, several moderately branching dendrites, which extend to sig-
nificant distances from the perikaryon;
b) cells having the round and spindle-shaped perikarya, with the processes of a similar structure in their initial seg-
ment. The spindle-shaped neurons are characterized by the presence of several morphological similar dendrites, emerging
from the opposite poles.
Both types of the neurons have a large centrally located or off center, bright nucleus. The nuclei contain 1 or rarely 2
large nucleoli of moderate density, occupying the central position. The cytoplasm contains gross grains of chromophilic
substance and well developed system of neurofibrilles, especially in the initial segments of an axon. There are cells pos-
sessing abundant (10 to 14) dendrites with a moderate or weak branching and with a small number of processes (3 to 5
processes with a weak branching in the proximal parts of dendrite). The study of series sections demonstrates that most
dendrites are long and have a straight or a little twisting course, frequently escaping outside the anatomical limits of the
nucleus. The comparison of the percentage of large neurons reveals the most expressed bias towards the giant nerve cells
in human, accompanied by a significant increase of the mean diameter and volume in comparison with all species ex-
amined. In rabbit and rat the large nerve cells forming from the perikarya have smaller number of processes (the cells
having 3 to 7 dendrites predominate) and less complex branching of these processes.
2. Middle-size nerve cells represent a morphologically heterogeneous group. They may be divided into cells with the
short processes having an expressed branching and cells with longer processes having moderate and weak branching. The
photo-optical morphologic features of the bodies of both cellular variants are similar and are characterized by the central
nucleus containing 1 to 4 middle- or small-sized hyperchromic nucleoli. The chromophilic substance of the cytoplasm is
fine, ill-defined. Dendrites and axons have 150 μm in length and more. In rat the percentage of middle-sized nerve cells
significantly exceeds this percentage in human and in dogs (P < 0.01); that results probably from the reducig of the cell
sizes in the general population and the partial transition from the large neuron cells to the middle-size ones.
3. Small multipolar round, spindle-shaped and rarely starlike cells, among which the populations with abundant and
thin branching of dendrites are revealed. The axons are ill-defined. The neurons with thick branching are characterized by
the short tortuous processes and the abundance of spines. Cells with thin branching have long and straight processes. The
major portion of dendrites of small neurons is located within the nucleus. The round, achromatous or hyperchromic nuclei
contain 1 to 3 small, strongly dyed nucleoli. The bright cytoplasm includes the basophilic substance, which is finely dis-
persed. The neurofibrillary system is ill-defined. Cytoplasm is achromatous, it is weakly bounded from surrounding neu-
ropil. The relative number of the small nerve cells within the limits of the nucleus examined is non-significant and differs
in the species investigated insignificantly. The size of the neurons in this population is substantially greater in humans and
in dogs.
Humans and dogs have more giant neurons in comparison with rabbits and rats, and this number in rats is the lowest.
The large neurocytes account for the greatest percentage in small animals (i.e. in rats), where they reach more than half of
all number of neurons. The small cells are seen rather rarely, they are frequently satellite with respect to the main popula-
tion.
Mesencephalic nucleus of trigeminal nerve is considered as a proprioceptive center for the masticatory and tongue
muscles,

Table 2
Proportion of the neuron types in the motor nucleus of the trigeminal nerve (M ± m)*

Species investigated Neuronal populations

Small-size (%) Middle-size (%) Large (%) Giant (%)
Human 4,8 ± 1,2 17,0 ± 2,3 32,9 ± 2,6 45,3 ± 4,7
Dog 2,1 ± 0,9 15,5 ± 2,5 51,4 ± 2,4*** 31,0 ± 3,5
Rabbit 6,2 ± 1,0 19,5± 2,1 62,0 ± 2,9*** 12,3 ± 1,75***
Rat 9,1 ± 2,3 26,6 ± 2,3*** 56,6 ± 2,8*** 7,7 ± 1,6***

* Note: in this Table and in all subsequent tables.

In all cases 200 measurements from 10 objects were made. *** - error probability of the significance of differences be-
tween the average arithmetic parameters P < 0.001; ** error probability of the significance of differences between the
average arithmetic parameters P < 0.01; * - error probability of the significance of differences between the average arith-
metic parameters P < 0.05.
 13
for the extraocular muscles, and for the innervation of teeth, hard palate, jaws and their joints. Phylogenetically it is
homologous to the cerebrospinal ganglia (Iu.P. Limanskiy, 1976). Several neurons of this nucleus form group Ia afferent
nerves, which terminate by the annulospiral endings of the neuromuscular spindles of masticatory and temporal muscles,
reactive to the tension (E.V. Gura et al., 1969; J Szentagothai, 1948).
The neurons of mesencephalic nucleus and of the trigeminal ganglion were investigated using the horseradish perox-
idase (J Hassanali, 1997). These neurons innervate the periodontal membrane in macacos and in baboons. The hetero-
geneity of localization of afferent neurons in this nucleus was demonstrated. The bodies of periodontal afferents were lo-
cated in the caudal ipsilateral region up to the level of lower quadrigeminal bodies and in the pontis area. The caudal peri-
odontal neurons of mesencephalic nucleus can establish collateral contacts with the motor nucleus of the trigeminal nerve
(J Hassanali, 1997). In the mesencephalic nucleus the bipolar neurons are present, which are nearly matured at the mo-
ment of birth in rats, in dogs and in humans. During the postnatal development the sporadic multipolar neurons in the
nucleus can appear (R.A. Zufarov, 1966; T.I. Belov, E.L. Golubeva, N.V. Sudakov, 1980). In dogs the large (diameter of
the perikarya of 62 to 38 μm), middle-size and small neurons may be specified, and the first group comprise the basic
amount of the general population of neurons (S.M. Blinkov, I.I. Glezer, 1961).
The anatomical position of the mesencephalic nucleus of trigeminal nerve in the studied animal species is generally
the same. This nucleus extends from the level of the motor nucleus of trigeminal nerve to the upper quadrigeminal bodies
(posterior commissure of mesencephalon). It appears as a narrow strip formed by the bodies of bipolar and pseudo-
unipolar neurons. The most abundant cellular population is typical for its lower portion, especially in rats and in rabbits.
On the cross section the neurons surround archwise the structures of locus coeruleus and are positioned by rows consist-
ing of 1-2 and rarely of 3-4 cells. Dorsally they adjoin the nuclei of tegmentum, ventrally they are adjacent to the oculo-
motor nucleus and nucleus of trochlear nerve. The maximum number of neuron bodies is revealed in the caudal part of the
nucleus. Among the main population of cells, which have a similar structure, cells with large and gigantic perikarya may
be distinguished in humans. The cells are isolated or they form small groups containing 2 to 5 bodies. Due to the low den-
sity of the perikarya, in these groups the distribution of capillary loops proceeds as a general rule in each cell individually.
At the mesencephalic level especially, the neurons can be distant from one another rather significantly, which could dem-
onstrate the relative independence not only of their localization, but of the microcirculation as well.
Some bodies of neurons can tie to each other; this indicates the active functional interdependence of these cells, con-
firmed by the presence of gap junctions between the bodies and the processes of the neurons, which are characteristic for
the mesencephalic nucleus of trigeminal nerve. Giant and large neurons are characterized by the formation of one or two
processes (Fig. 2).
Sometimes the sporadic bodies of multipolar star-like middle-size and small nerve cells may be noted near the large
neurons. Some middle-sized nerve cells can be morphologically similar to the large neurons, especially in rats, while the
others are characterized by starlike shape of the perikarya, achromatous cytoplasm, containing sporadic lumps made of
the finely dispersed basophilic substance. The round central nuclei contain small, dense nucleoli, 1 to 2 per cell. The
processes of small and middle-diameter multipolar nerve cells branch out in immediate proximity of the large neurons, or
(concerning predominantly middle-size neurons) they extend to significant distances. They go to the locus coeruleus and
to the central gray substance of mesencephalon. Both types have 1 to 4 moderately or weakly branching thin dendrites
with the abundance of spines and small varicosities. The small and middle-size neurons are sparse. There are also small
round and spindle-shaped cells with the nuclei, which occupy the main volume of the perikarya. The bodies of both last
cell types are situated in immediate proximity to the macrocellular neurons, either they lie separately or form groups with-
in the limits of nucleus.
Among the species examined the greatest percentage of the population of giant nerve cells is revealed in humans (P <
0.001). From humans to rats, in accordance with general dimensions of animals, the parallel decrease in the number of
large cells is observed. In rat the dominant population of bipolar neurons is represented by large and middle-size cells ra-
ther than by giant and large neurons (Table 3). The specific density of neurons in the nucleus grows simultaneously. The
bodies of cells in rabbit and rat lie more tightly and can form the compact agglomerations
 14
Table 3
Proportion of neuron types in the mesencephalic nucleus of trigeminal nerve (M ± m)

Species investigated Neuronal populations

Small-size (%) Middle-size (%) Large (%) Giant (%)
Human 3,3 ± 1,1 11,3 ± 1,8 47,7 ± 3,5 37,7 ± 3,5
Dog 3,1 ± 1,1 6,3 ± 1,3 78,5 ± 2,6* 13,1 ± 2,2*
Rabbit 11,8 ± 1,9* 31,5 ± 3,0*** 56,7 ± 4,3
Rat 9,2 ± 1,5* 25,6 ± 3,7*** 65,2 ± 4,1***

The parameters are compared with the human values.

(especially at the level of caudal zones) containing 2 to 5 cells. In rats some histochemical differences in the neurons
of nucleus are revealed. While the immunoreactivity for D1 dopamine receptors was revealed anywhere, D2-receptors
were concentrated in the caudal portion, indicating the heterogeneity of the postsynaptic perceptive mechanisms for the
proprioceptive information, which enters via these receptors (N Lazarov, 1997).
The sensitive nuclei of trigeminal nerve stretch from the caudal part of medulla oblongata to the rostral part of the pon-
tis. They are subdivided into the main sensitive nucleus and the nucleus of the spinal tract of trigeminal nerve. The nuc-
leus of the spinal tract includes the oral, interpolar and caudal nuclei. The role of the caudal nucleus of trigeminal nerve in
the structures of trigemino-vascular system was revealed (J S Clayton et al., 1997). The electrical stimulation of trigemin-
al nerve results in the intensification of blood supply in the caudal nucleus in cats (R.B. Mc'Call, 1997). The dopaminer-
gic neurons take part in ensuring the control over functional activity of the cholinergic neurons of trigeminal nerve
(A.Methur, 1997). The main sensitive nucleus of trigeminal nerve performs the coding of the sensory information, partic-
ularly of the proprioceptive response of the oculomotor muscles (Iu.P. Limanskiy, 1976; V.E. Pettrossi, E Manni, 1977).
The main sensitive nucleus forms collaterals with the neurons of reticular formation. (A Brodal, 1972). More than 50% of
neurons in this nucleus are capable of the spontaneous spikes of activation. The cells quantity increases with the increase
of years, indicating the refinement of processing of incoming information up to the moment of sexual maturity (V.M.
Sandler et al, 1998). The comparative analysis of the sensitive nuclei of trigeminal system revealed higher density of the
cell distribution in the main sensitive nucleus, where it varied over wide limits (G.P. Zhukova, 1975).
The main sensitive nucleus of trigeminal nerve has architectonic differences depending on the cranio-caudal position
of the section and the zone of neurons localization in the preparation. Actually, there are regions with a relatively compact
arrangement of neurons in the upper pole of the dorsomedial region, the focal distribution within the neuropil in the ven-
trolateral zone and the diffuse distribution in the lower parts, which resembles the reticular nuclei. This distribution allows
discriminating the antero-lateral and posterior-medial subnuclei. The morphometric studies were performed with the use
of the ventrolateral zone of nucleus, ensuring the isogenicity of structures being investigated. Dorsally the nucleus ex-
amined adjoins Bekhterev nucleus and the motor nucleus of trigeminal nerve, caudally the nucleus of olivary body and
the paraolivary nuclei. A small part of cells come near the mesencephalic nucleus of trigeminal nerve. The bodies of neu-
rons lie singly, or form the small groups of 2 to 4 neurons.
According to literature data, in humans beginning from the age of 2 years, 3 types of the cells may be distinguished:
- large, multipolar, 23 to 30 μm in diameter;
- average, spindle-shaped or irregular, 15 to 24 μm in diameter;
- small, 10 to 14 μm in diameter.
The middle-size cells are primarily predominating, then the content of large neurons increases, and the decrease of the
small types of nerve cells is observed (S.M. Blinkov, I.I. Glezer, 1961, L.E. Goncharenko, 1962).
In accordance with our data, depending on the diameter of the perikarya the neurons may be divided into macrocellu-
lar, middle-cell and small-cell populations. Every population, in turn, contains several cell types depending on the struc-
ture of the perikarya and processes (Fig. 3). The population of large neurons is represented by several types of cells (Ta-
ble 4):
1. The fusiform cells with the polarization of several short or middle-length, poorly branching, a little tortuous den-
drites (4 - 8) and straight axon having a direct course. The thin terminals of dendrites form varicosities;
 15

2. The round, spidery and fusiform cells. They have evenly distributed, thin, moderately or strongly branching den-
drites, with the abundance of varicosities along the 8 to 12 processes;
3. Starlike cells having 7 to 9 long, thick, uniform processes with a moderate or poor branching.
The round cells predominate. The macrocellular population is located essentially in the caudal regions of nucleus. The
large neurons contain 1 to 2 large nucleoli within the round, hypochromatous nucleus. Cytoplasm contains granules with a
basophilic substance. The large neurons are present in all the animal species under investigation, except the rats, where
this population appears among the nerve cells of middle size. The maximum amount of large neurons are present in hu-
mans, where they predominate significantly in comparison with other cell types. The basic features of dendritic tree con-
sist in the fact that the majority of cells have long primary dendrites, which give rise to several thin dendrites going away
under the acute or right angle. The latter form sometimes the short terminal processes.
The neurons with the middle-diameter perikarya can be subdivided into the starlike and round cells. Both groups of
cells are characterized by thin, moderately or strongly branching processes with an abundance of dendrites (8 to 12). The
region of the terminal branchings of processes of these neurons is limited by the adjacent zones of nucleus and of the
white substance as well as by the rather remote zones. The middle-size neurons have the round nuclei, which occupy
nearly half of the perikaryon.
The small neurons have a triangular, starlike or fusiform shape. The neurons having regularly distributed short, nu-
merous (7 to 9) processes with numerous branches or short processes with a poor branching (3 to 6 per perikaryon) are
predominant. Sometimes the nerve cells can be encountered, having processes which are concentrated on one of the poles
(3 to 4 short dendrites). The small nerve cells are characterized by high nuclear-cytoplasmic ratio, hypochromatous or
weakly argyrophil cytoplasm. The detection of the neurofibrillar system with the use of conventional methods is proble-
matic. The terminals of the small cells extend mainly to distances 20-30 to 50-100 micro m from the perikarya.
In dogs, rabbits and rats among the neurons of the main sensitive nucleus of trigeminal nerve middle-size and small-
cell populations predominate. Here the morphological types of large diameter nerve cells transform into the population of
middle-size and small neurons. The middle-size and small neurons in rabbits and in rat are characterized by the significant
polymorphism of the structure of the perikarya (starlike, fusiform, round), of the sites of formation of the processes (in the
antipoles of a cell, uniformly along its surface), of the number of dendrites (4 to 12) and of the intensity of their branching
(strong or moderate branching).
The neurons of the locus coeruleus and its interrelations with other nuclei are examined in detail. The authors distin-
guish the oral and caudal regions, differing by their structure (A.L. Mikeladze, 1968; T.I. Belova et al., 1980; G.P. Zhu-
kov, T.A. Bragina, 1981; A.S. Stupina et al., 1986; V.J. Massari et al., 1979). In rats the locus coeruleus extends from the
pontis to the lower quadrogeminal bodies. In human and in dogs it lies more compactly at the level of the pontis.
Two types of nerve cells are distinguished within the locus coeruleus (T.I. Belova, E.L. Golubeva, N.V. Sudakov,
1980): a) neurons having the irregular contours, the vacuolization of cytoplasm and the nuclei of irregular shape; b) round
shape neurons having the regular contours, morphologically similar to the neurons of the central gray substance. Accord-
ing to others data (V.A. Otellin, E.G. Gilerovich, N.B. Mikhaylov, 1993), three types of the cells can be isolated from the
locus coeruleus: large neurons, small neurons, intermediate cell type. The populations of neurons are heterogeneous and
depend on the level of the section.

Table 4
Proportions of the neuron types in the main sensitive nucleus of the trigeminal nerve (M ± m)

Species investigated Neuronal populations

Small-size (%) Middle-size (%) Large (%)
Human 26,41 ± 3,12 39,82 ± 2,56 34,03 ± 3,72
Dog 48,1 ± 3,2*** 48,8 ± 3,0 3,1 ± 1,5***
Rabbit 61,1 ± 3,2*** 32,5 ± 3,1 6,4 ± 1,5***
Rat 48,1 ± 2,5*** 51,9 ± 2,5 *

Parameters are compared with the human values.

 16

The study, that we have conducted with the use of impregnation of the silver nitrate and of Nissle staining, showed
that at the level of the pontis the multipolar middle- and small-diameter neurons predominate, while in the cranial portions
small cells are the most numerous. On the transverse sections in the caudal portion of the nucleus the cells which lie under
the ependyma are smaller than neurons in the ventral zones. Ventrolateral boundaries of the nucleus are characterized by
the superior degree of the neuropil expansion, especially in dogs and in rabbits.
The middle- and small-diameter neurons are predominating (Fig. 4). The large neurons having the starlike, round or ir-
regular shape of the perikarya are present. They amount for the significant percentage of population in human, in compar-
ison with the species of animals investigated (P < 0.05 – 0.001).
All types of cells are situated singly either they form groups consisting of 4 to 6 cell bodies.
The following populations can be distinguished in the caudal portion of the nucleus (Table 5):
1. Large multipolar cells, having starlike and triangular perikarya. The axon is determined according to its length and
the absence of branching. It departs outwards the nucleus. The nucleus is round, frequently excentric, containing 1 to 3
middle-size nucleoli. Cytoplasm of some cells is vacuolized. The basophilic substance is represented as a fine granularity.
The dendrites are 2 to 6 in number. Some of them have a lot of branches and extends 50 to 100 m from the body of a neu-
ron, the others, poorly branching in the initial segments, can extend to the great distances. The largest and most numerous
neurons of this type can be encountered in humans.
2. Middle-size neurons have the round and fusiform perikarya and 3 to 8 processes. Some of these cells have the den-
drites which arborize significantly and extend to the small distance from the neuron body. The dendrites are thin, contain-
ing a great amount of spinules and varicosities. Their course is moderately or strongly tortuous. The structure of the nuc-
leus and of the cytoplasm is similar to the structure of the large neurons, differing from them in terms of weaker tendency
for vacuolization.
3. Round or starlike middle-size neurons. The number of processes is similar to the neurons of the 2nd type. These cells
are characterized by the presence of long processes with a poor or moderate branching, among which the axon can be
hardly differentiated. The nuclei are central. Cytoplasm and the structure of nucleolar system coincide with the 1st cell
type. In terms of the extension of the processes this type of cells is similar to the macrocellular population; it predomi-
nates in rats and in rabbits.
4. Round, starlike, triangular and fusiform small neurons. Cells of this morphological type have the round nuclei,
which occupy the main volume of the perikarya and contain 1 to 4 nucleoli. The processes of these cells arborize mod-
erately or poorly, and the limits of their expansion in human are confined to the adjacent structures inside the nucleus,
suggesting their associative nature. In dogs, rabbits and rats the population is polymorphous and includes the having long
as well as short processes. Among them the cells with few processes can be encountered, rarely – the cells having a mod-
erate or great amount of processes.
In the cranial portions the neurons' proportion changes considerably. Here the following groups of cells are revealed:
1. Triangular and round middle-size neurons having 3 to 6 straight processes with a poor branching.
2. Fusiform, large neurons having the processes, which are formed on the opposite poles of cells.
3. Small round and fusiform cells.
The structure of cytoplasm and of the nuclei of middle-size and large neurons are similar to the 3rd and 4th types of
populations of caudal portion, earlier described.
Their processes extend to the significant distance and do not arborize or arborize poorly. In the small neurons the de-
gree of branching is also insignificant, but the expansion of the processes can confine to the adjacent or remote zones of
the nucleus.
In the locus coeruleus the A1 zone was discovered, where the barrier properties of endothelium are weakly expressed.
The importance of the nucleus in the control of daily rhythms, the regulation of the paradoxical sleep is proven. It influ-
ences the sympathetic nervous system under the stress conditions (T.I. Belova, E.L. Golubeva, N.V. Sudakov, 1980; A.
Rache Junior, C.F. Buffington, 1998). The idiopathic tendency toward seizures and generalized epilepsy is accompanied
by overall debilitation in the noradrenergic structures of the central nervous system (R.W. Cough et al, 1998). Virtually
all neurons of the locus coeruleus contain dopamine-beta- hydroxylase, indicating their noradrenergic nature (L.W. Swan-
son, 1976; G.J. Molenaar Et Al, 1997; Z.Q. Xu Et Al, 1994; P D ' Ascanio et al, 1998). Along with the predominant nora-
drenergic neurons, other mediators and modulators are revealed, i.e. including glutamate and enkephalin (in the projection
nerves) (J Fung Simon et al, 1994), pancreatic polypeptide (P.H. Luppi et al, 1995; F Okutani Et Al, 1998), galanin (Z.Q.
Xu et al, 1998).
The combination of norepinephrine
 17
with vasopressin or neurophysin can be observed (J Gugten, 1988). In primates and in rats the locus coeruleus con-
tains serotoninergic neurons, while in rats it contains the GABAergic neurons as well (J.R. Sladik, P Walker, 1977; I Koi-
chi, 1989). Locus coeruleus and the zone A5 of the lateral nucleus of the tegmentum of pontis express tyrosine hydrox-
ylase, rather than the neuropeptide Y (K.Y. Pau, 1997). Some bodies and processes of neurons possess the capability to
synthesize the nitric oxide, which modulates, like galanin, the synaptic signaling (Z.Q. Xu et al, 1994; N Singewald et al,
1988; Z.Q. Xu et al, 1998). The importance is attached to the wide representation of terminals of the neurons of locus coe-
ruleus in the central nervous system (T.I. Belova, 1980; V.K. Berezovskiy, T.G. Kebkalo et al, 1984,; P D ' Ascanio et al,
1998), which is provided by the axons as well as by the dendrites (E Jodo, G Aston-Jones, 1998). The substantial increase
in the neuron activity in the locus coeruleus during the stress situations in cats was demonstrated (A Reche Junior, C.A.
Buffington, 1998).
The central gray substance of mesencephalon contains the serotoninergic neurons (V.K. Berezovskiy, 1984). It is con-
sidered to be the intrinsic structure of the reticular formation; either it belongs to the group of non-specific nuclei, closely
related to the thalamus. With the use of the retrograde transfer of horseradish peroxidase the co-interaction of the central
gray substance of mesencephalon with the afferent terminals of hypothalamic locomotor region were revealed in cats
(V.K. Berezovskiy, 1984). The neurons of the central gray substance of mesencephalon are not uniform; each of them
controls the broad receptive fields. Some of them manage the motor activity in cats (mainly the dorsolateral region of the
nucleus); the other respond to certain acoustical stimulation (ventrolateral region); the third respond to the acoustical sti-
muli associated with the subsequent movement; the fourth response to the repeated sounds, causing the conditioned-reflex
activity (disseminated in all regions) (V.M. Storozhuk, S.F. Ivanova, 1984). The functional heterogeneity has a morpho-
logic confirmation. Situated around the Sylvian aqueduct, the central gray substance of mesencephalon has specific cy-
toarchitectonic, myeloarchitectonic and angioarchitectonic characteristics in different regions. The periaqueductal region
is characterized by the low concentration of neurons, by the uniform distribution of vessel tree and by the elongated capil-
lary loops. The lateral portions have a similar neuron composition, but they differ in micro-anatomic structure. The ven-
trolateral region is characterized by the increased spatial density of neurons and by the well developed fine-loop capillary
network. The dorsolateral zones have a fine-loop and large-loop capillary networks and a moderate concentration of neu-
rons. The neurons can be arranged in groups or situated singly.
We have attached the primary attention to the specific region of the central gray substance of mesencephalon, which
includes the dorsolateral zone of the nucleus. In the course of the interspecies analysis the cytoarchitectonics and the mye-
loarchitectonics of the nucleus were constant and represented generally by the analogous types of nerve cells in the spe-
cies examined. The neurons are arranged in groups consisting of 2 to 8 cells or situated singly. The nucleus in rats and in
rabbits is characterized by the substantially higher density of the neuron bodies (P < 0.05 in comparison with humans and
dogs). As a rule, 1 to 2 middle-diameter perikarya attract attention, the other have a small diameter. The nerves form the
reticular network. The following division of the nerve cells populations in the central gray substance of mesencephalon is
considered to be typical (Table 6, Fig. 5):
1. Large neurons having the elongated, starlike, spindle-shape perikarya and a mean diameter of 31 μm (in rabbits) to
36 μm (in human). This group of cells in all the species investigated is remote from the periaqueductal zone (i.e., it is si-
tuated in the lateral regions of the central gray substance). It contains the cells having a moderate number of processes (8
to 10 per

Table 5
Proportion of the neurons types in the locus coeruleus (M ± m)

Species investigated Neuronal populations

Small-size (%) Middle-size (%) Large (%)
Human 17,1 ± 2,2 38,0 ± 3,3 44,9 ± 3,2
Dog 41,8 ± 2,3*** 47,9 ± 2,8 10,3 ± 1,8***
Rabbit 56,9 ± 3,6*** 37,9 ± 3,5 5,2 ± 1,2***
Rat 39,2 ± 1,6*** 57,8 ± 2,4*** 3,0 ± 0,6***

Parameters are compared with the human values.

neuron), which arborize poorly in the initial segments. They have both long and short processes. The short den-
drites are predominantly thin, with the varicose ectasia. The second group of large neurons consists of weakly arborizing
cells (4 to 6 processes), with long dendrites without branching or having a weak branching and the straight processes. The
axons and some dendrites of the cells of both populations go beyond the limits of nucleus, as was shown during the study
of the series sections.
The large neurons are sparse in the central gray substance, accounting for a small fraction in humans, in rabbits and
in dogs. In rats no similar cells were revealed in the early ontogenesis and within 6 months of post-natal ontogenesis. The
volume of the perikarya in this population is substantially larger in humans, in comparison with the dog and the rabbit.
 18
2. Middle-size neurons. The mean diameter of the perikarya amounts to 21 to 23 μm. The cells with polygonal
or spindle-shape perikarya are predominant. Three to six short or long, thin dendrites arborize moderately. The neurons
having 3 to 7 uniformly distributed short processes with a poor branching either the neurons having largely extended pe-
rikarya can be encountered. All the dendrites of middle-size cells are tender, have the abundant varicose ectasia and
straight or somewhat tortuous course. The distinctive feature of human cells consists in the bias of the predominant popu-
lation to the middle-size neurons, in comparison with other animal species (P < 0.05 – 0.001), while the minimal number
of those cells was noted in rats.
3. Small-size neurons. They have rounded or spindle-shape contours of the body and the mean diameter varying
within the limits of 12 to 13 μm in all the species investigated. They have 3 to 6 processes which do not arborize or arbor-
ize slightly. Those processes are delicate, relatively equal in thickness and have a straight course. During the comparison
of the interspecies range, represented by human, dog, rabbit and rat, the content of small-size neurons increases, so that
this population becomes predominant in two latter species (P < 0.01).
The shape of the perikarya, the number of dendrites and their branching are substantially more variable in human
and in dog, in comparison with the rat. In rabbits this parameter has an intermediate value.
In the central gray substance of cats the middle-size neurons are present, situated in the lateral regions of the cen-
tral gray substance, and the small-size neurons, lying mainly near the sylvian aqueduct. Both types of neurons belong to
the reticular or isodendritic type (E.O. Bragin, Z.V. Eliseyeva et al., 1984).
Thus, the comparative analysis of the nuclei under investigation demonstrates the specific features of the arrange-
ment of neuron ensembles in every nucleus. They vary by the shape and sizes of the perikarya; by the particularities of the
structure of nucleus, cytoplasm, cytoplasmic basophilic substance, neurofibrils; by the processes number and their degree
of branching; by the neurons’ body density and by the complexity of the neuropil; by the myeloarchitectonics; by their
situation within the brain stem structure (Fig. 6, 7, 8, 9).
While examining the neuron ensembles in the aspect of interspecies comparison, from rats, rabbits and dogs to
humans the tendency toward their complication is revealed. At the background of the repeating specific features of cy-
toarchitectonic and myeloarchitectonic structure, the nuclei investigated are characterized by the increasing variability of
neurons populations and of the degree of their processes development (Fig. 10). Our purpose did not consist in the inves-
tigation of interneuronal relations. We used as a basic criterion the possibilities of trophic and other extra-synaptic reci-
procal effects, rather than the interneuronal co-interactions, i.e. synaptic contacts. Meanwhile we do not at all depreciate
the significance of synaptic contacts in the course of structuring and of functioning of the central as well as peripheral
nervous system. The formation of the specialized neural ensembles – columns – in the cerebral cortex – may serve as an
example of such co-interaction.

Table 6
Proportion of the neuron types in the central gray substance of mesencephalon (M ± m)

Species investigated Neuronal populations

Small-size (%) Middle-size (%) Large (%)
Human 47,1 + 2,4 49,1 + 2,0 3,8 + 1,0
Dog 56,1 + 3,6** 36,7 + 3,5* 6,6 + 1,6
Rabbit 63,6 + 2,9*** 34,5 + 3,1*** 1,9 + 0,7
Rat 68,4 + 3,1*** 31,6 + 3,1***
The parameters were compared with the human values.
 19
The data concerning the complex structural-functional units as a form of organization in the central nervous system are
supplemented by the information concerning the possibility of presence of analogous formations in other brain regions.
The formation of the structural-functional units in the form of columns was demonstrated in the tectum of mesencepha-
lon, where they are vertically oriented (A.S. Batuyev, V.P. Babmindra, 1993). The regularities of structuring of such bar-
reloides in the nuclei of trigeminal nerve complex and some of their changes associated with the neonatal damages are
revealed (P.M. Wait, P.J. de ' Permenteir, 1997).

II.2. Structure and function of neuroglia in the central nervous system

In the recent decades the interest towards neuroglia and its role in the functioning of the nerve tissue has consider-
ably grown up. In the course of ontogenesis and phylogenesis along with the significant structural rearrangement of neu-
rons the reorganization of neuroglia occurs, appearing in its morphological variability, degree of differentiation, special
features of functional reactions and complication of neuroglial co-interactions. The attempts in the systematization of the
obtained data were made (O.S. Sotniks, N.K. Boguta, 1994). The interest towards neuroglia results, particularly, from the
demonstration of its important role in psychopathology (N.A. Veretennikov, D.A. Naumova et al., 1996). The following
aspects are the most essential in the glial-neuron co-interactions: 1) the control over the level of metabolism in the brain;
2) the regulation of genes expression; 3) the molecular mechanisms of neurons degeneration.
Neuro-astrocytic communications play the leading role in the developing and mature brain. The glial cells take part
in the neuroblasts programming, controlling their migration and the growth of processes, providing the growth of the neu-
rites both in vivo and in vitro (R.D. Fetter, K Broadie, C.S. Goodman, 1995). Thus, Bergmann’s cells and granular neu-
rons are sensitive to N-methyl-D-aspartate (NMDA). The Bergmann’s cells perceive the signal produced by the granular
neurons upon their stimulation (S Yanping, K D Mc'Carthy, 1997). In the central nervous system the astrocytes contain
the receptors to different growth factors, neurotransmitters and neuromodulators, cytokines, nitric oxide. The neurons, on
their part, contain the receptors to the growth factors of astrocytes.
The astrocytes are capable of producing rapid current and to transfer it into other cells, changing considerably the
local ion exchange in the membranes of adjacent neurons. This ability is different in vivo and in vitro conditions (G
Glassmeier et al, 1994). The study of the pyramidal neurons, co-cultivated with the astrocytes or without them, revealed
the polymorphism in the neurons activation. The response changes correlate with the degree of co-interaction with the
astrocytes, indicating their modulating influence on the excitation transfer in the neurons (Wi Rui Lin, M.E. Borish,
1994). Glia depolarizes in association with the increase in the potassium ions concentration in the intercellular substance,
reacting to neurons excitation (B.I. Tkachenko, 1994). The membrane potential of astrocytes comprises 70 to 90 mV and
changes depending on the chemical composition of intercellular medium. The impulses run from one cell to another for
the distance up to 50 μm at the rate of 30 to 60 m/s (B.I. Tkachenko, 1994; R. Bach- y -Rita, 1994).
The presence of the gap junctions between the processes of glial cells serves as a morphological indication to the
possibility of the excitation transfer (A.P. Novozhilova, 1993). The importance of macroglia in the mechanisms of so-
called volume signals transmission, of transformation of impulses, of adaptation and synchronization of neurons ensem-
bles implicated into the adaptive responses is assumed (M.Shch. Samoilov, A.A. Mokrushin, 1999). The significant num-
ber of gap junctions around the synapses is considered to be important (J.C. Sipe, R.Y. Moore, 1976). The gap junctions
serve nearly undoubtedly as the basis of the buffer structure, ensuring the electrical redistribution of potassium ions in the
glial syncytium (A.I.Roytbak, 1993).
Neuroglia has a significant importance in the adaptive processes of reconstruction of the energy metabolism in
neurons, manifesting in the coherent variation in the neurons exchange, oligodendrocytes and astrocytes within the day
(which were revealed with the aid of the ATP-ase assay) (V.S. Gusatinskiy, L.A. Kondratyeva, 1986). Those reactions
occur under the conditions of the pathologic impairments, manifesting in the variations of glycogen concentration and in
the ultrastructural changes (M.M. Svinov, 1999). One of the most important specific effects of the glial environment in
CNS consists in its stabilizing influence affecting the neurons and their processes. In adult mammals and in human ma-
croglia inhibits formation and growth of the nervous processes, ensuring simultaneously viability and regeneration of neu-
rons (S.C. Clemens, U Klans, 1994; T.J. Sims, S.A. Gilmore, 1994).
A number of data were obtained indicating the important role of the astrocytes in the processes of regeneration.
 20
The group of substances, known as fibroblast growth factors, represents one of the most important control fac-
tors released by the astrocytes. The base and acid fibroblast growth factors are revealed in the developing and mature cen-
tral nervous system in hens, mice, rats, monkeys and human (W.D. Woodward et al, 1992; G Labourdette, M Sensen-
brenner, 1995). The base fibroblast growth factor and its receptors are widely expressed in the periaqueductal zones and
in the nuclei executing the neuroendocrine function (A.M. Gonzalez et al, 1994). The receptors with a high affinity to-
wards these factors, containing the tyrosine -kinase domains, are present on the glycocalyx of the membranes of neurons
(A Baird, P Bohlen, to y990; E. Rouoshalti; Y Yamaguchi; 1991). The base and acid fibroblast growth factors stimulate
survival and differentiation of neurons of the central nervous system both in vivo and in vitro (P.M. Swectman et al, 1991;
T Mayer Et Al, 1993; D Zhou, M Di ' Figlia, 1993; G Ferrary Et Al, 1993). The reactive astrocyte is characterized by the
increase in the expression of in the cytoplasm and in the cellular nucleus (on the internal surface of the nuclear membrane,
where the receptor is situated) (M.K. Stachowiak et al, 1997). The study that investigated the effect of the chronic admin-
istration of the base fibroblast growth factor and of the ciliary neurotrophic factor on the cellular death under the condi-
tions of the brain damage in rats, revealed the considerable decrease of dead cells number in comparison with the control
group within the prolonged period after the damage. They presumably inhibit the triggering of the program of cellular
death, without preventing atrophic changes in the neurons affected. These peptides provide one of the mechanisms of
plasticity of the nervous system upon the damage (S Agarwala, R.E. Kali, 1998 a.b). On the 2nd day the proliferative ac-
tivity in the glial cells and in the vessels was demonstrated in case of the ischemic brain infarction in rats. The reactive
astrocytes, macrophages and endothelial cells express the base fibroblast growth factor, stimulating the angiogenesis
(H.H. Chen, 1994).
The function of adhesive molecules in the intercellular communications in the nerve tissue is at least also important
(B Marchetti, 1997). The epidermal and the transforming growth factors, produced by neuroglia, represent the cognate
peptides and belong to the group of nerve neurotrophic factors. They are revealed in the tissue culture of embryonic me-
sencephalic dopaminergic neurons in rats (D Casper et al, 1991) and can stimulate the proliferation in the culture of astro-
cytes in the cerebral cortex (R Avola et al, 1993).
The demyelinating diseases are associated with the damage in oligodendroglia, and the recovery in these cases
consists in essentially in the regeneration of oligodendrogliocytes. The platelet growth factor and the base fibroblast
growth factor represent the substances stimulating their repair. The platelet growth factor is produced by endothelium and
by neuroglia. It activates the development of oligodendrocytes from the precursor cells, whereas the fibroblast growth
factor provides their proliferation and dedifferentiation (J.B. Grinspan, 1994).
After the axotomy the synthesis of type I and type II insulin-like growth factor and of its receptors in the reactive
perineural astrocytes of the nuclei of the facial nerve in rats increases on the days 3d to 7th. Their receptors were as well
localized on the neurons, which responded to this factor by the activation of regenerative processes (J Gehrmann et al,
1994). Insulin, type I and II insulin-like growth factors contribute to the survival and stimulate the development of the
central and peripheral cholinergic and dopaminergic neurons in the culture (E Recio-Pinto et al, 1986; P Nissley, Y Lo-
paczynski, 1991). Type I insulin-like growth factor prevents the triggering of the program of cellular death and provides
the protective effect in the stress situations (C.C. Matteus et al, 1997).
The astrocytes can induce the release of tumors necrosis factors - eicosanoids. The eicosanoids exert their influence
on the immune control. (E.G. Gilerovich, 1993; I.G. Akmayev, 1996; P.K. Haugen, P.C. Letoumeau, 1991; E.N. Benve-
niste, 1995). The affinity of the nerve and glial cells to interleukin I produced by the microglia and macroglia of the cen-
tral nerve system, was revealed. Furthermore, the astrocytes are capable to produce interferon, which increases the release
of interleukin 2 in the brain structures (I.G. Akmayev, 1996). Interleukin 2 represents as a modulator of the cellular
growth in the neurons and in neuroglia, of cells survival, of the synthesis of hormones; it modulates the synaptic transmis-
sion and controls the neuroimmunologic co-interactions. It stimulates the penetration of T- and B-lymphocytes into the
brain and the intra-cranial agglutination of the large number of MHC class 2 positive cells, which can cause the decora-
tion of glial cells and neurons by the exogenous antibodies (U.K. Hanisch et al, 1996; U.K. Hanisch et al, 1997). The in-
terleukin 2 receptors are also revealed in the brain structures. Interleukin 2 can influence the maturing of oligodendrogli-
ocytes, of the peripheral neurons of sympathetic ganglia and of endothelium (P.K. Haugen, P.C. Letoumeau, 1991, U.K.
Hanisch, et al, 1997).
 21
Astroglia is assumed to specialize in the local antigen presentation (E.G. Gilerovich, 1993; I.G. Akmayev, 1996;
E.N. Benveniste, 1995).
The apprehension of the role of microglia has considerably enlarged. Its proportion in the white substance of the
central nervous system in adults comprises about 13 percent in comparison with the total population of glia. Together
with the classical phagocytic and antigen-presenting properties, the significance of microglia in the process of synthesis of
the considerable number of cytokines in the central nervous system was demonstrated (M. Righi, 1991). The activity of
microgliocytes is affected in the endogenous mental disorders, such as schizophrenia (A.S. Tiganov, 1999; V.P. Chekho-
nin, 1999). The activated microgliocyte are established to possess the capability of synthesis of the nitric oxide and of
beta-endorphin (S Betz-Corradin, 1993; P Sacerdote, 1993), while some neurons are sensitive to these substances (F Lica-
ta et al, 1998). Interleukin 3 and interleukin 6, expressed by microglia, ensure the survival of cholinergic and dopaminer-
gic neurons in the mature rats (M Kamegai et al, 1990, T. Hama et al, 1991).
Cytokines and the dissoluble factors of microglia, of the astrocytes and of the infiltrating cells (neutrophils and
lymphocytes) play an important role in the responses of the central nervous system in the process of diseases. Microglia is
essential in case of the neurons impairment (A.H. Cross, B Canella, C.F. Brosnam, C.S. Raine, 1991; E.N. Benveniste,
1995; D Guilian, 1990; H Wekerle, 1995). The capability to produce the molecules of type 2 main histocompatibility
complex is discovered in the astrocytes and in microglia. In recent years the attempts of activation of the regenerative
processes after axotomy were made. The transplantation of peritoneal macrophages into the zone of impairment is pro-
posed as one of the versions for this stimulation. Macrophages stimulate the development of the damaged axons, which
transforms into the morphological and immunohistochemical changes in the spinal cord in the mature rats (R Franzen,
1998).
Thus, the important property of glial cells consists in their great plasticity. They respond to a change of the func-
tional load rapidly and actively by the change in structure and distributing of the glial complexes (M.G. Zhvaniya, N.A.
Kostenko, 1995; E.E. Perevozshchikova et al., 1999). The literature data indicate the role of neuroglia (astrocytes in par-
ticular) in the development and functioning of neurons and in the organization of microcirculatory tree in the central
nervous system. However, thus far no morphological description of their co-interactions depending on the neuroarchitec-
tonics and angioarchitectonics was made. The investigations of the communications of astrocytes are performed in con-
nection either with the nerve cells or with the vessels. They are examined on the molecular-biochemical or on the func-
tional levels, whereas the comprehensive studies at the tissue level are sporadic in the literature reviewed.
In this context we examined in detail this aspect of the structuring of macroglia. Here we attached the great impor-
tance to the micro-architectonics of neuroglia in accordance with the pertain of its cells to one or other nuclear center.
In the motor nucleus of trigeminal nerve the proportion of the number of neurons and neuroglia is biased towards
the glial cells. The main population of neuroglia in the nucleus is composed of the protoplasmic astrocytes, but besides
them the fibrous astrocytes, oligodendrocytes and single microgliocytes can be encountered. The protoplasmic astrocytes
in the motor nucleus can be subdivided into several morphological versions (Table 7, Fig. 11):
1. Satellite astrocytes. They are situated between the adjacent capillary and the surface of neuron. They seem to be
spread on the surface in accordance with the boundary of a nerve cell. The extension of the processes is constrained by
one or more adjacent vessels. Their long axis is directed in parallel to the surface of neuron’s body. The processes of pro-
toplasmic astrocytes of this type are short and arborize strongly or moderately.
2. Astrocytes, contacting with the adjacent large neurons, but drawn towards one of them. They can surround one
large neuron and one or more middle-size and small neurons. The processes of neuroglia are distributed uniformly in all
directions. The cells form the pericapillary muffs at the significant distances from the body (up to 75-100 μm in human
and in dog). The astrocyte contacts with 2 or more vascular loops.
3. Astrocytes, which distribute their processes uniformly towards the bodies of several adjacent neurons. This pop-
ulation of cells in human and in dog is characterized by the abundant of relatively long multibranching processes, contact-
ing with 2 or more adjacent vascular loops. The cells are characterized by the significant longitudinal extent and by the
ability to form the integrated chain with the regions of the interlacings of processes. In human and rarely - in dogs, the
astrocytes having very long processes were revealed, which approach the bodies of 4 to 6 neurons, participating in the
formation of a glial muff with several vessels. In spite of a significant number of processes, some of them
 22
occupy the transitional position between the protoplasmic and fibrous astrocytes, due to the remoteness of the
processes’ terminals and their light gauge.
The quantitative interspecies analysis indicates the progressive increase in the length of the processes of protop-
lasmic astrocytes and of the representation of satellite neurogliocytes from rats to humans. The parameters of the number
of neurons, surrounded by the processes of one protoplasmic astrocyte, and of the number of vessels being in contact with
one astrocyte, are stable. Thus, the increase in the dimensions of protoplasmic astrocytes compensates the increase of the
representation of neuropil and of the sizes of vascular microbasins, preserving the basic special features of nuclear en-
semble organization.
The fibrous astrocytes (Fig. 12) are encountered in the marginal zones of the nucleus and in the region of neuropil,
especially in the loci of accumulation of the nerves, which form the roots of trigeminal nerve. Their processes extend
within the limits of adjacent capillary loops in accordance with the regions of vascular microbasinss.
Oligodendrocytes are rarely encountered near the bodies of neurons, which can be due to the specific features of
the procedure applied and to their minor absolute number. This is confirmed by a small amount of the nuclei of gliocytes
in the environment of the perikarya of neurons, which is typical for oligodendrocytes upon the staining with the use of the
conventional histological methods. Among them the satellite cells can be seen, located near the bodies of neurons, but
their occurrence is very scanty, especially in comparison with the mesencephalic nucleus of trigeminal nerve. The signifi-
cant density of oligodendrocytes is revealed in the region of the predominance of neuropil and in the white substance ad-
jacent to the nucleus.
Sometimes the single microgliocyte may be identified, mainly by the specific features of their nuclear structure (ir-
regular shape, intermediate diameter). No regular patterns are revealed concerning the distribution of microglia in the re-
gion of a nerve center.
The following groups of protoplasmic astrocytes can be identified in the mesencephalic nucleus of trigeminal nerve
(Table 8):
- protoplasmic astrocytes co-interacting with the adjacent vessels and with the large neuron. The structure of the
processes of an astrocyte as a whole seems to depend on the arrangement of the neurons. Its processes circumvent one or
more adjacent vascular loops and cover the surface of a nerve cell, forming the arcs. These gliocytes have a relatively
small number of short, thin, moderately arborizing processes. They include also the cells having longer processes with
moderate or significant branching;
- the astrocytes, which come in contact with 1 to 2 vessels and 2 to 3 adjacent large neurons. These astrocytes, with
a quite uniform spatial distribution of the processes, cover the adjacent nerve cells of the main population. Among them
the cells having short or long processes with the abundant system of branching can be encountered;
- the protoplasmic astrocytes, which come in contact with the bodies of the large neurons and extend their
processes to the regions, which correspond to the boundaries of locus coeruleus and of the central gray substance. The
cells with long, significantly arborizing processes predominate among them.
The peculiar transitional forms between the protoplasmic and fibrous astrocytes can be frequently encountered,
having thin short processes, practically without branching (up to 15-25), which continue within the limits of the adjacent
capillary loop, of the body of a large neuron and of its environment. The average length of the processes of all the protop-
lasmic astrocytes is generally small.

Table 7
Morphometric parameters of the astrocytes in the motor nucleus of trigeminal nerve (M ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Max La (μm) 97,58 + 2,28 89,12 + 3,25 76,12 + 3,91** 54,05 + 1,78***
Min La (μm) 68,42 + 1,86 62,56 + 2,10 52,25 + 2,52** 42,11 + 1,27***
Ng (Units) 6,55 + 0,19 5,86 + 0,21 5,21 + 0,23** 4,37 + 0,14***
Nn/a 1,41 + 0,09 1,48 + 0,09 1,89 + 0,14* 1,73 + 0,11
Ns/a 2,57 + 0,14 3,06 + 0,15 2,72 + 0,13 2,68 + 0,18
Parameters are compared with the human values.
 23
Among the astrocytes, situated between the gray substance of the tectum and the mesencephalic nucleus the
clone of cells having long processes, which arborize moderately or significantly, is predominating. Frequently the long
axis, formed by the processes, extends from the neurons of the mesencephalic nucleus of trigeminal nerve to the bounda-
ries of the locus coeruleus or of the central gray substance of mesencephalon. The tendency persists toward the decrease
of the abundance of the processes of protoplasmic astrocytes along the studied range of species from human to rats, like
that in the motor nucleus, but here the number of vessels, co-interacting with the processes of one astrocyte, is relatively
stable, which indicates the identity of the neuroglio-vascular ensemble organization. The number of satellite cells is simi-
lar too. At the same time the parameters indicating the less degree of autonomy of individual neurons trophic supply in
the mesencephalic nucleus of trigeminal nerve from human to rats coincide with the decrease of independence of their
glial environment. In rabbits and in rats the protoplasmic astrocytes having abundant processes extending to the adjacent
neurons are predominating. The specific conglomeration forms consisting of the central neuron, surrounding protoplasmic
astrocytes and “satellite” neurons. The network of blood capillaries lies on its periphery.
The interest is attracted to the oligodendrocytes of the white substance adjacent to the mesencephalic nucleus,
which arborize within the limits of the adjacent vascular loops. Some processes of these cells can extend to the anatomical
structures of the mesencephalic nucleus of trigeminal nerve. The processes of these cells correlate poorly with the blood
vessels. The similar morphology of the processes is characteristic for the fibrous astrocytes, but the substantial some part
of these processes terminates in the perivascular regions. Among oligodendrocytes a number of satellite cells are present
with the bodies, adjoining immediately to the perikarya of the large neurons. This type of cells, in comparison with all the
nuclei examined, is predominantly revealed in the mesencephalic nucleus of trigeminal nerve, especially in larger species
(human, dogs). Their processes are spread on the surface of neurons bodies of and form the structures homologous to the
glial capsules of peripheral ganglia. The satellite oligodendrocytes in rats are rare, in contrast to human and dogs.
In the main sensitive nucleus of trigeminal nerve the processes of protoplasmic astrocytes can involve 1 to 6 bodies
of the nerve cells. The protoplasmic astrocytes are characterized by the significant variability of arborization of the
processes, of their thickness and directionality. So the cells may be distinguished having the uniformly distributed middle-
length processes with a significant arborization, contacting with 2 to 3 adjacent vessels and several neurons. They vary in
the thickness of processes, in the predominance of distal or proximal terminal ramifications. This type of astrocytes is
predominant. The cells having the short processes are also present, contacting predominantly with 1 or 2 blood capillaries
and neurons. The processes can be situated in 1 to 2 planes predominantly, varying in turn by their length and configura-
tion. These cells are concentrated along one of the vessels, frequently on the boundary of the gray and white substance.
From human to rats (Fig. 13) the reliable decrease in dimensions and complexity of arborization of the processes of
the protoplasmic astrocytes, associated with the decrease of their qualitative variety (Table 9). The number of neuron bo-
dies included in the system of the metabolic concernment of one astrocyte (P < 0.01), is growing, which can indicate a
smaller degree of autonomy of the neurons groups in rats and in rabbits, in comparison with human and dogs.

Table 8
Morphometric parameters of the astrocytes in the mesencephalic nucleus of trigeminal nerve (M ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Max La (μm) 68,89 ± 2,83 67,73 ± 2,40 52,57 ± 1,65*** 49,38 ± 1,48***
Min La (μm) 45,56 ± 1,56 47,47 ± 1,38 37,43 ± 1,51** 37,83 ± 1,23***
Ng (Units) 3,95 ± 0,15 4,86 ± 0,21*** 4,29 ± 0,16 3,91 ± 0,15
Nn/a 1,22 ± 0,12 1,36 ± 0,12 1,79 ± 0,09*** 1,71 ± 0,08***
Ns/a 2,04 ± 0,14 2,25 ± 0,17 2,16 ± 0,13 2,42 ± 0,15
The parameters are compared with the human values.
 24

The fibrous astrocytes in the main sensitive nucleus lie at the regions of predominance of the nerves and on the
boundary of this nucleus. Their processes are restrained within the limits of vascular microbasinss and contact with sever-
al adjacent capillary loops. The oligodendrocytes usually predominate in the regions of accumulations of the nerve fila-
ments, penetrating into the nucleus from the roots of trigeminal nerve.
The interspecies analysis of the main sensitive nucleus of trigeminal nerve has showed that in the row comprising
human, dog, rabbit and rat, the extension of the processes of protoplasmic astrocytes and the number of satellite neurogli-
ocytes per neuron decreases, while the number of neurons, involved by the processes of one astrocyte, increases. This can
be caused by the more compact arrangement of the perikarya of nerve cells, whereas the decrease of dimensions of the
processes of astrocytes is less significant. In human and in dogs the significant morphological variability of protoplasmic
astrocytes is observed.
Among the protoplasmic astrocytes of the locus coeruleus the following populations can be distinguished (Fig. 14):
1. Astrocytes having short thick processes, abundantly arborizing and distributed uniformly. These сells are com-
mon in all the mammalian species investigated.
2. Astrocytes having abundantly arborizing thin processes, which are distributed uniformly and widespread. They
are much more numerous in human and in dogs.
3. The cells, which resemble two first types, but possess one or more processes which arborize poorly and have a
significant extension. They are predominantly encountered in human and are rare in dogs.
4. Astrocytes having thin or thick processes which arborize abundantly and whose maximum length falls within a
certain plane. They are revealed in all the species investigated.
All the populations mentioned above are characterized by the significant polymorphism of processes, providing the
variability of potential neuroglial co-interactions. They form the specific conglomerations, where the processes of adja-
cent astrocytes anastomose, forming the zones of mutual trophic control. The astrocytes involve 1 to 4-6 bodies of neu-
rons in their branches (Table 10).
In the cranial zone the protoplasmic astrocytes with an abundant and uniform arborization extend their branches to
significant distances, contacting with 1 to 3 adjacent vessels, while in the caudal region the arborization and the length of
processes in the space is somewhat smaller, especially in the central regions (zones of close-packed arrangement of the
neurons). The protoplasmic astrocytes having relatively short, abundantly arborizing processes are most widely
represented in the caudal region. Either the processes can disperse uniformly toward every direction, or 2 to 3 processes
can prevail; as a consequence, those processes acquire the complex configuration of the distribution limits. Upon Golgi-
Bennett impregnation, the mosaic arrangement of the ensembles of protoplasmic astrocytes and of the bodies of neurons
can be noted, especially at the periphery of the nucleus and in the regions of the sparse distribution of the neurons bodies.
The interesting feature of some protoplasmic astrocytes in human consists in the ability of forming the isolated
processes significantly extended, with a poor arborization, which terminate either in the perivascular space or rarely in
close proximity to the bodies of nerve cells. The astrocytes extend within the boundaries of adjacent vascular loops. The
latter can be represented by the capillaries as well as by the precapillary and postcapillary structures. If the adjacent capil-
lary loops are situated wide apart, the length of the processes of this type of macrogliocytes changes appropriately.

Table 9
Morphometric parameters of astrocytes in the main sensitive nucleus of trigeminal nerve (M ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Max La (μm) 95,71 ± 2,70 95,10 ± 3,62 75,91 ± 3,72*** 54,75 ± 1,20***
Min La (μm) 83,11 ± 3,29 81,47 ± 4,49 60,54 ± 1,95** 42,31 ± 0,75***
Ng (Units) 3,04 ± 0,11 3,19 ± 0,19 3,25 ± 0,14 3,01 ± 0,17
Nn/a 2,47 ± 0,14 2,33 ± 0,16 3,63 ± 0,12*** 3,61 ± 0,1***4
Ns/a 2,64 ± 0,13 2,57 ± 0,11 2,26 ± 0,09 2,67 ± 0,09
Parameters are compared with the human values.
 25
Table 10
Morphometric parameters of the astrocytes in the locus coeruleus (M ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Max La (μm) 88,45 ± 3,10 74,27 ± 2,08* 72,0 ± 2,91* 51,43 ± 1,89***
Min La (μm) 64,14 ± 3,90 57,35 ± 2,87 56,90 ± 2,26 41,03 ± 1,50***
Ng (Units.) 3,09 ± 0,13 3,39 ± 0,13 3,53 ± 0,17 3,95 ± 0,15*
Nn/a 2,39 ± 0,15 1,84 ± 0,12* 3,25 ± 0,18*** 4,14 ± 0,16***
Ns/a 2,84 ± 0,15 2,31 ± 0,15* 2,20 ± 0,12* 3,40 ± 0,16
Parameters are compared with the human values.

In the central gray substance of mesencephalon among the neuroglia the protoplasmic astrocytes predominate hav-
ing the processes arborizing abundantly and uniformly, which surround the bodies of adjacent nerve cells (1 to 5-6) and
participate in the formation of perivascular muffs around 1 to 5 vessels (2 to 3 capillaries as usual). The perivascular pro-
toplasmic astrocytes are also present, which concentrate their processes along the course of the vessels of system of mi-
crocirculation. The following forms of protoplasmic astrocytes are distinguished (Fig. 15): a) astrocytes which distribute
their processes longitudinally along the course of one vessel; b) astrocytes which contact predominantly with one vessel,
but point several processes to the adjacent capillary loops. The protoplasmic astrocytes in human and to a lesser degree in
dogs, are characterized by the significant dispersion of processes, which can allow to preserve the overall character of the
micro-architectonics of nucleus, taking into account the sparse arrangement of the nerve cells. Several structural modifi-
cations are revealed among the cells of this type. They differ by their relationship with the vessels and with neurons. So,
one may observe the perivascular astrocytes, which encompass predominantly one capillary loop (or along the course of
an artery and a vein). Some of these cells participate in the formation of singular processes going to the adjacent vascular
structures. There are cells, which distribute uniformly their processes, which are situated immediately adjacent to the
walls of 2 or more capillary loops. According to the specific features of the processes structure, the cells may be distin-
guished which have the abundant arborization, beginning from the proximal parts, or with predominant well developed
arbor in the distal segments. The last astrocytes are characterized by the abundance of very short terminal processes.
Together with the features of glioarchitectonics which are common in all the species, the significant interspecies
differences are observed. They are expressed through the wide variability of the extent of arborization, of the length of
processes and in the variability of their thickness and shape in human and in dogs, especially in comparison with rats,
which repeats similar phenomena in the nerve centers described earlier (Table 11).
In the central gray substance of mesencephalon the astrocytes concentrate in the space between the neurons or are
arranged diffusely. In any case, the processes of some astrocytes interlace, forming the zones of mutual control. Some
cells in human and in dogs, but not in rats, constitute the transition group to the fibrous astrocytes, having the thin, long
processes which arborize abundantly. The last type of cells is frequently revealed in the zones with the rare distribution of
neurons and in the periaqueductal region. The single cells may be encountered, identified as fibrous astrocytes, which are
characterized by the abundant, long processes with a poor arborization. The course of their branching is limited by the
adjacent vascular loops. On the average every protoplasmic astrocyte of a mature rat involves 3.18 bodies of nerve cells,
while each neuron is surrounded by 3.42 gliocytes on an average.
Thus, the results obtained indicate the morphological variability of the populations of neurogliocytes, especially of
astrocytes, when they are compared in terms of the interspecies particularities, of the analysis of different nuclei in ani-
mals belonging to one species and inside the zones of a nucleus. This is confirmed by the data concerning the quantitative
heterogeneity of neuroglia in the different regions of the central nervous system.
 26
Table 11
Morphometric parameters of the astrocytes in the central gray substance of mesencephalon (M ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Max La (μm) 79,33 ± 1,92 79,13 ± 2,03 64,45 ± 2,38* 58,47 ± 2,00***
Min La (μm) 61,37 ± 1,59 63,36 ± 1,60 56,57 ± 1,67 46,31 ± 1,97***
Ng (Units) 2,43 ± 0,16 3,21 ± 0,16** 3,78 ± 0,11*** 3,42 ± 0,17***
Nn/a 2,73 ± 0,20 3,03 ± 0,15 3,12 ± 0,17 3,18 ± 0,16
Ns/a 1,84 ± 0,09 2,26 ± 0,13 2,16 ± 0,10 2,34 ± 012***
Parameters are compared with human values.

In the brain stem in human, in comparison with the spinal cord, the reliable increase in the number of fibrous astro-
cytes and oligodendrocytes against the protoplasmic astrocytes and microglia is revealed (N.L. Mikeladze, 1968). In the
studied sequence of animal species (rats, rabbit, dog and human) the specific features of the structure of protoplasmic as-
trocytes exist. The substantial proportion of these differences can be due to the trophic conditions and to the arrangement
of the neuron ensembles in the nuclei. More close-packed arrangement of the bodies of neurons, the smaller mean diame-
ter of cells are observed in the course of the analysis of nuclear structure in rats. The vascular networks are finer. At the
same time the maintenance of the common morphology of protoplasmic astrocytes is accompanied by the characteristic
feature of the structure of the central nervous system of mature rats consisting in the predominance of cells having short
processes with abundant arborization. By comparison of the studied parameters in rabbits and in dogs, the increase of va-
riability of the extent of arborization and of the length of processes of protoplasmic astrocytes is observed. The most ob-
vious polymorphism is noted in human. Together with the increase of morphological heterogeneity the proportion of the
number of the bodies of neurons and of macroglia changes in a sequence from rats to human. This regularity was also
noted by other authors (S.M. Blinkov, I.I. Glezer, 1961; A.I. Roytbak, 1993)
The amplification of organ intra-tissue and structural intertissue interrelations can be explained in terms of evolu-
tion as well as of the adaptation. The important is attached to the suggestion concerning the compensatory changes in the
neuroglia, appropriate for the changes in the trophic supply of neurons and of their processes, along with the maintenance
of the basic principles of intranuclear extra-synaptic co-interactions and of the basic functions of the nuclei mentioned
above. Thus, neuroglial co-interactions do not appear as the unconditional indicator of the evolutionary development of
the given species, but they are of adaptive nature depending on the dimensions of neurons and development level of the
neuropil. These parameters particularly increase in parallel to the formation of glial-neuron relationship. This corresponds
to the opinion of other investigators (A.I. Roytbak, 1993).
Thus, in the range investigated including the species from rats to human several multidirectional processes occur:
1. The sizes of the perikarya of neurons increase.
2. The density of their arrangement per volume unit decreases.
3. The density of the arrangement of capillary networks decreases.
The interspecies differences are most obviously observed in the nuclei, where significant changes in the dimen-
sions of neurons and in the density of their arrangement emerge (the central gray substance of mesencephalon, the main
sensitive nucleus of trigeminal nerve). In human nuclei average cell the middle-size and even large-size neurons begin to
account a significant proportion, together with the predominant small-size neurons; it may affect the nature of trophic ex-
change. At the same time, the research findings demonstrate the identity of cytoarchitectonics and of myeloarchitectonics
of the structures being investigated, in spite of their significant variability. The structural features of arrangement ob-
served, the nature of the formation of complexes “neuron-astrocyte-capillary” in the individual nuclei are also similar in
all the species, allowing to suggest the probability of the identity of the mechanisms of formation of the complexes in the
course of ontogenesis.
The anatomical arrangement of astrocytes and of their processes is unique. They can contact simultaneously with
the synapses as well as with the blood vessels.
 27
The astrocytes isolate the synaptic contacts from the perivascular space of microvessels, thus enabling the astro-
cytes to fulfill the active role in the ionic, aqueous and neurotransmitter supply in the central nervous system (B. Ranson,
1992; S.G. Sims, 1992). Kuffler and Nichols, (1966) revealed for the first time the co-interaction between the neurons and
the glial cells, which necessarily implicate the diffusing substances of the intercellular brain zones. This exchange is not
exceptionally trophic. The suggestion that the glial cells can play the key role in the processes of neuronal excitation and
co-interactions, in the modulation of synaptic transfer and of processing of the information, related to education and to the
memory, has a fair amount of sense (B Ranson, 1992; K.T. Ng, M.E. Gibbs et al, 1992; A. Schousboe, N Westergaard et
al, 1995; C.M. Muller, 1995). The reciprocal exchange of information molecules is accomplished between the neurons
and the neuroglia. These molecules include neurotransmitters, ligands and growth factors (F Hefti, 1986, 1994; D.F. Con-
dorelli, F Ingrao et al, 1989; A. Arender, J de'Pellis, 1992; G Labourdette, M Sensenbrenner, 1995; B Marchetti, 1996).
The attention is attached to neurotropic factors, fibroblast growth factors, epidermal growth factor, insulin-like growth
factors (F Hefti, 1994; G Labourdette, M Sensenbrenner, 1995).
The numerous growth factors that are frequently referred as neurotrophic can stimulate the development and diffe-
rentiation of neurons. They participate in the maintenance of structural integration and synthetic plasticity of the nerve
tissue (F Hefti, 1994). The interest is growing to the neuroglial co-interactions at the molecular level; the possibility of an
active reciprocal effect of microglia, macroglia and neurons contacting with them under varying physiological and patho-
logical conditions was demonstrated (F. Bloom, A. Leyzerson, 1998; B Ranson, 1992; E.N. Benveniste, 1995; K.E. Bo-
venkamp, P.A. Lapchac, et al, 1997; J.M. Conner, S Varon, M.S. Hoener 1998). The important role of macroglial precur-
sors in the control of the processes of neuroblasts migration and of the development of axons in the central nervous sys-
tem was revealed (R Hardy, R Reynolds, 1993; R.B. Norgen, R Brackenbury, 1993; S.V. Saveliev, B.A. Korochin et al.
1997).
With the use of the above-mentioned methods of investigation the significant variability of the morphological
types of protoplasmic astrocytes was discovered, allowing considering them as qualitatively different morphological cell
populations or as the cells characterizing by the significant mobility of processes depending on the state of the adjacent
neurons and of the elements of neuropil. Among the protoplasmic astrocytes in the nerve centers investigated the follow-
ing morphological cell types can be differentiated (Fig. 16, 17):
1. The astrocytes having the uniform spatial distribution of processes. Among them the following subtypes are dis-
tinguished:
a) The cells with thick, short or long processes which arborize abundantly,
b) The cells with thin, relatively short processes which arborize abundantly,
c) The cells with thin, relatively long processes which arborize abundantly,
d) The cells with short or long processes which arborize abundantly and include one or more processes extending
to the significant distances.
2. The astrocytes with a predominantly single-plane arborization. The following subtypes are distinguished among
them:
a) The cells with short thin or thick processes. They are frequently thin and have moderate branching,
b) The cells with the long, abundantly arborizing, thick or rarely thin processes.

A certain fraction of these cells occupies the intermediate position before the fibrous astrocytes, as is evident from
the presented description; thus, the morphological partitioning of these cells may be considered as somewhat relative.
Relative to the capillary loops, the astrocytes can be subdivided into perivascular and “satellite”, which cover by
their processes the neuronal bodies. This mode of division is very conventional. The considerable proportion of the astro-
cytes extend their processes both to the vessels (forming the perivascular “muffs”) and to the bodies and processes of the
neurons. The discrimination of the groups of protoplasmic and fibrous astrocytes depending on their relation to the capil-
laries and other adjacent vascular loops is considered important:
1. The cells inclined predominantly towards one of the vessels and extending their processes along through its
course. These astrocytes can contact either with one large neuron and its small “satellite” nerve cells (macrocellular nuc-
lei); or with several neurons, adjacent to the corresponding capillary loop (small-cell nuclei). This type of cells is most
characteristic for the motor and mesencephalic nuclei of trigeminal nerve.
2. The astrocytes which distribute their processes uniformly between two or more vessels, covering the bodies and
processes of the adjacent nerve cells as well. Those gliocytes are characterized by the relatively uniform spatial distribu-
tion of the processes.
 28
3. The cells of intermediate type, having a primary affinity for one of vessels, but extending some of processes
to the adjacent capillary loops.
4. The astrocytes which have no immediate contact with the capillary loops. This type of cells is comparatively in-
frequent, which can be connected with the incomplete identification of the vascular bed in the nucleus under investigation
(due to the possible errors in the procedure or in its application).
Such a micro-anatomical location of the cell processes plays the specific functional role, according to the special
features of the diffusion of high molecular weight substances. In case of the structural damage of hematoencephalic bar-
rier in rats and in rabbits these substance are demonstrated to penetrate the cerebral parenchyma and infiltrate the brain,
penetrating to the significant distances. The morphological staining pattern with tracers indicates the predominance of
transport through the system of astrocytic processes, suggesting their active role in the transfer of substances in the cere-
bral parenchyma. Thus, the astrocytes can actively control the regional traffic in the central nervous system, together with
the neuronal processes and with the vessels. The directionality of the processes of oligodendrocytes and their extent can
indirectly indicate that the phenomena of the trophic transfer can play an important role in the vital activity of these cells.
The presence of a particular population, which is identified morphologically, is immediately related with the neuron en-
sembles in the nuclei under investigation and their angioarchitectonics as well.

II.3. Relationship between the angioarchitectonic and structural-functional structure of the nuclear centers.
Ensemble structure of the nuclear centers

In the recent decades the significant attention has been attached to the cerebral blood-vascular system. In classical
terms the vessels were assigned the predominantly trophic role. They are similarly considered in the ontogenesis (I.V.
Gannushkina et al., 1977; D.B. Cheek, 1975). The researches in the angioarchitectonics of the pontis and of mesencepha-
lon have a long-standing history. Stopford as far back gave an anatomical description of their arteries (Stopford, 1916). It
is known that the pontis is anatomically perfused with two arterial systems. In human the larger arteries, 150 to 200 μm in
diameter, branch from a.basilaris 1.5 to 2 mm away, while the small (100 μm in diameter) – 0.5 to 1 mm away. The arte-
ries of both types make a total of 32 to 45 at each side. All the arteries are directed toward the 4th ventricle and resemble
the truncated cone by their architectonic characteristics. The afferent vessels are scattered in the cerebral tissue to 3 to 7
branches and reaching the bottom of the 4th ventricle, they divide into the ascending and descending branches, reaching
the ependymal layer. The long-stemmed and short-stemmed branches are present. The structure of the intra-organ vascu-
lar bed of the nuclei of the pontis is characterized by the abundance of anastomoses and by the reticular structure (S.M.
Ogneva, 1950). On the basis of electron microscopical studies the arterial anastomoses may be subdivided into the groups
according to their localization (in the place of precapillary sphincters, along the same artery, between the small arteries of
meninx) (B.G. Anderson, W.D., Anderson, 1978).
At the opinion of N.G Vereshchagina et al., (1999), three levels of the structural-functional organization of the sys-
tem of cerebral arterial supply can be distinguished. These levels include extracranial arteries (main arteries), extracere-
bral and intracerebral (arteries of the base of brain and of the brain stem, large perforating arteries and small intracerebral
arteries), and also tissular or metabolic vessels (microcirculation system). Their reactions under the pathologic influences
vary depending on the form of pathology.
The quantitative study of intra-organ vascular bed is performed with the use of measuring the capillary density per
one unit of area or of the volume. The detailed investigations of the trophic supply of some brain stem structures in adults
were conducted (I.I. Shvorin, 1988). The macroanatomy of the blood supply of mesencephalon and of metencephalon is
rather thoroughly investigated, taking into account the species variability. These differences are shown to be closely re-
lated to the anatomic-functional characteristics of the brain (L.Ia. Dotsev, 1982). By the example of dogs the abundance
of intervenous anastomoses and the presence of the collateral draining ways were demonstrated (I.I. Kogan, 1995). The
vegetative nuclei of mesencephalon differ from the somatic nuclei due to the exceptionally abundant fine-meshed network
of capillaries and to the presence of the own arteries, which are positioned along the length of nuclei in the middle of neu-
rons, analogous to the vegetative nuclei of the spinal cord. The principle of organization of the blood supply of the pontis
is similar in the sequence of mammalians investigated by the authors (human, monkey, dog, rabbit, guinea pig) (P.L. Mi-
keladze, 1968).
The majority of the cerebral capillaries belong to IAb type according to H.Bennet classification (1959).
 29
Morphologically the endothelium of such capillaries has no fenestrations; it is surrounded by the pericapillary cells,
enclosed into the well-marked, continuous basement membrane. The endotheliocytes contain a small number of the mem-
brane organelles, with exception of mitochondria and small number of vesiculae. The large number of the gap junctions is
revealed amid the cells.
The pericapillary cells contain numerous acting-like microfilaments. The dense pericapillary casing, formed by the
astrocytes, is present in the peduncles, where the pinocytosis vesiculae are revealed. In the zones possessing the poorly
expressed barrier functions the system of large pores is well developed (P.A. Motavkina et al., 1983; V.V. Kuprianov et
al., 1986).
The significant changes in the vascularization are observed under the conditions of experimental venostasis in rab-
bits and in dogs, showing as a change in the significant overall quantitative parameters of microcirculation (S.V. Cheme-
zov, 1999). At ultrastructural level the vessels are observed to react to prolonged hypoxia by proliferation and by elonga-
tion. The diameter of capillaries changes. Structural reconstruction affects the pericapillary cells (P.A. Stewart, 1997).
The study of the morphological reactions of endothelium in the cerebral vessels revealed its high sensitivity to different
medicinal and other external influences, manifested as the complication of nuclear contours, increase of the representation
of the synthetic apparatus of cells and system of large pores, increase of the permeability (I.A. Mezhibrovskaya, 1981;
M.M. Serdenko, 1984). As was shown in white rats, the microcirculatory cerebral bed is characterized by the high-level
reactivity to the changes of osmotic pressure. In particular, in case of local increase of the osmotic pressure the diameter
of vessels and blood flow rate increase, the hydrostatic pressure rises (in the veins primarily). The contrary pattern is ob-
served in case of the decrease of osmotic pressure in the brain tissues (M.N. Avakova et al., 1999).
The cerebral blood flow must be maintained at the proper level even under the conditions of impaired systemic cir-
culation and must be adequate to the metabolic requirements of brain. Afferent blood vessels (arterioles especially) are
the basic regulators of blood flow intensity (G.I. Mchedlishvali, 1986). The high plasticity of cerebral blood flow leads to
the functional changes in the nerve tissue in conditions of cerebral blood flow reduction by 50 to 60 percent. The compen-
sation occurs due to the regional redistribution of blood circulation in the brain. Morphofunctional reactions to the iden-
tical influence can differ essentially in different regions of the brain. In rats chronic hypoxia results in the significant acti-
vation of angiogenesis in the cerebral cortex and in the hippocampus, but not in the medulla oblongata and the cerebel-
lum, since in the latter structures the vascular reaction consists in the dilatation of the vessels (S Patt, 1997). The regional
cerebral blood flow changes considerably in different psychopathological states, associated with the varying level of the
activity of brain. Thus, in studies of the cerebral blood flow in human with the use of rapid series cerebral angiography
and of intra-carotid injection of the radioisotope 133Xe, 10 to 8-fold reduction of the measured parameters was revealed in
case of the irreversible coma and 2-fold – in case of the reversible coma and lacunary dementia (A.P. Romodanov et al.,
1992).
In spite of the great importance of local vascular reactions to the adequate supply of nuclei, groups and individual
neurons, the description of micro-pools in most zones of the central nervous system is incomplete. It primarily concerns
the cerebral cortex (V.V. Turigin, 1988; V.I. Kozlov et al., 1994) and some motor nuclei (S.B. Gerashchenko, 1987). The
significant differences in the description of architectonics of such ensembles between the nuclear and screen-type centers
in the central nervous system are revealed, complicating the comparative analysis of these structures. At the same time, in
the opinion of V.I. Kozlov et al. (V.I. Kozlov et al., 1994), the modular organization of the neuronal apparatus is specifi-
cally connected with the similarity of power supply of the neuron ensembles. The author distinguishes 4 basic compart-
ments of the internal environment: cellular (parenchymatous), blood, interstitial and lymphatic. Sometimes the subendo-
thelial compartment is mentioned. Three compartments are characteristic for the nervous system. Each compartment pos-
sesses different permeability and is isolated by the barrier system. The different portions of vessels exhibit likewise the
heterogeneous capability for the diffusion of substances through their wall.
However, in recent years the apprehension of the role of the tissue components of the vascular bed and of neurogli-
al environment in the vital activity of neurons developed considerably. It is far from being restricted by the barrier, troph-
ic and support functions.
At present the vessels can not be considered as the pure supplier of nutrients and oxygen into the central nervous
system. The blood stream performs the transfer of a significant number of biologically active substances, whose delivery
plays an important role in the development and functioning of the nerve tissue.
 30
Thus, the tyrosine, which is transferred with the blood flow, stimulates the differentiation of neuroblasts
(through the determination of nerve growth factor, in particular) (Y Hashimoto et al, 1994). The endogenous glucocorti-
coids actively participate in the processes of maturing of the cholinergic neuron complexes in the central nervous system
at the point of the early post-natal development (L.K. Tacahashi, C.S. Goh, 1998), and in the increase of the mass of brain
(B.Ia. Ryzhevsky, 1999). One of the mechanisms of action of glucocorticoids consists in the inhibiting influence on the
synthesis of vascular endothelial growth factor, stimulating the angiogenesis (G.R. Criscuolo, 1996). The great determin-
ing importance is attributed to the sex hormones (I.B. Akmayev, L.B. Kalimullina, 1995). The blood stream brings into
the central nervous system at the points of development and of maturity the glial growth factor (somatomedin B), released
from adenohypophysis, salivary glands and from hepatocytes; as well as the family of nerve growth factors, secreted in
the cells of many peripheral organs (M.P. Chernysheva, 1995).
There is evidence that the prevailing biological motivations are formed as the integrative chemical co-interaction of
the neurons in the different systems of the brain. Thus, the sensitivity of neurons to neuromediators and neuromodulators
changes (K.I. Sudakov, 1996). This influence is probably most effective under the conditions of impairing of hematoen-
cephalic barrier and at the point of the early ontogenesis, when the barrier properties of endothelium are modest. The in-
creased penetrability of the barrier for the proteins is also observed under the conditions of angiogenesis and regeneration,
especially in case of the pathologic process in the zones of neovascularization (S Nag, 1996). Some stimulating amino
acids and their derivatives can easily penetrate the structures of hematoencephalic barrier (M.C. Josek, W.H. Griffith,
1998). The possibility of increasing permeability of hematoencephalic barrier was also observed under the conditions of
the mental load, resulting in the considerable changes of the particularities of cerebral response to atropine (V.B. Semeni-
utin et al., 1999). In case of the injury the repair of the barrier occurs not sooner than in 30 days (I.N. Saburina, 1993).
The particular interest is provoked by the high-molecular protein of the extracellular matrix - tenascin, which is re-
leased in the developing brain. This protein is of great importance in the processes of cellular adhesion, migration and
proliferation. In adult normal brain the content of tenascin is low. Its secretion increases at the point of embryogenesis and
in the human astrocytomas. It causes the hyperplastic processes in the vessels, associated with the influence on the exis-
tent endothelial tyrosine -kinaze receptors Tie-1 and Tie-2 (D Zagzag, 1995, 1995).
The complex study of the components of nerve tissue showed that neuronal morphological reactions to the damage
are not at all maximal every time. The roughest changes of the astrocytes (especially protoplasmic) in the comparison
with other cells were observed in cases of the experimental audiogenic epilepsy. These changes were of reactive, produc-
tive, and sometimes degenerative nature. The architectonics of neuroglia changes dramatically. The significant transfor-
mations were noted in the vascular bed as well. (N.A. Veretennikov et al., 1996). The above-listed factors allow assuming
that this structure is one of the most mobile structures of neuro-glio-vascular complexes. The high degree of the reactivity
of neuroglia to different pathophysiological irritations was demonstrated, appearing as the change of structure and of redi-
stribution of cells in nerve tissue parenchyma. Hypoxia and dysfunction of cardiovascular system lead to the increase of
the fermentative activity in oligodendrocytes and to the hypertrophy of astrocytes, resulting in the formation of drainage
complexes around the center of damage. The number of perivascular gliocytes, accompanied with the decrease of the
number of perineural gliocytes (Iu.N. Kvitnitskiy-Ryzhov, R.V. Matviyenko, 1988). The morphological manifestations of
astrocyte activation after the axotomy in rats coincide with the point of neurons’ death. The correlation exists between the
death of neurons and the activity of astrocytes (S Agarwala, R.E. Kalil, 1998).
The neuroglial co-interactions have the reciprocal nature. The neurons exert an active influence on the glial cells.
The leading mediators of the central nervous systems (glutamate, norepinephrine, vasointestinal peptide - VIP) may cause
the intense physiological responses of the astrocytes. VIP-neurons are shown to co-interact with the astrocytes, containing
the receptor complexes for the vasointestinal peptide. VIP- and norepinephrine applications in the pure strains of the as-
trocytes cause the rapid glycogenolysis and control the resynthesis of glycogen through the activation of cAMF and of the
transcription factors (J.L. Martin, 1989; E. Pralong, P.J. Magistretti, 1994). The receptors to somatostatin sst-1 and sst-2
were revealed with the use of radio-immune methods and of in situ hybridization in the hypothalamic cultures in mice.
Type sst-1 receptors predominate in neurons, while type sst-2 receptors are present in the astrocytes (C. Lanneau, 1997).
In studying the protooncogene Bcl-2 acting as the apoptose inhibitor in different cerebral cells the expression of this sub-
stance was demonstrated in the neurons, but was absent in the neuroglia.
 31
The protooncogene Bcl-2 can provide control over the development level of glial elements in the central nerv-
ous system (S Vyas et al, 1997). The fibroblast growth factor-9 is secreted and exerts stimulating effect on the growth of
glial cells. In the normal human brain and in rats this factor is revealed in the neurons of many regions, including the
black substance, the motor nuclei of the brain stem, the mesencephalic and motor nuclei of trigeminal nerve (T Todo et al,
1998). The family of fibroblast growth factors intensifies the angiogenesis in the developing brain tissues and in case of
cerebral malignancies. All fibroblast growth factors have a strong affinity for heparin-like polysaccharides. The modula-
tion of proteoglikane geparan-sulfate with the use of the growth factors can be considered as one of the leading factors in
the regulation of increase and differentiation (A Seddon, 1995; D Hecht, 1995).
The behavior of embryonic transplants in the mature brain of rats can serve the proof of the role of macroglia and
of vessels in the formation of neuron ensembles. The high migration capability of the transplanted astrocytes (up to 230-
1000 μm) at the 50th day was revealed, as well as the capacity of immigration of oligodendrogliocytes into the tissues of a
recipient during the myelination of the axons of donor neurons and of the recipient cells. The neurons can migrate (max-
imally up to 200 μm), but it concerns only the middle- and small-size cells, but not cells large in diameter. The migration
of cells proceeds along the vessels (M.A. Aleksandrova et al., 1993). The extensive perspectives for studying of the nerve
tissue arise from the implantation of the donor tissues into the brain not only in closely-related animal species, but even
between different types (from the invertebrates to the mammalians). Such transplantations are characterized by the forma-
tion of contact co-interactions between the graft and host neurons (E.B. Smirnov, I.P. Bystrov, 1997; S.V. Savelyev, L.A.
Korochkin et al., 1997). The astrocytes that migrate from the compact neurografts may be suggested to exert an influence
on the processes carried in the brain of recipient, since the immature astrocytes are capable to stimulating the axon growth
and to change the regional processes (G Smith et al, 1990).
The apprehension of the functional organization of vessels developed considerably in the last decade. The poly-
morphism of the sensitivity of contractile structures of vessels to the vasoactive substances and of the activity of Na+/K+
pump was demonstrated not only in different organs and between the parallel parenchymatous arteries and veins, but also
along the course of one vessel. This indicates the very complex functional organization of the control of trophic guarantee
in the vascular channel and the functional heterogeneity of vessels (V.A. Govyrin, T.G. Leontyeva, 1994; O.Iu.Gurina,
V.V. Kuprianov, 1997; A.V. Ialtsev, S.V. Shormanov, 1997). The heterogeneity was confirmed by morphological data,
demonstrating the differences of endotheliocytes along the course of the vessel concerning their configuration, permeabil-
ity, structure of organelles and number of nuclei (A.N. Gansburgskiy, 1995). The significant differences in the responses
of middle coat of vessel along the cerebral arteries are observed (A.V. Ialtsev, 1997), as well as by comparison of the af-
ferent vessels, veins and capillaries. The capillaries exhibit also the variability in the responsiveness of endothelial lining
(N.V. Markaryan, I.V. Maliksetyan, 1998). The arterial end of the capillary differs from the venous end by hemodynam-
ics conditions, lumen diameter, hydrostatic pressure, velocity and blood flow resistance (V.I. Kozlova et al., 1994).
The apprehension enlarged on the role of the vascular structures in the hormone-producing function (particularly,
concerning the class of endothelins), as well as on the qualitative heterogeneity of endothelium, on its role in the
processes of physiological responses and of regeneration in the nervous system (V.V. Kuprianov, 1993; V.V. Banin,
1995; I.V. Fesenko, 1995; Y Hashimoto, S Furikava et al, 1994; J.W. Shim, J.G. Chi, et al, 1996; J Kripinski, J Kaluza, et
al, 1996). The endothelial cells of the arterioles release the endothelial relaxing factor, which increases the blood afflux
into the organ via the relaxation of smooth muscles (R.F. Furchgott, J.V. Zawadzki, 1980). This factor is identified as ni-
tric oxide (S Moncada et al, 1991). It is secreted by the endothelial cells through the basal surface and exerts a direct dif-
fuse influence on the adjacent structures (including the contractile elements) (T.F. Luscher, 1993). NO ensures the auto-
regulation of cerebral blood circulation, integrates the trophism and the metabolic rate, the neurotransmission, participates
in the formation of memory and in the control of the behavioral activity (M.T. Onufriev, M.Iu. Stepanichev, 1999). Thus,
endothelium can exert both the vasoconstrictor (endotelin-1, -3, prostaglandin PGH2) and vasodilating (NO) influence
(T.F. Luscher, 1993).
The serum albumin plays an active role in the deposition of calcium ions and thus participates in the control of the
vascular tone and of permeability (E Fuentes, A Nadal et al, 1997).
 32
The secretion of the nitric oxide, in turn, is under control of the intracellular calcium content in the endothelium
through the formation of the enzyme nitric oxide-synthase (M Hecker, A Mulsch et al, 1994), while the vascular permea-
bility is regulated through the endotheliocytes contacts (C.C. Michel, 1988). The endothelial points of permeability appear
as zones defined by the high intracellular content of calcium ions. Calcium can influence the intracellular contractile ele-
ments, causing their contraction accompanied with the dilation of intercellular contacts (F.E. Gury, 1992). Serum albumin
reduces the content of intracellular calcium not only in endotheliocytes, but in the astrocytes too, exerting an immediate
physiological effect on these cells. The lysophosphatidic acid presented in the blood is characterized by the similar effect
(E Fuentes, A Nadal et al, 1997; A. Nadal, E Fuentes et al, 1996). The intercellular space plays also an important role in
the maintenance of homeostasis in the nerve tissue (S.I. Riabov, 1993).
The particular role of endothelium in the development of immune reactions was demonstrated, manifesting under
specific conditions as the antigen-presenting ability and as the expression of the main histocompatibility complexes class
I and II in the endothelium; these processes influence actively on the immunological processes in the region of nervous
grafts (E.G. Gilerovich, 1990).
The in vitro models showed that the degeneration of the basal lamina is one of the important elements of extracel-
lular matrix, controlling the angiogenesis. The substrate consisting of the gel that it secretes contains collagen, fibrin, la-
minin. It induces the formation the capillary-like vascular tubes of endothelial cells (H.K. Kleinmanl, 1993). The matrix
gel, arising after in vivo membrane destruction, is activated in association with the fibroblast growth factor and with hepa-
rin (A Passaniti, 1992). The phenomenon of stromal cellular invasion characteristic for angiogenesis, preceded with the
destruction of basal lamina in the point of endothelial growth is present not only after birth, but serves as basis for some
processes in the embryogenesis. The stromal invasion is very important during the development of the nervous tube de-
rivatives in vertebrates. One of the mechanisms of angiogenesis consists in the destruction of the main structural compo-
nents of basal lamina (collagen types IV and V) with the migration of endothelial cells (T Kalebic, 1982). The cellular
migration is related with an increased expression of the urokinase-type plasminogen activator on the cellular surface. The
plasminogen activators are produced in the endothelium; they convert plasminogen into plasmin and thus mediate the de-
struction of laminin and of fibronectin. Plasmin can also stimulate the activation of secreted collagen- specific proteases,
including the protease of collagen type V, primarily in case of the basal laminae destruction (M.S. Pepper, 1987). The
basic fibroblast growth factor controls the production of plasminogen activator-1 in the endothelial cells (O Saksela,
1987; A. Gualandris, 1995). Laminin acts as the angiogenesis inductor in the course of the embryonic development. Some
pathologic variants of angiogenesis are caused by the impairment of genetic regulation of the embryonic expression of
laminin (H.K. Kleinman, 1993). The endothelial cells (including the migrating endothelium) were shown to express in
vitro the cellular membranes-bound proteins, specific for the collagen of the basal laminae (T Kalebic, 1982).
The influence of corticosteroids on angiogenesis was studied. They prevent proteolysis and inhibit the formation of
new blood capillaries in the chicken embryos, in the cornea of rabbits and in certain mice tumors. Thus, the heparin
treatment stimulates the tumor angiogenesis, while hydrocortisone suppresses it (R Crum, 1984, 1985; D.E. Ingber,
1985).
Fibroblast growth factors 1 and 2 exert their influence not through the heparan-sulfate exhibiting a low affinity to
them, but through heparinase or the matrix-degrading proteases, such as plasminogen activator. They may also exert an
immediate mitogenic effect, like the factor of chemotaxis (K.J. Kim et al, 1993; D Coltrini, 1995; D Ribatti, 1995). To-
gether with the above-mentioned ability of astrocytes to produce these factors, the possibility of expression of this factor
as well as of its receptors was revealed in microglia (M Presta, 1995).
The vascular endothelial growth factor and the platelet growth factor can immediately induce the proliferation of
endothelium. (D.T. Connolly, 1989; K.H. Plate, 1992; D Shweiki Et Al, 1992; K.J. Kim Et Al, 1993; C Kremer, K.H.
Plate et al, 1997). Their secretion is dependent on hypoxia and inflammation (D Shweiki et al, 1992; W.M. Kavanaugh,
1988; M Marx, 1994). The receptors to the derived platelet growth factor are actively synthesized by endothelium in the
conditions of the excessive angiogenesis stimulation causing an active proliferation of endothelial cells (J.G. Beitz, 1991).
The neurogenic regulation of vascular tone is complex and is provided not only due to the direct synaptic control.
In the experiments with the use of rabbit basal artery the neuronal vasoconstrictor effect was shown to be caused both by
the adrenergic structures (D.F. Cechetto, V Hachinski, 1997) and by neuropeptide Y released in the sympathetic nervous
system (I Laher et al, 1994).
 33
Glutamate, being one of the main mediators in the central nervous system, exerts a stimulating influence on the
synthesis of nitric oxide, resulting in the dilation of vessels and the significant neuronal responses, including their death
(I.G. Akmayev, L.B. Kalimullina, 1995).
In recent years significant attention was given to the role of angiotensins in the brain. Angiotensin II modulates the
secretion of endotelin I, thus controlling the vascular tone status. The conversion of angiotensin II into angiotensin III in
the central nervous system was revealed. Angiotensin III causes the synthesis of angiotensin IV. Angiotensin III acts on
the receptor subtypes for angiotensin I and II, while angiotensin IV activates the receptor subtype for angiotensin IV.
These effects are exerted through the maintenance of the fluid balance, through the control of blood pressure and the in-
fluence on the vascular growth. The “angiotensin IV zones” were revealed in the neopallium, hyppocampus, cerebellum
and in the basal ganglia. The pathologic influence of angiotensins represents itself as the memory impairment, the elec-
trophysiological neuronal activation, the increase of the potentiation period, indicating the modulating influence of these
hormones (G.W. Wrigth, 1997). The chronic angiotensin II cerebral stimulation results in the increased capture of norepi-
nephrine, connected with the stimulation of the transcription of its transporter and of the tyrosine hydroxylase gene. Thus,
angiotensin II is also the modulator of the neuronal activity (D Lu, M.K. Raizada, Y Yang, 1998).
The diverse effects of platelet-activating factor were demonstrated in the central nervous system. Its production
was revealed in the endothelial cells, while in human fetuses in the microgliocytes as well, resulting in the paracrine and
autocrine effects (F Bussolino et al, 1995a, 1995b; A. Jaranowska, 1995). Its effects include the control of the endothelial
migration in vitro and of the proliferation in vivo. The effect of platelet-activating factor is accomplished through the he-
parin-dependent mechanisms (G Camussi, 1995). Other authors suggest that the platelet-activating factor in the physio-
logical concentrations stimulates the migration rather than the proliferation of endothelium, (G Camussi, 1995).
Thus, the above-mentioned data indicate the diverse influences of endotheliocytes, macroglia and microglia on the
neuronal status, on the mechanisms of the synaptic transmission of activation, of the responses modulation in the postsy-
naptic structures. Few studies of the microarchitectonics of neurogliovascular complexes are confined to the individual
nerve centers and do not embrace their whole spectrum. Thus far no objective criteria of their comparative analysis were
drawn out. At the same time the nerve centers under investigation have no detailed description of the specific features of
the structure of capillary loops, which complicates substantially the study of relationships between the neuroarchitecton-
ics, the glioarchitectonics and the angioarchitectonics.
The analysis of the organization of the extra-organ vascular bed showed that the arteries on the surface of the pon-
tis and of mesencephalon do not have a reticular structure and are not connected together by means of the anastomoses.
They embed into the cerebral parenchyma almost at the right angle. At the same time the veins form networks and abun-
dant anastomoses. In substance, the arterial and venous systems of the brain stem in mammals represent two isolated col-
lectors, according to B.N. Klosovsky opinion (1961). In the posterior and middle zones of the brain the arteries and the
veins are spatially demarcated and practically never go together. In the nuclear zones they form abundant micro-vascular
networks. In all the nuclei examined the general principle of organization is the continuity, which creates the initial im-
pression of the unity of trophic supply in all cerebral regions. These facts as a whole result in the impossibility of the iso-
lation of elementary arterial-venous units, revealed in many invertebrate and vertebrate animals (B.N. Klosovsky, 1961).
The arteries of the motor nucleus of trigeminal nerve can be subdivided into the main arteries, that emerge from the
nerve center and form within its boundaries several terminal branches; and small arteries, forming the terminal branches.
The first arteries are predominant. In contrast to the veins, the arteries arborize at an acute angle and form the branches
more scarcely. At each level the arteries produce 3 to 5 regional microbasins with the autonomous system of blood influx.
They inflow into 1 to 2 veins. The veins converge at the nearly right angle and are of larger diameter predominantly.
The capillary loops of the motor nucleus of trigeminal nerve surround the groups including one large or giant and
several small adjacent neurons, or they encompass the conglomeration including the bodies of 2 to 4 large nerve cells
(Fig. 18). The investigation of linear sections showed that the vessels are predominantly revealed in the zones of concen-
tration of nerve cells and rarely - in the regions with predominant nerve fibers. The capillary networks of neuropil are
large-meshed and possess the morphological specific features that are observed in the white substance of the brain. The
micro-vessels pass in parallel with the nerves. The arterioles and the venules diverge or converge at the nearly right angle,
in contrast of the regions of accumulation of the neuronal bodies, where the afferent vessels are characterized by the shar-
per angle of arborization. The travel direction of the micro-vessels of neuropil is nearly straight.
 34
Thus, in the neuropil the loops having the polygonal form, with a uniform spatial distribution are formed. The
fibrous astrocytes which arborize abundantly, participate in the formation of perivascular muffs along the course of one
vessel or of the adjacent vessels. The close interrelation of the adjacent trophic structures is noted (Fig. 19). The microcir-
culatory bed is considerably modified in the zones of accumulation of nerve cells, where it exhibits with the more close-
packed arrangement of vessels, their twisting and undulating course, the stereo-architectonic variability. The fine-meshed
capillary loops situated in close proximity to the large neurons form frequently the abundant network around them (vascu-
lar “baskets”). In this case the postcapillary and precapillary structures are included into the vascular network. This could
facilitate and equalize the exchange. The plasmatic capillaries are frequently encountered. Around one large neuron the
capillaries predominate, arising from 1 to 2 afferent and efferent vessels, while more complex co-interaction can be ob-
served as well (for example, 3 arterioles and 1 venule). One large neuron can possess several capillaries (3 to 5 in aver-
age, depending on the dimensions of the cellular body), in line with the data of E.G. Balashova (1956, a). The parallelism
between the direction of the initial segments of dendrites and of the capillaries is frequently observed. The point of inter-
est of astrocytes consists in their participation in the formation of the perivascular terminal structures within the bounda-
ries of 1 to 3 capillary loops, which form contacts within one vascular basin (arterioles or venules). The aggregates of the
closely anastomosing processes of astrocytic glia form the conglomerations, which ensure the intimate co-interactions
with the peripheral to them vascular loops. This particularity can contribute to the drainage functions of this type of glia.
The extent of the processes is limited by the only vascular basin, which allows assuming indirectly the close co-
interaction of micro-vessels and astrocytes in the process of their formation in the post-natal ontogenesis.
The relatively scarce vascular networks having the linear or arcade-like form of capillary loops are localized in the
zones of the regularly situated myelinic fibers (Fig. 20). These regions are characterized by the abundance of oligoden-
drocytes and of fibrous astrocytes. Their arborization is restrained within the adjacent capillary loops and their microba-
sins. The main portion of fibrous astrocytes and of oligodendrocytes possess the perivasal terminals around 2 to 3 micro-
vessels (precapillaries, capillaries and postcapillaries).
The parameters of blood supply of the giant and large neurons in human are considerably inferior in comparison
with the values in animals species of smaller sizes and are similar to the level of supply in dogs’ neurons (Table 12, 13).
At the same time, the level of trophic supply in the neurons of human and dogs cannot be considered as poor in compari-
son with this level in rabbits and in rats, because of the close value of the relative area of internal microvascular surface,
exhibiting the most effective exchange with the body of nerve cell. This characteristic is connected both with the increase
of the mean capillary diameter and with the diameter of nerve cell. The significant quantitative differences of the relative
microcirculatory parameters of the middle-size neurons between the rabbits, rats and human are observed (Table 14). This
characteristic can be due to the arrangement of the neurons of this population in the rodents under investigation. Among
them the groups containing 2 to 3 large and middle-size neurons, surrounded by the united vascular microbasins, are en-
countered much more commonly. It suggests the lower level of autonomy of vascular microbasins in the different popula-
tions of nerve cells. The vascularization extent of the small neurons is higher in rats and in rabbits, but the relative area of
effective exchange with the body of neuron is similar in all the groups investigated. The difference in the number of large
and small nerve cells bodies lying within the limits of the vascular trophic is leveled down by their sizes, resulting in rela-
tively similar parameters of microcirculatory bed, excluding the specific area of the exchange surface of a microvessel,
providing the most effective exchange with the body of neuron (Table 15). The last parameter changes in connection with
the variations in the value of the angle of effective diffusion between the giant, large and small neurons. The differences
are significant upon comparison of large and giant neurons with the cells having middle (P < 0.05) and small (P<0,001)
pericarya diameter.
The general parameters of trophic supply in the range of mammalians under investigation are defined by the signif-
icant increase of the specific length of vessels and of diameter of pericapillary ultrafiltration, associated with the decrease
of maximal and minimal diameters of the vascular microbasin in the range including the human, the dog, the rabbit and
the rat (Table 16). However the given indices are leveled down due to the decrease of microvessels diameter in the same
sequence.
 35
Table 12
Parameters of microcirculation around the giant neurons of the motor nucleus of trigeminal nerve (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 96256,1 ± 17798,7 89675,2 ± 7853,0** 63412,5 ± 5174,0** 82457,8 ± 8235,1**
Ns (Units) 4,11 ± 0,16 4,75 ± 0,19 4,47 ± 0,17 5,29 ±0,21**
Lvn (mm/mm3) 1096,1 ± 41, 4 1234,6 ± 41,9 1441,8 ± 47,6* 1608,8 ± 52,5**
Ssn (mm2/mm3) 18,07 ± 0, 64 20,39 ± 0,65 21,49 ± 1,23 * 22,25 ± 0,69**
Sasn (mm2/mm3) 4,98± 0,19 5,38 ± 0,19 1 5,54 ± 0,19 5,87 ± 0,18 *
Parameters are compared with the human values.

Table 13
Parameters of microcirculation around the large neurons of the motor nucleus of trigeminal nerve (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 21277,9 + 1416,0 29292,7 + 28089,7 + 1997,6 24565,3 + 1322,4
1888,7***
Ns (Units) 3,09 + 0,15 3,18 + 0,15 3,79 + 0,13* 4,02 + 0,12***
Lvn (mm/mm3) 1110,2 + 69,1 1289,5 + 65,9 1524,85 + 52,7* 1550,4 + 60,1***
Ssn (mm2/mm3) 17,43 + 1,14 21,29 + 1,09 22,90 + 0,78* 20,84 + 0,81
Sasn (mm2/mm3) 4,01 + 0,21 5,02 + 0,25 * 5,38 + 0,18* 4,79 + 0,19
Dpfn (μm) 259,3 + 6,19 217,4 + 13,6 187,21 + 6,30* 206,86 + 8,04*
Parameters are compared with the human values.

Table 14
Parameters of the microcirculation around the middle-size neurons of the motor nucleus of trigeminal nerve
(М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (micro m3) 7385,2 + 432,5 7297,9 + 405,1 5453,5 + 329,6* 6837,5 + 445,5
Ns (units) 2,20 + 0,12 2,18 + 0,15 2,45 + 0,11 2,83 + 0,11
Lvn (мм/мм3) 1019,4 + 69,7 1317,6 + 90,6 1622,2 + 67,0* 1752,1 + 67,7***
Ssn (мм2/мм3) 16,75 + 1,14 21,76 + 1,49 23,16 + 0,98* 23,54 + 0,91*
Sasn (мм2/мм3) 3,12 + 0,21 4,05 + 0,28 4,17 + 0,18 * 4,29 + 0,17***
Dpfn (micro m) 254,8 +13,8 245,4 + 22,6 148,4 + 11,1** 197,0 + 9,6*
Parameters are compared with the human values.

Table 15
Parameters of the microcirculation around the small-size neurons of the motor nucleus of trigeminal nerve
(М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (micro m3) 1699,6 + 101,5 1702,3 + 112,4 977,6 + 84,7*** 1212,3 + 112,3*
Ns (units) 1,05 + 0,08 1,35 + 0,10 1,44 + 0,09* 1,59 + 0,10*
Lvn (мм/мм3) 877,2 + 67,6 1125,4 + 83,4 1314,5 + 91,3** 1414,1 + 56,6***
Ssn (мм2/мм3) 14,46 + 1,12 17,10 + 1,27 19,36 + 1,34* 19,00 + 1,16***
Sasn (мм2/мм3) 2,08 + 0,16 2,46 + 0,18 2,32 + 0,16 2,47 + 0,15
Dpfn (micro m) 340,6 + 12,6 301,6 + 5,1* 251,0 + 19,4*** 256,1 + 12,8***
Parameters are compared with the human values.
 36

Table 16
Parameters of microcirculation in the motor nucleus of trigeminal nerve (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vvn (%) 12,44 ± 1,07 14,99 ± 1,16 18,34 ± 1.14** 22,14 ± 1,09***
Nnkp 1,23 ± 0,09 1,18 ± 0,06 1,27 ± 0,06 1,37 ± 0,07
Lv (mm/mm3) 441,8 ± 46,5 510,9 ± 23,8 609,4 ± 22,5* 595,2 ± 14,8
DK (μm) 5,25 ± 0,19 5,26 ± 0,16 4,47 ± 0,14* 4,28 ± 0,12
Ss (mm2/mm3) 7,29 ± 0,72 11,00 ± 0,38 8,97 ± 0,33 7,99 ± 0, 19
Lm (μm) 97,29 ± 3,88 76,12 ± 2,73* 69,39 ± 2,78** 64,55 ± 1,68
Dm (μm) 64,05 ± 1,92 51,98 ± 1,94*** 57,04 ± 1,85* 46,49 ± 1,12***
Dpf (μm) 444,2 ± 18,6 382,8 ± 12,0 288,2 ± 21,6 534,8 ± 14,8***
Dpfpn (μm) 55,08 ± 2,30 57,42 ± 1,80 93,37 ± 3,97*** 118,3 ± 3,26***
Vvk(%) 5,32 ± 0,36 6,45 ± 0,36 6,54 ± 0,62 5,10 ± 0,30
Parameters are compared with the human values.

Thus, the parameters of the volume velocity in the vessels and of the relative area of the exchange surface of the
microvessels in the nucleus are equalized.
More close arrangement of the neurons in rabbits and in rats converge the specific pericapillary ultrafiltration di-
ameter, pertaining to the neuronal bodies in the nucleus. At the same time, taking into account the physical and biological
regulations of substances distribution during their metabolism, in the smaller neurons of the rats the simplified processes
of exchange of such important substances as oxygen, carbonic acid and glucose, are suggested. The high concentration of
the vessels in rabbits and in rats is not an immediate proof of the better blood supply of this nucleus, but may compensate
the particularities of neuroarchitectonics and the intensive metabolism in the neurons. Microcirculatory bed in human and
in dogs is more distinctly subdivided into: a) vessels which supply the neuron bodies or b) vessels supplying the nerve
fibers. This is accompanied by the qualitative sophistication of the structure of neuroglio-vascular ensembles and by sig-
nificant quantitative differences of the parameters such as intensity of microcirculation around the neuron bodies and in
the nucleus as a whole. The comparative analysis of capillary networks surrounding the neuronal populations in the nuc-
leus of one animal species allowed revealing the general regulation, which is manifested in the regression of the number
of vessels within the perineuronal zone of the perikarya, compensated by the reduction of the area of this zone and by the
size reduction of the neurons. This leads to the adjustment of the basic parameters of the trophic supply, except the rela-
tive area of the surface of capillary defined by the most effective exchange with body neurons. This parameter reduces
proportional to the size decrease of neurons in all the animal species examined.
The angioarchitectonic ensembles in the mesencephalic nucleus of trigeminal nerve are formed according to the
close mutual dependence of the nuclear cytoarchitectonics. The arterioles which penetrate from the laterally-adjacent
white substance diverge into the capillary networks immediately near the large neurons or their accumulations (Fig. 21).
The arterial inflow proceeds autonomously. There are several arterioles, which form separate microbasins around one
large neuron or their group in one transverse section. The microvessels may radially converge to the places of neuronal
accumulations; the arteriole and the precapillaries arise from one terminal artery, going longitudinally with respect to the
nucleus, as was demonstrated during the stereo-architectonic reconstructions of the transverse sections (Fig. 22). Along
the cranio-caudal axe there are regions having the autonomous blood supply. The system of microcirculation around the
neuronal bodies is defined by the significant abundance, forming the small rounded loops, parallel to the surface of the
perikarya. The vessels agglomerations are the most significant around the large neurons in dogs (Table 17, 18). The re-
gion of the arborization of astrocytes is restricted by the nearest capillaries, the neuron bodies and their processes (Fig.
23). The capillaries form the loops, which are closely adjacent to the perikarya. The small-size and middle-size associa-
tive neurons appear in the immediate proximity to the main population or slightly removed. The neuropil zones are cha-
racterized by the coarse large-meshed network. The specific length of the vessels in the nuclei as in the unique anatomical
structures increases significantly from human to rats, but this tendency is accompanied by the notable increase of the ap-
parent density of the neuronal bodies, by the change of microvessel diameters, leading to the ambiguous changes of the
parameters of microcirculation.
In the mesencephalic nucleus of trigeminal nerve the number of vessels around neurons, the specific
 37
Table 17
Parameters of microcirculation around the giant neurons in the mesencephalic nucleus of trigeminal nerve
(М ± m)

Parameters Species investigated

Human Dog
Vn (μm3) 78823,3 ± 8030,1 74644,7 ± 6183,0
Ns (Units) 3,78 ± 0,17 3,26 ± 0,19
Lvn (mm/mm3) 1220,0 ± 58,3 1774,6 ± 107,4***
Ssn (mm2/mm3) 16,31 ± 0,82 30,42 ± 1,69***
Sasn (mm2/mm3) 4,23 ± 0,21 6,43 ± 0,47***
Dpfn (μm) 269,0 ± 13,8 154,6 ± 4,51***
Parameters are compared with the human values.

Table 18
Parameters of microcirculation around the large neurons in the mesencephalic nucleus of trigeminal nerve
(М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 38439,9 + 2306,6 34968,8 + 1896,1 28823,8 + 2202,8* 32583,1 + 1739,7
Ns (Units) 3,19 + 0,19 3,27 + 0,11 3,28 + 0,13 4,22 + 0,11*
Lvn (mm/mm3) 1210,1 + 80,5 1670,6 + 73,3*** 1299,8 + 35,5 1698,2 + 46,2***
Ssn (mm2/mm3) 16,14 + 1,10 34,44 + 1,22*** 17,87 + 0,51 21,33 + 0,58**
Sasn (mm2/mm3) 4,02 + 0,26 6,67 + 0,29*** 4,19 + 0,12 5,02 + 0,13*
Dpfn (μm) 286,6 + 19,8 134,3 + 2,8*** 227,8 + 8,1* 201,7 + 6,36**
Parameters are compared with the human values.

area of exchange surface, the diameter of pericapillary filtration in the perineuronal zone around the neuronal bodies are
substantially higher in dogs and in rats (P < 0.01). The similar patterns of the blood supply were shown by other authors
during the comparison of interspecies characteristics (B.N. Klosovskiy, E.N. Kostomarskaya, 1961). The data of B.N.
Klosovskiy, E.N. Kostomarskaya (1961) are derived from the calculation of the profile field of cells to the length of mi-
crovessels within 25 μm from the boundaries of the large neurons. These data can be easily converted into the relative
values, with the use of our formulas. It follows from theses results that the intensity of the blood supply of the bodies of
large neurons in human is equal to 1000-1100 mm/mm3, in dogs - 1800-2000 mm/mm3, in rabbit - 1100-1200 mm/mm3,
in rats - 1700-2100 mm/mm3. These data are quite comparable with our results, taking into account the differences in the
procedures employed. In rat the high values are less meaningful, when the specific surface area of the microvessels is ex-
amined, exchanging the most effectively with the bodies of neurons. At the same time, in all the animal species the ten-
dency toward the decrease of this parameter from the giant and large neurons to the small neurons is clearly observed
(probability of the error of difference in the arithmetic means between the groups from P < 0.05 to P < 0.001).
Thus, the tendency toward the individual supply of the perikarya of individual neurons, that was revealed during
our investigations of the motor nucleus of trigeminal nerve, appears more obvious in the mesencephalic nucleus of this
nerve (especially in human and in dogs). The neuron bodies’ vascularization in dogs is characterized by the high intensity,
probably due to the species characteristics of larger functional load (Table 19, Table 20, Table 21). The perikarya of neu-
rons in the mesencephalic nucleus of trigeminal nerve are characterized by the significant amount of “satellite” gliocytes
(both oligodendrocytes and astrocytes). This is the most obvious in the studies of glioarchitectonics in human and in dogs.
In rabbits and in rats the compact agglomerations of the neurons are frequently encountered, while in human and in dogs
they are isolated or situated by the small groups including 2 to 3 cells. In all species the vascular plexuses cover thickly
the neuropil, adjacent to the neuronal bodies. They acquire a complex configuration, while the capillary networks have a
fine-meshed structure.
The vascular network in the main sensitive nucleus of trigeminal nerve is formed due to the main arteries, which
release the terminal branches into the nuclear structure. On each section several arteries of this type pass through the nuc-
leus. The veins are formed according to the diffuse type
 38
and converge into the larger vascular collectors beyond the limits of its anatomical boundaries (Fig. 24). The capillary
networks are not uniform and constitute the fine-meshed plexuses in the zones of the neuron bodies’ concentration. Each
capillary loop encompasses the groups consisting of 2 to 6 neuronal bodies. The wide, polygonal loops are encountered
near the boundaries of nucleus, especially in the zones of accumulation of myelinic nerve fibers. The concentration of the
microvessels near the neuronal bodies is observed (Figures 25, 26). This leads to the alternation of the regions having the
high and low density of vessels. The microvascular basins around the neurons consist of the terminal branches of one ar-
teriole and one venule, but sometimes the adjacent precapillary formations can be involved.
In human the large neurons which have slightly more vessels around the perikarya, nevertheless, are inferior to the
smaller neurons by the other parameters of the trophic supply (Table 22, Table 23, Table 24), but the value of specific
surface area of the effective exchange of microvessel with the body of neuron is equal.
Among the range of species investigated the highest parameters were revealed in dogs and in rats.

Table 19
Parameters of microcirculation around the middle-size neurons in the mesencephalic nucleus of trigeminal nerve
(М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 9304,2 ± 691,6 6468,0 ± 632,8 6339,8 ± 588,5 6451,8 ± 543,8
Ns (Units) 2,06 ± 0,18 1,97 ± 0,45 2,51 ± 0,11 2,82 ± 0,12***
Lvn (mm/mm3) 1157,8 ± 89,6 1238,6 ± 92,3 1471,6 ± 55,6* 1807,1 ± 82,1***
Ssn (mm2/mm3) 15,92 ± 1,23 20,61 ± 1,53 20,24 ± 0,77* 23,64 ± 1,06***
Sasn (mm2/mm3) 3,11 ± 0,19 3,71 ± 0,23 3,64 ± 0,14 4,09 ± 0,18*
Dpfn (μm) 303,0 ± 24,6 232,3 ± 19,1 202,8 ± 10,3* 211,6 ± 15,7*
Parameters are compared with the human values.

Table 20
Parameters of microcirculation around the small-size neurons in the mesencephalic nucleus of trigeminal nerve
(М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 1740,4 ± 125,2 1392,5 ± 116,1 1143,8 ± 80,1* 754,1 ± 99,4***
Ns (Units) 1,33 ± 0,14 1,32 ± 0,11 1,41 ± 0,11 1,63 ± 0,14
Lvn (mm/mm3) 1102,8 ± 117,7 1187,8 ± 96,2 1252,6 ± 92,7 1581,3 ± 166,0***
Ssn (mm2/mm3) 15,17 ± 1,08 13,93 ± 1,60 17,23 ± 1,22 19,81 ± 1,72
Sasn (mm2/mm3) 2,24 ± 0,23 1,95 ± 0,23 2,23 ± 0,17 2,18 ± 0,19
Dpfn (μm) 325,2 ± 34,5 262,1 ± 23,4 306,1 ± 23,7 250,1 ± 17,8
Parameters are compared with the human values.

Table 21
Parameters of microcirculation in the mesencephalic nucleus of trigeminal nerve (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vvn (%) 9,42 ± 0,54 10,21 ± 0,58 14,48 ± 0,52*** 18,84 ± 0,88***
Nnkp 1,26 ± 0,09 1,36 ± 0,07 1,76 ± 0,08* 1,70 ± 0,09*
Lv (mm/mm3) 307,4 ± 10,9 473,7 ± 15,4*** 649,8 ± 21,4*** 551,3 ± 14,0***
DK (μm) 5,32 ± 0,13 5,31 ± 0,17 5,10 ± 0,19 4,00 ± 0,11***
Ss (mm2/mm3) 5,97 ± 0,18 7,89 ± 0,26*** 10,40 ± 0,34*** 6,97 ± 0,27
Lm (μm) 89,75 ± 2,80 67,73 ± 1,50*** 64,47 ± 1,89*** 54,40 ± 1,20***
Dm (μm) 61,27 ± 2,39 51,67 ± 1,34*** 43,98 ± 1,32*** 42,30 ± 1.07***
Dpf (μm) 731,6 ± 30,8 534,1 ± 17,6*** 408,7 ± 16,3*** 628,9 ± 22,1
Dpfpn (μm) 38,92 ± 2,91 54,49 ± 1,77 59,24 * 2,32 118,12 ± 4,14***
Vvk(%) 4,07 ± 0,39 5,43 ± 0,34 4,73 ± 0,27 3,49 ± 0,24
Parameters are compared with the human values.
 39
Table 22
Parameters of microcirculation around the large neurons of the main sensitive nucleus of trigeminal nerve
(М ± m)

Parameters Species investigated

Human Dog Rabbit
Vn (micro м3) 21907,4 ± 1882,3 11674,7 ± 1337,3*** 11448,0 ± 1660,6***
Ns (Units) 3,07 ± 0,13 2,62 ± 0,19 2,61 ± 0,24
Lvn (mm/mm3) 1197,7 ± 52,3 1325,4 ± 99,0 1299,1 ± 122,3
Ssn (mm2/mm3) 17,36 ± 0,87 23,72 ± 1,73* 19,67 ± 0,85
Sasn (mm2/mm3) 3,77 ± 0,14 4,98 ± 0,46* 4,33 ± 0,19
Dpfn (μm) 386,0 ± 28,7 195,1 ± 20,3* 242,2 ± 28,3*
Parameters are compared with the human values.

Table 23
Parameters of microcirculation around the middle-size neurons of the main sensitive nucleus of trigeminal nerve
(М+m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (micro m3) 5424,0 ± 352,5 11842,4 ± 1227,4* 5489,2 ± 429,6 3932,9 ± 350,1*
Ns (Units) 1,91 ± 0,11 2,27 ± 0,09 1,96 ± 0,12 2,47 ± 0,13*
Lvn (mm/mm3) 1159,7 ± 76,4 1315,7 ± 79,9 1277,4 ± 71,3 1712,5 ± 95,1***
Ssn (mm2/mm3) 16,91 ± 1,27 23,55 ± 1,41* 19,34 ± 1,16 21,29 ± 1,19
Sasn (mm2/mm3) 3,14 ± 0,23 4,47 ± 0,27*** 3,50 ± 0,21 3,74 ± 0,21
Dpfn (μm) 376,5 ± 10,6 204,8 ± 13,6*** 249,8 ± 14,1*** 243,7 ± 8,94***
Parameters are compared with the human values.

Table 24
Parameters of microcirculation around the middle-size neurons of the main sensitive nucleus of trigeminal nerve
(М+m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (micro m3) 1422,6 ± 125,0 1412,9 ± 115,2 890,2 ± 82,3* 727,6 ± 59,8***
Ns (Units) 1,26 ± 0,11 1,43 ± 0,08 1,25 ± 0,07 1,74 ± 0,11*
Lvn (mm/mm3) 1073,6 ± 89,7 1223,9 ± 70,3 1161,7 ± 69,5 1607,1 ± 102,4***
Ssn (mm2/mm3) 15,66 ± 1,48 21,910± 1,26*** 17,66 ± 1,06 19,99 ± 1,27
Sasn (mm2/mm3) 2,12 ± 0,13 3,44 ± 0,18*** 2,13 ± 0,12 2,22 ± 0,15
Dpfn (μm) 385,7 ± 10,8 216,0 ± 13,0*** 291,7 ± 16,6* 275,7 ± 20,2***
Parameters are compared with the human values.

While in rats the significant intensification of the local blood flow is provided by the increase of the specific
length, and, therefore, of the number of vessels, in dogs the significant diameter of the vessel lumina is observed. At the
same time in dogs the area of the vessel exchange surface per volume unit grows in comparison with human considerably
more significantly (P < 0.05) than in rats (P > 0.05).
When compared with human (Fig. 27, 28), the parameters of microcirculation in the main sensitive nucleus of tri-
geminal nerve in dogs are substantially higher (the probability of error of the arithmetic mean differences by all the crite-
ria listed above comprises less than 0.05). In rats (and in rabbit to a lesser degree), in comparison with human, the specific
length of vessels is higher, while the diameter of pericapillary filtration is lower (Table 25). It does not affect the impor-
tant parameters, such as the specific total area of the capillary surface and the most effectively exchanging with neuronal
bodies area of the capillary surface. The specific vessels length, the diameter and higher in comparison with human, while
the capillary diameter is smaller and neuronal bodies are distributed more densely. This ensures the close parameters of
the volume of microvessels and of the specific area of the pericapillary ultrafiltration for the neuron bodies in the nucleus
in all the mammalian species examined.
 40
Table 25
Parameters of the trophic supply in the main sensitive nucleus of trigeminal nerve (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vvn (%) 8,94 ± 0,48 9,17 ± 0,47 10,67 ± 0,53* 10,51 ± 0,39*
Nnkp 3,36 ± 0,26 3,78 ± 0,19 4,58± 0,21* 5,12 ± 0,36***
Lv (mm/mm3) 396,7 ± 11,7 384,6 ± 8,5 491,1 ± 17,9*** 685,7 ± 19,5***
DK (μm) 5,26 ± 0,18 5,67 ± 0,17 4,85 ± 0,16 3,96 ± 0,13***
SS (mm 2/mm 3) 6,51 ± 0,18 6,88 ± 0,15 7,47 ± 0,26* 8,53 ± 0,20***
Lm (μm) 88,21 ± 5,21 73,61 ± 5,39* 78,68 ± 2,95 77,70 ± 2,12
Dm (μm) 58,36 ± 2,40 66,39 ± 2,95 56,16 ± 2,05 46,83 ± 1,75***
Dpf (μm) 676,7 ± 22,1 596,2 ± 14,1* 528,3 ± 24,8* 503,9 ± 15,8***
Dpfpn (μm) 60,22 ± 1,96 54,86 ±1,31 56,54 ± 2,66 52,90 ± 1,66*
Vvk(%) 5,19 ± 0,41 4,56 ± 0,30 4,43 ± 0,19 4,72 ± 0,22
Parameters are compared with the human values.

At each cross-section level 2 to 3 small arteries penetrate into the structure of the locus coeruleus and 1 to 2 veins
walk out. The arterial influx is exercised by means of several small terminal branches of the vessels which converge ra-
dially. They penetrate into the nucleus from the lateral, ventral, and ventromedial sides. Like the previous nuclei, the indi-
vidual zones of arterial influx are formed. The main veins lie between the mesencephalic nucleus of trigeminal nerve and
the locus coeruleus, and they leave from the brain in the dorsal direction. Their branches serve as collectors for the capil-
laries both of the mesencephalic nucleus of trigeminal nerve and of the locus coeruleus. The main type of venous draining
appears the most distinctly in rats.
Both in the caudal and cranial portions of the locus coeruleus the capillary loops embrace from 2-3 to 8-10 peri-
karya of neurons. Some neurons can closely adjoin to one another (2 to 3 perikarya). The capillary loops can have both
the fine-meshed and large-meshed pattern. Some of them are elongated in the medio-lateral direction (Fig. 29). The shape
of loops depends on the concentration of neurons and of the nuclear region. Several neurons lie within the limits of each
microvascular basin, which is especially obvious in the regions of their compact arrangement. The system of microcircu-
lation includes several afferent and 1 to 2 efferent vessels at each cross-section. The variety of the angioarchitectonics of
microcirculation system depending on the zone of nucleus and differences in the morphology of neuroglial ensembles is
observed (Fig. 30). In the kaudo-ventral regions with the compact arrangement of the neuronal bodies the abundance of
fine-meshed networks is observed. The adjacent capillary branches diverge from one afferent structure and converge to
the only efferent terminal structure, rarely the more complex structure can be observed, represented as the adjacent capil-
lary loops, which arise from several arterioles and converge into one postcapillary structure.
The microcirculation of the separate neurons of the locus coeruleus is higher in rats and in rabbits on a number of
parameters (the vessels number per one neuron, their specific length and pericapillary ultrafiltration diameter) (Table 26,
Table 27, Table 28). In rats and in rabbits the considerably smaller neuron sizes and distances between the neuronal bo-
dies are accompanied by the decrease of the microvascular basins diameter. The parameter such as the specific area of the
exchange surface of capillary, in human differs to a lesser degree, while the volume vessel density is even lower, due to
the larger diameter of microvessels. The parameters of pericapillary ultrafiltration areas of the neuron bodies in rats and in
human are virtually equal, on account of the close arrangement of the neurons in the nuclear structure in this rodent spe-
cies. The number of contacts of the astrocyte processes with the pericapillary zones of the vessels is lower in dogs and in
rabbits in comparison with human and rats (Table 29), probably due to some differences in the shape and sizes of the mi-
crovascular basins. The number of contacts is commonly confined to 1 to 4 microvessels.
The arteries converge radially towards the sylvian aqueduct and diverge forming the terminal capillary networks in
the central gray substance of mesencephalon. In the ventral region, especially in rats, this network is fine-meshed and is
characterized by the high concentration of capillaries per volume unit, whereas the dorsal portions are defined by a com-
paratively scarce, uniformly distributed pattern of capillary arborization.
 41
Table 26
Parameters of microcirculation around the large neurons of the locus coeruleus (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 21353,4 ± 1045,1 18294,2 ± 108,2 12435,6 ± 932,2*** 12723,2 ± 2072,0***
Ns (Units) 2,29 ± 0,18 2,14 ± 0,17 2,93 ± 0,21 3,75 ± 0,28***
Lvn (mm/mm3) 1082,0 ± 87,4 1163,6 ± 76,6 1440,3 ± 91,1* 1873,7 ± 114,0***
Ssn (mm2/mm3) 18,73 ± 1,39 19,11 ± 1,17 19,81 ± 1,26 24,36 ± 1,81
Sasn (mm2/mm3) 4,27 ± 0,32 4,24 ± 0,25 4,16 ± 0,26 5,11 ± 0,38
Dpfn (μm) 296,3 ± 15,4 268,5 ± 12,9 231,1 ± 10,3** 181,3 ± 15,1***
Parameters are compared with the human values.

Table 27
Parameters of microcirculation around the middle-size neurons of the locus coeruleus (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 8519,3 ± 428,3 6936,6 ± 423,1 6440,1 ± 461,4* 4082,4 ± 290,3***
Ns (Units) 2,18 ± 0,09 1,87 ± 0,11 2,26 ± 0,11 2,62 ± 0.12*
Lvn (mm/mm3) 1234,6 ± 74,6 1150,7 ± 69,3 1397,6 ± 59,3 1818,0 ± 75,8***
Ssn (mm2/mm3) 20,97 ± 1,19 17,48 ± 1,05 19,22 ± 0,81 23,63 ± 0,98
Sasn (mm2/mm3) 3,50 ± 0,23 3,18 ± 0,19 3,46 ± 0,15 4,11 ± 0,18
Dpfn (μm) 327,2 ± 12,6 285,9± 22,3 234,7 ± 13,9** 201,3 ± 11,2***
Parameters are compared with the human values.

Table 28
Parameters of microcirculation around the small-size neurons of the locus coeruleus (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 1620,3 ± 149,7 1702,3 ± 112,4 839,9 ± 91,7*** 852,0 ± 69,4***
Ns (Units) 1,19 ± 0,12 1,35 ± 0,10 1,41 ± 0,10 1,41 ± 0,09
Lvn (mm/mm3) 1017,9± 126,3 1125,3 ± 83,4 1324,0 ± 90,4 1390,9 ± 84,0***
Ssn (mm2/mm3) 19,21 ± 2,02 17,10 ± 1,27 18,21 ± 1,24 18,08 ± 1,09
Sasn (mm2/mm3) 2,54 ± 0,24 2,99 ± 0,18 2,22 ± 0,15 2,16 ± 0,13
Dpfn (μm) 339,4 ± 27,3 301,7 ± 21,5 272,4 ± 18,5 288,3 ± 18,5
Parameters are compared with the human values.

Table 29
Parameters of microcirculation in the locus coeruleus (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vvn (%) 11,27 ± 0,54 13,14 ± 0,63 14,27 ± 0,74* 14,81 ± 0,82***
Nnkp 3,34 ± 0,27 4,18 ± 0,19 4,42 ± 0,24* 4,54 ± 0,23**
Lv (mm/mm3) 388,9 ± 13,5 517,2 ± 11,5 495,8 ± 24,2* 587,3 ± 16,7***
Dk (μm) 5,09 ± 0,16 4,54 ± 0,12 4,31 ± 0,19* 4,14 ± 0,14**
Ss (mm2/mm3) 6,23 ± 0,21 7,16 ± 0,17* 7,24 ± 0,25* 7,13 ± 0,21*
Lk (μm) 93,59 ± 4,24 78,19 ± 2,84* 73,21 ± 1,93** 62,16 ± 2,77***
Dk (μm) 61,8 ± 2,06 41,81 ± 2,84*** 55,10 ± 1,86* 42,30 ± 1,59***
Dpf (μm) 717,3 ± 25,8 522,2 ± 12,5*** 623,4 ± 27,9 577,8 ± 28,1***
Dpfpn (μm) 131,1 ± 15,6 93,64 ± 5,77 98,73 ± 7,05 104,01 ± 5,04
Vvk(%) 6,11 ± 0,39 5,67 ± 0,28 4,25 ± 0,23*** 3,88 ± 0,40***
Parameters are compared with the human values.
 42

In the central gray substance of mesencephalon the microcirculatory bed in human consists of the rounded or elon-
gated loops, which furnish the relatively autonomous blood supply of the particular areas. The adjacent capillary arcs
form the microbasins, composed of some precapillaries and one postcapillary. Sometimes the anastomoses between 2 ad-
jacent arteriolar structures may be observed, which represent the system of the integrated influx in the segmental trophic
loci (microbasins). The capillary network predominantly middle-meshed. Each capillary encompasses several neurons.
The angioarchitectonics of the central gray substance is characterized by the complex system of vascular interlacings, as-
sociated with the formation of the open-circuit capillary groups, constituting the repetitive sections, which contain the
conglomerations of neurons and astrocytes. The astrocytes join them together into the unified structure, while co-
interacting with several adjacent components of microcirculation system, with the bodies as well as the adjacent processes
and terminals of the neurons.
The arteries are the final branches of the vessels, penetrating from the cerebral surface structures. They represent
the relatively autonomous structures, that are seen both in studies of the transverse sections and on the vertical reconstruc-
tions. The structure of microcirculatory bed can slightly differ in different nuclear zones, in correlation with the arteriolar
microbasins. The more compact agglomerations of the neurons in the ventrolateral and ventromedial nuclear structures
are accompanied with the abundant vascular round networks. The capillary networks in the lateral zones are sparser. In
the areas of the condensation of the capillaries the complex system of the blood supply of certain nuclear zones may be
observed. Together with the autonomous system of influx and draining within the limits of adjacent capillary loops the
various co-interactions at the level of larger vascular basins can have place. One terminal artery is capable to form the
adjoining microbasins with two to three small veins, while the venules collect the blood from several arterioles. The gen-
eral principles of organization of the microcirculatory bed are similar in all the species investigated. The substantial dif-
ferences concern the dimensions of the microvascular basins, particularly in rats in comparison with human. This is ac-
companied by an increase of specific length of the vessels in the sequence from human to rats and by the decrease of the
diameter of pericapillary ultrafiltration.
In all the mammalian species investigated the externally uniform pattern of the blood supply of adjacent areas of
the central gray substance of mesencephalon is characteristic, which does not correlate to the arrangement of the neurons
(Fig. 31). In fact, the vessels do not form the conglomerations in immediate proximity to the neuron bodies either in the
motor or in the mesencephalic nuclei of trigeminal nerve. However the arrangement of neurons in the areas of microvas-
cular conjunctions, their proximity to certain capillaries and their groups, provide the privileged conditions for the micro-
circulation for the neuronal bodies, in comparison with the neuropil and the nucleus as a whole. In human considerably
less neurons are present within the boundaries of one microvascular basin, in comparison with other species (P < 0.05)
(Table 30, Table 31, Table 32, Table 33). The maximal number of neurons within the microvascular basin appears in rats
(P < 0.01). The decrease of the extension of astrocyte processes and of microbasins dimensions provides the maintenance
of the high value of the number of contacts with microvessels in the sequence from human to rats. While forming con-
glomerations, the astrocytes merge via their processes into the unified chain between the adjacent capillaries, the bodies
and the processes of neurons. All this allow suggesting the integration of the trophic supply within the neuroglio-vascular
ensembles examined.
The conditions of the vascularization of the perineuronal area of the perikarya are more proximal in human and in
dogs, while differing considerably from the values in rabbits and in rats. Among all the neuronal populations these differ-
ences are the most evident in the case of the parameters of the specific microvessel lengths and of the area of their ex-
change surface - pericapillary ultrafiltration diameter. Nevertheless, the area of the most effective exchange of capillary
with the neuronal body within the allied cell populations appears as the value sufficiently stable (P > 0.05 for most para-
meters) and is related with the interspecies characteristics, as well as with the differences in neuron sizes. There is a
marked tendency toward the decrease of this parameter from the large and middle-size neurons to the small neurons (P <
0.05 for all the animal species investigated). The higher capillary density around the neuron bodies in rats and in rabbits,
in comparison with human and dogs is probably equalized on account of the capillary diameters.
Thus, the quantitative data concerning the vascularization of the central gray substance of mesencephalon are cha-
racterized by the significant interspecies variability. The data could indicate the privileged conditions of the trophic
supply in small animals (rabbit, rat). However, taking into account the compact
 43
Table 30
Parameters of microcirculation around the large neurons of the central gray substance (М ± m)

Parameters Species investigated

Human Dog Rabbit
Vn (μm3) 18099,4 ± 1557,6 17215,8 1768,4* 9945,0 ± 807,9***
Ns (Units) 2,32 ± 0,18 2,71 ± 0,14 3,04 ± 0,19***
Lvn (mm/mm3) 1154,9 ± 90,4 1297,7 ± 54,0 1596,3 ± 85,5*
Ssn (mm2/mm3) 18,74 ± 1,85 20,26 ± 0,90 23,62 ± 1,03*
Sasn (mm2/mm3) 4,22 ± 0,31 4,57 ± 0,20 4,95 ± 0,21
Dpfn (μm) 257,6 ± 24,6 199,8 ± 9,1 193,8 ± 13,4
Parameters are compared with the human values.

Table 31
Parameters of microcirculation around the middle-size neurons of the central gray substance (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 5799,9 ± 286,2 5669,7 ± 330,9 5340,8 ± 255,0 4475,8 ± 368,1*
Ns (Units) 2,10 ± 0,14 2,26 ± 0,11 2,19 ± 0,11 2,52 ± 0,13
Lvn (mm/mm3) 1331,7 ± 91,7 1460,5 ± 72,4 1412,4 ± 70,1 1736,7 ± 95,3***
Ssn (mm2/mm3) 19,91 ± 1,37 22,93 ± 1,38 21,56 ± 1,06 23,23 ± 1,57
Sasn (mm2/mm3) 3,59 ± 0,24 4,12 ± 0,25 3,88 ± 0,19 4,13 ± 0,22
Dpfn (μm) 290,2 ± 23,4 208,8 ± 13,8* 222,2 ± 4,2* 206,4 ± 14,1***
Parameters are compared with the human values.

Table 32
Parameters of microcirculation around the small-size neurons of the central gray substance (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vn (μm3) 978,3 ± 60,8 1037,5 ± 79,5 1074,2 ± 96,1 1000,8 ± 99,9
Ns (Units) 1,18 ± 0,08 1,29 ± 0,09 1,48 ± 0,09 1,88 ± 0,12***
Lvn (mm/mm3) 1108,3 ± 10,5 1101,9 ± 11,8 1328,6 ± 81,5* 1750,3 ± 113,9***
Ssn (mm2/mm3) 15,90 ± 1,41 22,21 ± 1,33*** 20,27 ± 1,24 23,41 ± 1,52***
Sasn (mm2/mm3) 2,07 ± 0,18 2,89 ± 0,17* 2,63 ± 0,16 2,81 ± 0,18***
Dpfn (μm) 321,7 ± 20,1 226,6 ± 14,8* 240,8 ± 13,7* 215,3 ± 12,7***
Parameters are compared with the human values.

Table 33
Parameters of the trophic supply of the central gray substance (М ± m)

Parameters Species investigated

Human Dog Rabbit Rat
Vvn (%) 8,27 ± 0,93 9,54 ± 1,11 13,14 ± 1,09* 13,61 ± 1,08*
Nnkp 3,37 ± 0,21 4,37 ± 0,15* 4,71 ± 0,11** 6,27 ± 0,33***
Lv (mm/mm3) 374,8 ± 13,6 427,3 ± 13,1 462,5 ± 22,1* 660,3 ± 19,1***
Dk (μm) 5,76 ± 0,17 5,29 ± 0,16 4,86 ± 0,15* 4,25 ± 0,14***
Ss (mm2/mm3) 5,53 ± 0,21 7,11 ± 0,22* 7,06 ± 0,33* 7,34 ± 0,26***
Lk (μm) 93,22 ± 2,30 90,05 ± 3,74 79,39 ± 2,78** 70,27 ± 2,29***
Dk (μm) 56,18 ± 1,20 56,51 ± 1,46 57,04 ± 1,85 43,52 ± 1,5***
Dpf (μm) 795,3 ± 39,6 591,3 ± 19,8** 639,0 ± 32,4* 604,6 ± 27,8**
Dpfpn (μm) 65,76 ± 3,24 56,47 ± 1,88 83,09 ± 4,16* 82,22 ± 3,79***
Vvk(%) 3,57 ± 0,22 4,56 ± 0,30 4,53 ± 0,31 3,76 ± 0,28
Parameters are compared with the human values.
 44

arrangement of the neuron bodies, the value of the relative area of pericapillary ultrafiltration, which falls on the neuron
bodies in human and in rats, is equalized. The significant concentration of the vessels in smaller animals can result from
the higher rate of metabolic processes in the tissues as well as by more close arrangement of the neuron bodies which ac-
tively participate in the metabolic exchange and by the smaller vessel diameters. The last parameter equalizes the volume
density of the vessels and the relative area of the exchange surface of microvessels in the nuclei of all the species investi-
gated.
The data obtained suggest that the micro-architectonics is characterized both by the specific features in each of the
nuclei investigated and by the essential common features. The similarity consists in the following. The arterial influx in
the structures of the pontis and of mesencephalon under investigation is performed by regions and by several “levels”.
The basins provide the separate blood supply of the morphologically differed nuclear zones. At the same time the unified
basins in the regions of different nuclei which are anatomically closely associated, can be observed (mesencephalic nuc-
leus of trigeminal nerve - locus coeruleus - central gray substance of mesencephalon).
The system of microcirculatory bed is variable and mutually depends on the structural-functional particularities of
the neuronal-tissular ensembles. The fine-meshed capillary networks are characteristic for the mesencephalic nucleus of
trigeminal nerve in the locus of concentration of the large neurons, for the locus coeruleus and for the area of the compact
distribution of the neuron bodies in the central gray substance of mesencephalon. The large-meshed networks are revealed
in the areas of predominance of the processes and of the nervous terminals in the central gray substance of mesencepha-
lon, in the motor nucleus of trigeminal nerve, where they are frequently elongated along the predominant direction of the
nerve fibers.
The system of microcirculation has also the specific features concerning the organization of the large-cell and
small-cell nuclei. The vascular loops in the small-cell nuclei surround the conglomerations consisting of several adjacent
neuronal bodies, similar in their micro-anatomical structure, whereas large-cell nuclei are characterized by the regionali-
zation of the blood flow, which allows supplying autonomously the basic neuronal populations. This is most expressed in
the mesencephalic nucleus of trigeminal nerve. The anatomical position of the nucleus plays a morphogenetic role in the
angioarchitectonics. While in the central gray substance of mesencephalon and in the locus coeruleus the influx is per-
formed due to the terminal arterial arborization, the motor and the main sensitive nuclei of trigeminal nerve are supplied
from the main vessels. The neurovasal relations are characterized by the high degree of variability both in terms of the
functional and morphological spatial characteristics. This peculiarity can suggest the significant individual variability of
the system of microcirculation and the capability for the rapid rearrangement of the system under the conditions of chang-
ing functional and morphological characteristics of the nerve tissue (V.I. Butinova, 1981; V.A. Pastukhov, 1993). In par-
ticular, the high degree of reactivity was revealed not only in the microcirculatory bed, but also in the perivascular astro-
cytes in case of the development of atherosclerotic dementia (E.N. Popov, O.V. Zagrebina, 1998).
The relative areas of the exchange surface of capillary and of the capillary most effective exchange surface with
the neuronal bodies are the stable parameters for neurons having the similar dimensions. This is due both to the increase
of vessel diameters and to the increase of neuronal bodies sizes. The last parameter is very dynamic, according to the
comparative analysis of the blood supply in the large-cell, middle-size and small-cell populations within one species,
where the unique tendency toward the reduction of this supply along with the perikarya sizes decrease, was revealed.
We suggest the comparative examination of the neuro-glio-vascular complexes is most reasonable in human. In the
investigation carried out the nuclei were examined in such a way that would allow encompassing the maximal amount of
the possible variations. The phylogenetically identical origin and the close anatomic-functional co-interaction were taken
into account. The selection of nuclei was also determined by the neuroarchtectonic and myeloarchitectonic characteristics.
The organ particularities of the neuron ensembles in the centers investigated are considerably interconnected with
the qualitative and quantitative parameters of macroglia. The study of the morphological characteristics of the processes
structure (thickness, length, density of arborization), revealed the high degree of variability depending on the neuroarchi-
tectonics. The maximal length of processes and the value of their dispersion, the variety of arborization, the presence of
the transitional forms between the fibrous and protoplasmic astrocytes are revealed in the motor and main sensitive nuclei
of trigeminal nerve. They are characterized by the nested arrangement of the neurons. This value is minimal in the me-
sencephalic nucleus, due to the high proportion of the satellite cells, which surround
 45
one nerve cell. The mesencephalic nucleus of trigeminal nerve is characterized by the significant number of astrocytes
and oligodendrocytes with the preponderance of processes in one of planes (the processes are spread on the surface of the
neuron). Among the nuclei investigated in this one precisely the oligodendrocytes are encountered with the greatest fre-
quency. These cells are most generally represented in the nuclei with the developed system of neuropil. These nuclei in-
clude, as was mentioned above, the mesencephalic nucleus of trigeminal nerve, as well as the areas with a sparse distribu-
tion of the neurons in the motor and main sensitive nuclei of trigeminal nerve. The length of processes and the peculiari-
ties of the structure of macroglia are the most similar in the central gray substance of mesencephalon and in the zones
with a less compact neuron distribution of in the locus coeruleus.
Large-cell and giant-cell nuclei are characterized by a high level of autonomy of the macroglial environment. This
appears as the co-interaction of the astrocytes with one neuron predominantly. This parameter corresponds to the inde-
pendence of their vascularization. The large dimensions of the neurons are accompanied with a higher content of the sa-
tellite gliocytes in comparison with the middle-cell and small-cell nuclei.
The pattern of the distribution of microglia is generally diffuse; with the use of methods available we did not ob-
serve any explicit consistent patterns in its arrangement.
The number of vessels, in whose perivascular area one astrocyte forms its terminalities, is similar in all the nerve
centers, except the mesencephalic nucleus of trigeminal nerve. Their number varies from 2 to 3 on the average, which
allow assuming the significant participation of astrocytes in the processes of active transport and in the probable “pump”
mechanisms of their regulation.
The shape, the sizes and the components of the microvascular basins are variable and mutually depend on the con-
centration, dimensions and shape of the neuron bodies, of the peculiarities of the neuropil development (Fig. 32, 33, 34,
35). The vicinal capillary branches, which form microbasins around the neuronal bodies, arise from one afferent and
some efferent preterminal structures. The more complex organization can be observed as well: the vicinal capillary loops,
which arise from 2 to 3 precapillaries and converge into 1 to 2 venous collectors. These microbasins have the most so-
phisticated arrangement in the giant-cell and large-cell ensembles of the motor nucleus of trigeminal nerve. Such a distri-
bution of arterioles and of the venules could allow furnishing the uniform blood supply of the entire volume of the neu-
rons. This opinion is confirmed by the studies of Iu.Ia. Kisliakov (1975), showing with the use of the methods of mathe-
matical modeling of oxygen transport processes in the cerebral tissue, that the differently directed distribution of the cere-
bral traffic ensures the most effective exchange.
According to the data of morphometric analysis, in all the nuclei investigated a positive correlation exists between
the sizes of neurons and the number of microvessels, situated within the area adjacent to the perikarya (Table 34). This
correlation is maximal in the nuclei characterizing by the significant variability of neuron sizes (motor and mesencephalic
nuclei of trigeminal nerve). This rule is effective in case of diffuse distribution of neurons as well (central gray substance
of mesencephalon). Here the coefficient of correlation balances between the significant and the moderate. At the same
time, in the nuclei characterizing by a moderate dispersion of neuronal sizes and by their nested distribution the correla-
tion between the number of vessels and their dimensions is less significant. The analysis that we performed suggests the
insufficient accuracy of this parameter which is commonly employed in the scientific work. The additional argument con-
firming this opinion lie in the fact that this parameter does not take into account either volume of the neurons or the vo-
lumetric and area characteristics of the area, immediately adjacent to this nerve cell. The examination of one of these pa-
rameters

Table 34
Correlation of the intensity of microcirculation around the neurons and of their sizes in human

Nuclei Parameters compared

Nv : Vn Sas : Vn Ss : Vn
Motor 0,788 ± 0,031 0,611 ± 0,052 0,183 ± 0,081
Mesencephalic 0,505 ± 0,062 0,589 ± 0,054 -0,048 ± 0,083
Main sensitive 0,276 ± 0,076 0,456 ± 0,065 -0,078 ± 0,082
Coeruleus 0,422 ± 0,068 0,235 ± 0,078 - 0,134 ± 0,081
Central gray substance 0,544 ± 0,058 0,562 ± 0,057 0,216 ± 0,079
Parameters are compared with the human values.
 46
which are directly related, reveals that the specific length of the vessels around the perikarya of neurons has a non-
significant inverse dependence or very weak direct correlation with the sizes of neurons. Such parameters as the specific
area of the exchange surface of the microvessels and the microvessel diameter of the pericapillary ultrafiltration have the
similar characteristics, being derivative parameters of the specific length. At the same time, the correlation was revealed
between the area of the specific effective exchange surface between the microvessels and the neuronal perikarya (pro-
posed in our studies) and the dimensions of a nerve cell. This parameter takes into account the specific area of the micro-
vessels exchange surface, the diameter of the perikaryon and the distance between the vessel and the surface of a nerve
cell. The area of the specific effective exchange surface between the microvessels and the neuronal perikarya, reflects
more reliably the conditions of the trophic supply of the body of an individual nerve cell. The best microcirculatory con-
ditions, according to this parameter, are revealed in the motor and mesencephalic nuclei of trigeminal nerve. While the
correlation between the number of vessels and the sizes of neurons in the mesencephalic nucleus is significantly lower in
comparison with the motor nucleus of trigeminal nerve, the specific area of the most effective exchange between the mi-
crovessels and the neuronal body correlates with the size of a neuron in both nuclei in the similar proportions. This pecu-
liarity is due to the close disposition of the vessels and of the neuronal bodies, as well as to the larger value of the ratio of
the specific capillary length, lying in immediate proximity to the body of a nerve cell, to the nucleus as a whole.
The main sensitive nucleus of trigeminal complex and the central gray substance of mesencephalon have some par-
ticularities. Here the linear correlation between the variable values of the most effective exchange surface between the
microvessels and the body of neuron and of the nerve cell size is moderate. The weakest correlation of these parameters is
observed in the locus coeruleus. It is characterized by the disposition of several neuronal bodies within one microvascular
basin, that could provide the unified microcirculatory conditions for the neurons having different diameter.
Thus, we can distinguish several versions of the ensemble organization among the nuclear type centers being in-
vestigated. From the one side there are nuclei where the large neurons compose the main population. The small-sell nuclei
occupy the opposite pole. The large-cell populations are characterized by the vessel concentration around the neuronal
bodies, forming the relatively detached micro-ensembles, which are represented by one cell body and the macrogliocytes
surrounding it. The processes of these cells are restrained within this cell, the adjacent structures of neuropil and the mi-
crovessels. In this version of ensemble organization the microvascular system has the most complicated structure, provid-
ing the relatively uniform trophism. The central gray substance of mesencephalon containing the small, diffusely distri-
buted neuronal bodies and having the reticular structure of neuropil, exhibits the supply of several neurons all at once
within the unique microvascular basin. The astrocytes form processes in the direct proximity to the neuronal groups. In
such a center the protoplasmic astrocytes serve as an important joining element, uniting the microvascular basins. The
nuclei having the predominant middle-size neuronal population, where both versions of the ensemble organization are
represented equally, occupy the intermediate position.
 47
CHAPTER III.
FORMATION OF THE NEUROGLIO-VASCULAR COMPLEXES DURING THE ONTOGENESIS

While the structural and functional rearrangement of some portions of mesencephalon and metencephalon during
the ontogenesis is described rather thoroughly, the main body of data concern the formation of the neuron ensembles
(A.L. Mikeladze, 1968; N.A. Khristolyubova 1970; E.B. Arushanyan, 1979; A.I. Gorbachevskaya, 1994; R.W. Albers,
1967; S Fahn, L.R. Cote, 1968; R.D. Huffman R.D., R Davis, 1977; C.J. Molenaar Et Al, 1997; K Sato Et Al, 1998). No
generalized data concerning the development of the overall complex of the micro-anatomical structures of the centers in-
vestigated are available in the existent literature.
Unfortunately, thus far no detailed description of architectonics of the vessel tree in the area of the aniages of me-
sencephalon and metencephalon during the early ontogenesis and of the relationship between the development of micro-
circulation and the formation of the cerebral tissue structures was given. During the late period of embryogenesis in hu-
man fetus the angioarchitectonics was exclusively investigated in detail (N.L. Mikeladze, 1968).
Two main ways of the vessel formation during the ontogenesis are known:
1. Vasculogenesis, i.e. the differentiation of endothelial cells in situ from the mesenchymal precursors.
2. Angiogenesis, i.e. the formation of endothelial cells from the previously existing vessels.
Vasculogenesis is characteristic for the embryonic development, whereas angiogenesis proceeds due to the forma-
tion of vascular networks both in the embryo and in adult animals. Both processes are important for the neurogenesis.
Some angiogenic and vasculogenic factors and proteins of extracellular matrix are produced in the central nervous system
during its development and in case of the damage.
During the ontogenesis of the circulatory system of the pontis and mesencephalon as a whole, and of the nuclei ex-
amined in particular, we distinguish several stages. During the early period of organogenesis of the nervous tube (initia-
tion, obliteration of the nervous groove) its trophism proceeds diffusely on the account of the primary capillaries adjacent
to the mesenchyma or (earlier) due to the direct transfer of the substances from the amnion and the chorion. In this stage
the determination of medulloblasts occurs, the determination of the mains layers of the nervous tube begins (ependymal
layer, mantle layer and marginal veil).
Beginning from the 5th week in human and to 10 – 12th day in rats (Fig. 20), (to the moment of the initiation of ce-
rebral vesicles) the first blood vessels penetrate into the nervous tube, breaking through the external border lamina. This
process which is rather early, coincides with the intensive proliferation of matrix cells and with the beginning of the neu-
roblast migration process, preceding the initiation of the definitive nuclear centers. The formation of microcirculation in
the nervous tube proceeds according to the common patterns in rat and human embryos. Angioarchitectonics is analogous
at the corresponding development stages. In both cases the extensive microvascular network in the adjacent mesenchyma
is present. This network is in some degree the source of the primary capillaries and endothelial cords of the vasal precur-
sors (prevasoids). After achieving the area of the ependymal layer adjacent to the ventral region and the mantle, the ves-
sels diverge into vascular plexus located parallel to the surface.
The embryonal angiogenesis in the nervous tube results in the formation of the system of primary capillary net-
works in the nervous tube. During the migration of the neuroblasts to the initiation sites of the definitive nuclei the vessel
tree in the nervous tube is characterized by the following particularities: the penetrating arterial and venous aniages are
directed radially in the dorsomedial way. They have a forward course and end with the terminal branches in the area be-
tween the ependyma and the adjacent mantle layer, forming the extended vascular plexus. In the mantle layer the main
vessels produce the anastomotic branches that arise at the almost right angle and lie for the very large distances from each
other. In the course of the nuclear initiation and appearance of the initial signs of their differentiation the complication of
the vaso-capillary networks of the tube itself occurs. The development consists in the angiogenesis in the anatomical nuc-
lear aniages. The own vascular plexuses begin to form, complicating considerably the angioarchitectonic pattern of the
pontis and of mesencephalon. In fact, the insignificant hemodynamic disturbances during the late prenatal ontogenesis in
rats, which do not result in the death of neurons, still cause the impairment of the tissular and, in particular, of the neuron-
al organization of brain (A.M. Radayev, 1999). Angiogenesis, as a whole, is determined by the relative topology of the
cells of environment to the growing vessel. The immediate (contact) interactions of endothelium
 48
The immediate (contact) interactions of endothelium with the pericapillary cells and their analogs and the
changes of the composition and structure of matrix are also very important (V.V. Banin, 1999). One of the key specialists
on angiogenesis, Judah Folkman, determined the following chronology of the process of neovascularization. The local
degeneration of the basal laminae in the zone adjacent to the endothelial cells, usually pertaining to the capillaries or ve-
nules, is accompanied by the subsequent locomotion of endothelial cells from the vessel- precursor in the direction of an-
giogenic stimulus. The elongation of the endothelial cells which migrate into the precapillary precedes the endothelial
cellular proliferation in the venule and the precapillary. Then the formation of the lumen and the generation of anasto-
moses with vessels occur. The appearance of the blood flow and production of the components of basal laminae by endo-
thelial cells and by the pericapillary cells penetrating into the vascular wall, are the closing phenomena in this chain (J
Folkman, 1985, 1990).
The possibility of the active influence of microvessels on the embrionic nervous system formation in the embryo-
genesis, may be due as well to the absence of hematoencephallic barrier (E.V. Loseva, 2001). The absence of the barrier
provides the diffusion of a great amount of biological substances into the brain; their content is substantially higher in the
areas having maximal vascularization, which can create the gradient of the subsequent neuroblasts development. The ear-
ly vessels penetration into the nervous tube contributes to such influences. Thus, while the neuroblasts migration process
in the neopallium in rats occur from the 17 - 18th day of ontogenesis (E.P. Chepur, 2001), the vessels penetrate the front
cerebral vesicles as early as beginning from the 15th day.
The data about the role of mechanical tension in the intensive transformation of mesenchymal cells into the vascu-
lar tubes can render assistance in the understanding of embryonal angiogenesis. This process can be of importance during
the development of numerous vasal precursors (prevasoids) around the nervous tube (I.V. Fesenko, 1995). The fundamen-
tal role in the formation of microcirculatory system in the central nervous system during the embryonic development be-
longs to the penetration of endothelial channels into the aniages of the nervous systems, accompanied by the correlation
between the development of the cerebral structures and their vascularization (M. Dambska, 1995). The development of
blood flow coincides with the increase of the brain’s dry mass, with the intensive growth of neuroblasts and is connected
with an increase of vessels’ amount. The underdevelopment of blood supply results in the perineural pathology (D.B.
Cheek, 1978). The cerebral vascular bed during the prenatal ontogenesis in mammalians has the unique “embryonic” pat-
tern until the birth. The vascular loops are polygonal and are characterized by the abundance of anastomoses between the
arterioles (L N Garmasheva, 1988; D.B. Cheek, 1978).
Upon the birth the significant complication of the vessel tree occurs, and the definitive system of nuclear microcir-
culation is formed. In the same time the morphogenesis of the ensemble organization of the nuclei proceeds. Macroglia
sets in the permanent interaction with the vessel tree and the neuroarchitectonics. The complication of the trophic supply
occurs in several directions: maturing of the tissue structures of vascular wall (in particular, of the contractile apparatus of
the afferent vessels), changes of arborization of the vascular tree, territorial subdivision of the blood supply to the distinct
micro-anatomical nuclear zones and even to the individual neurons or groups of neurons. This can provide the most ade-
quate conditions of the trophic supply of polymorphous structures.
The suggestions concerning the role of glia in the central nervous system development have long been done. His
has already revealed the transformation of neuronal epithelium during the detail studies of the nervous tube, and pointed
that neuroblasts and macroglia arise from this source. He described the transformation of postmitotic neuroblasts and the
formation of their axons and dendrites, accentuating the interaction of the developing neurons and glia (W His, 1886,
1889). Cajal and His examined the movement of neuroblasts to the peripheral zones of nervous tube and the characteris-
tics of their photo-optical structure at the early stages of differentiation (V.S. Hamburger, 1980). The trophic factors play
an important role in the mechanisms of neuron maturation and of the apoptosis in mammalians. In this respect the in-
growths of the nerve fibers and the content of potassium and calcium ions in the intercellular substance are of great im-
portance (L Franclin James, M Johnson Eugene, 1994; B Marchety 1997).
The significance of the nerve growth factor in the maturation and maintaining of the vital activity both in the peri-
pheral and central nervous system was shown. This factor is synthesized during the embryogenesis in the target organs,
and is also secreted by astrocytes, lemmocytes, neurons. The specific importance of the factor is emphasized at the early
stages, when its absence leads to the massive death of neurons (T. P Kloshnik, 1999).
During the early prenatal development a great amount of types 1 and 2 insulin-like growth factors is synthesized in
the brain of mammalians, exerting the control of the processes of maturation and apoptosis. Their concentration in the
mature brain is limited (S.A. Bondy, 1991). The epidermal growth factor
 49
enhances the processes of proliferation, preventing the apoptosis, prevents the formation of the neuroblast colonies (V
Nagane, F Coufal, H Lin, 1996). The activation of the processes of maturation of neurons and glial complexes is stipu-
lated by the fibroblast growth factors (O Bsoumligler et al, 1995). The fibroblast growth factor-2 acts in the nervous sys-
tem the mediator of cellular growth and proliferation. The ability of astrocytes to release this factor during the early onto-
genesis and to react to it specifically has been proven (M.K. Stachowiak et al, 1997). The available data result in the con-
tradictory explications. Thus, the suggestion exists that the main fibroblast growth factor exerts its influence on the astro-
cytes, rather than on the hypothalamic neurons, after which it induces the morphological differentiation of neurons via
maturation of the astrocytes (R.E. Pertavski et al, 1991). In the opinion of other authors, the fibroblast growth factor-2 and
the epidermal growth factor are capable to stimulate the precursors of neurons in the developing central nervous system.
The fibroblast growth factor-2 was shown to stimulate both the precursors of neurons and the astrocytes in the culture of
the brain tissues of the 17-days old mice embryos (T.J. Kilpatrick, 1995).
It was proven that the migration of neuroblasts during the embryogenesis occurs in the close connection with the
neuronal and neuroglial molecules of cellular adhesion. These molecules are revealed in the precursors of the astrocytes
and of oligodendrogliocytes (R Hardy, R Reynolds, 1993; R.B. Norgen, R Brackenbary, 1993; O.K. Ronnekleiv, J.A.
Resko, 1990). Alpha-v integrins are initially localized on the surface of the bodies of radial glia, and then in the corres-
ponding processes, as was demonstrated immunohistochemically in mice (E Hirsch et al, 1994). Together with the mole-
cules of cellular adhesion the components of extracellular matrix play an important role. The astroblasts detach the groups
of extracellular adhesive molecules along the travel pathways of the axonal processes during the prenatal ontogenesis. In
any case, in some regions of brain the first neurites are directed along the ways which were previously determined by the
neuroepithelial cells, converted afterwards into the astrocytes. These cells release from their surface the laminin and, like
neuroblasts, the adhesive molecules C-CAM and N-cadherin. This must stimulate the growth of the neurites. Some astro-
cytes synthesize the molecules of extracellular matrix in case of the damage or degeneration, inhibiting the growth of the
axons in the mature nerve tissue. These molecules belong essentially to the super-family of immunoglobulins (R Hardy, R
Reynolds, 1993; R.B. Norgen, R Brackenbary, 1993; O.K. Ronnekleiv, J.A. Resko, 1990). The role of extracellular ma-
trix in the migration of glioblasts was demonstrated (C.J. Pilkington, 1996).
Thus, the fact is definitely established that the precursors of neuroglia control the migration of neuroblasts. In the
different areas of the mammalian brain the migration of neuronal precursors and their final localization, the direction of
the axonal growth and their projection compose two critical moments in the development of the nervous systems. These
moments are related with cellular-cellular and cellular-matrix interactions.

We shall now examine some particularities of formation of the individual nerve centers. The anatomical aniage of
the nuclear centers is not identified in rat embryo on the 12th day of intrauterine development. We examined as the model
of development of the motor nucleus of trigeminal nerve the peculiarities of ventrolateral region of the mantle zone of
nervous tube which approximately corresponded to the level of the aniage of the nuclei of trigeminal complex. The nerv-
ous tube at the level of the aniage of the pontis consists of 6 to 12 layers of medulloblasts (Fig. 38). The mantle and epen-
dymal zones are not visually separated. The cells of this zone are poorly differentiated, they have the oval nuclei and are
characterized by a high mitotic activity and small sizes. The identification of the direction of their differentiation is diffi-
cult with the use of available methods. The immediately adjacent mesenchyma is characterized by the numerous primary
capillary networks having a large diameter and irregular contours. They form the abundant anastomoses and go both lon-
gitudinally and transversely. The first vessels arise of these networks, break through the external lamina and penetrate
deep into the nervous tube. The vasal precursors have radial or transverse directivity, penetrating into the tube virtually
across its surface. The course of the perforating efferent and afferent structures is nearly straight. The wall of the primary
capillaries is uniform and is exclusively represented by a tender endothelial lining. It is impossible to distinguish the affe-
rent and efferent vessels with the use of conventional methods of investigation. The vascular structures continue up to the
region, which directly adjoins the ventricles aniage, and then dissociates into the intraorgan capillary plexus. This plexus
resembles the extraorgan plexus, except of the considerably lower content of the vascular elements. Some of capillaries
form the cellular cords, which do not contain erythrocytes and represent the probable zones of vasculogenesis. The level
of the blood supply of the nervous tube aniage in
 50
the mantle zone is considerably weaker in comparison with the embryos of later stages of embryogenesis and with
young rats.
In human 5-week old embryo the structure of nervous tube in the corresponding zone is similar to one described
above. The distinctive feature consists in somewhat greater thickness of nervous tube, which contains 12 to 20 layers of
slightly differentiated, dividing cells (Fig. 39). By this development stage the primary vessels enter already in the nervous
tube, forming well visible periventricular vascular plexuses.
The primary capillary networks of the nervous tube develop from existing by that time abundant capillary network
of the adjacent mesenchyma via “budding”. They can also differentiate from the mesenchymal cells into the endotheliob-
lasts which further perforate and invade the marginal veil and the mantle layer. The invasion of the primary capillaries
into the nervous tube precedes the anatomical origin of nuclear centers of the pontis and of mesencephalon. The process
of specialization of mesencephalic neurons in human begins to become apparent in the individual neurons beginning from
the sixth week, while to the 10th week it involves the major portion of the population, which was demonstrated, in particu-
lar, in the dopaminergic neurons (M.T. Ugryumov, 1998). Even at first view of the other zones of nervous tube (including
the anlage of hemispheres) the similar regularity is obvious. It is most clearly manifested in the structures of the cerebral
cortex and cerebellum which differentiate later; here the penetration of the vessels occurs simultaneously with the points
indicated in the section concerning the anlages of the brain stem, of mesencephalon and of mtencephalon. The stage of
neuroblasts migration, the formation of the cortical layers and their differentiation as well occurs at much later stages of
intrauterine development. However, the commitment of neuroepithelium to stem cells, ensuring the development of neu-
roblasts and glioblasts, occurs just earlier (prior to the beginning of migration) (N.V. Omelchenko, E.B. Smirnov, 1999;
C. Walsh, C.L. Cepko, 1990). It is manifested in the expression of specific antigenic complexes of neuroglia and neurons,
when the precursor cells do not possess the distinct morphological signs, sufficient for their identification.
On 15-17th day of prenatal ontogenesis (Fig. 40) the anlage region of the motor nucleus of trigeminal nerve has the
appearance of agglomeration of the small cells which nuclei occupy the predominant volume of a cell. The neurofibrillary
apparatus and basophilic substance of cytoplasm are poorly revealed. Among the total population the cells probably cor-
responding to the neuroblasts are observed. These cells are polygonal, triangular or spindle-shaped, have 2 to 5 processes
which do not arborize or arborize slightly. The perikarya of these cells are somewhat larger than in the glial precursors.
The processes are thicker, have a wavelike course and frequently lose their radial directivity.
On the 15th day of embryogenesis the primary capillary network is widely represented in the adjacent mesenchyma.
They arborize intensely and mutually anastomose in a longitudinal and transverse direction. The thin wall is formed by
endothelium, is irregular and has both the large- and small-diameter regions. The vessels converge radially to the zones of
the aqueductal and ependymal anlages. The main vascular trunks penetrate into the cerebral anlages relatively regularly
(at the intervals of 100-150 μm). In the mantle zone the sparse capillary loops directed transversely to the main vessels are
visualized among them. The neuronal and neuroglial precursors are present between them. Their processes can frequently
decline in accordance with the direction of vessels. Nearby the ependyma the blood vessels diverge to capillary networks.
The vascular networks consist of the endothelial pavement solely. In the nervous tube the active processes of angiogene-
sis can be observed, appearing as the endothelial “buds” or cords.
In contrast to the locus coeruleus and the mesencephalic nucleus, the zone of the aniage of the motor nucleus of
trigeminal nerve is characterized by the elongated vascular loops. They are formed by the efferent and afferent blood ves-
sels. The main vessels perforate the anlages zones and are characterized by the system of the transverse capillaries which
arise from them and appear as the weakly twisted “arcades”. The vessels number in the nuclear anlage moderately differs
from the adjacent structures which are relatively poor in cells. The nuclear blood supply is thus provided in an integral
structure; thus, the level of the trophic supply of individual neurons is similar to the supply of a whole nucleus. The im-
provement of the blood supply in the anlages during these periods occurs due to the uniform increase of the vessels in the
aniage, while the intensity of the trophic supply of individual neuroblasts and of the whole nucleus is similar.
The structure of the pontis anlage of the rat embryo on the 15th day is similar to the corresponding structure in hu-
man embryo on the 7-8th week (Fig. 41) of intrauterine development. They resemble each other in the structure of micro-
circulatory tree, in the general architectonics of the pontis. However, the nuclear morphological organization in human is
generally inferior in comparison with the rat embryo.
 51
While in rat embryo the neuroblasts are identified on the 15th day, and more clearly to 17th day (Fig. 42), in 8-week
human embryo the neuroblasts cannot be distinguished from the slightly differentiated cells and glioblasts. In general, the
morphology of the pontis anlage in human, having large sizes, with the abundant vasocapillary tree has a less mature neu-
riarchitectonics and glioarchitectonics. The discrimination of its nuclear centers is quite relative. Only the extensive man-
tle and ependymal regions are clearly identified. The insignificant differences of the distribution of the neuroblast bodies
and in the myeloarchitectonics of their processes in different zones of the mantle layer are present.
Our data are in accordance with the results of other authors, suggesting that the anatomical anlage of the motor
nucleus of trigeminal nerve begins on the 7th week of the intrauterine human development (L.E. Goncharenko, 1963). The
functional interdependence was shown between the formation of the nuclei of trigeminal nerve and the discordance be-
tween the level of neuronal morphological maturing and the beginning of their specific functional activity (K Sato et al,
1998).
During the study of microcirculation during the early periods of intrauterine development it is necessary to keep in
mind that the mechanisms of vasculogenesis do not coincide with angiogenesis, which is confirmed by the studies, sug-
gesting the different mechanisms of integration of the mammalian endothelial cells in the first and in the second half of
the intrauterine development (J Partanen, J Rossant et al, 1997).
In the 8 to 17th -week human embryos the vessel tree of the frontal cerebral lobes is formed from the precursor ves-
sels of leptomeningeal tunic. No proliferation of endothelial cells in the brain structures is revealed after the 8th week of
the intrauterine development, indicating the importance of endothelial penetration and migration over the endothelial
channels in these periods. The behavior of the angioblasts can change under the influence of different factors. The amount
of extracellular matrix and the cellular-cellular interactions are the key factors in these processes. These factors can pro-
vide the organ specificity during the differentiation of endothelial cells and the formation of hematoencephalic barrier (T.
Wierzba-Bobrowicz, E Lawandowsks, 1995). The endothelial cells of different organs are heteromorphic as early as in
mammalian embryos. The significant immunohistochemical differences in the concentration of lectins, Peanut agglutinin,
angiotensin-converting enzyme, von Willebrand factor, antibodies to the corpuscles of Weibel-Palade and of the other
factors were revealed. These principles were demonstrated in the endothelial cells of the brain and in other organs of pig
embryos (J Plendl et al, 1996). The vasal endothelial VE-cadherin which is specific for the endothelium, provides the
possibility of the formation of intraendothelial cellular interactions. This cadherin is revealed in mammalian during the
early stages of development. The differential characteristic of the brain consists in the relatively low concentration of VE-
cadherina in the angiogenesis; the tendency toward the further decrease persists in adults (L Martin-Padura et al, 1995; P
Navarro, 1995; M.G. Lampugnani, 1995; G Dreer, 1996). Endothelium produces the vascular cell adhesion molecules 1
(VCAM-1) (B.S. Bochner, D.A. Klunk, 1995).
In the newborn rat the cyroarchitectonics of the motor nucleus of trigeminal nerve is represented by the compact
neuronal groups (Fig. 43). Among them several types of cells can be distinguished, that differ in their sizes and in the lev-
el of maturation. The large neurons are starlike, their average diameter is equal to 32.65 μm. The nuclei with a hypoch-
romic matrix occupy less than half-section of the perikaryon. They are located to the periphery (polar with respect to the
axonal origin), contain large nucleoli which are moderately tangible or hypochromic, centrally situated. The basophilic
substance of cytoplasm contains the middle-size, large and small elongated lumps, frequently forming the reticular struc-
tures. The initial segment of axon is well identified. The neurofibrils are thin. The cells having few processes (3 to 7) are
predominating. Their number is considerably lower in comparison with the rats during the following development stages.
Middle-size neurons are triangular, spindle-shaped or starlike and have a mean diameter of 23.71 μm. This group
of cells constitutes the major portion of the neuronal population of the nucleus. From the point of view of the pro-
grammed differentiation they probably constitute the heterogeneous structure, which includes both the group of middle-
size cells, persisting in mature organism, and cells transforming later into the macrocellular and giant-cell populations.
This is confirmed by the presence of neurons which are morphologically similar to the large cells in body shape, in the
directivity pattern of the long axis of the perikarya and of the processes arborization, and in the fact that they compose the
major portion of neurons. The chromophilic substance of cytoplasm is finely-dispersed, the nucleolar apparatus is smaller,
the nucleus occupies about half-diameter of the cell body. The second subgroup
 52
of these cells are rounded or starlike and have a central nucleus. The chromophilic substance of cytoplasm is signifi-
cantly dispersed or is not revealed. The cytoplasm is hypochromic, the neurofibrils cannot be impregnated. In the initial
portions the dendrites and the neurite have a similar structure. The major part of specific parameters of the intensity of
microcirculation is similar to the macrocellular and small-cell types, while differing considerably by the value of the most
effective exchange surface area between the capillar and the neuron bodies.
The small neurons having the mean diameter of 11.42 μm are spindle-shaped or round. Their relative content is
higher than during the later terms, due to the participation of both the small neuron populations of the mature animals, and
of slightly differentiated nerve cells. The central nucleus occupies the major volume of the perikaryon and contains 1to 3
small nucleoli. In the hypochromic no neurofibrillary apparatus or basophilic grains are revealed. The processes are short.
The identification of the initial axonal segment is difficult. The middle-size and small neurons have 2 to 6 thin processes
with poor branching. The capillary density in all neuron types varies within the limits of the close statistical populations,
with a certain delay of dynamically developing middle-size cells. It is due to the slower processes of formation of micro-
vascular basins in comparison with neuronal differentiation. The surface area of the most effective exchange between the
capillar and the neuron bodies represents a unique parameter indicating the better trophic supply of the large neurons,
proportionally decreasing in parallel with the decrease of their overall size. The degree of differences between the value
of trophic supply of neuron bodies and of the nucleus as a whole is considerably lower in comparison with the 6-month
rats: 2.06 - in newborns and 2.69 - at 6 months. These differences are more significant in comparison with certain nuclei
with the predominance of small neurons (1.5 in the central gray substance of newborn rats). Thus, to the moment of birth
both the absolute increase of microvessels number within the nuclear anatomical anlage and their distribution near the
bodies of neurons (beginning later during the prenatal ontogenesis) occur.
To the moment of birth of the young rats the differentiability of macroglia is sufficient, allowing identifying it with
the use of the methods we employ. The gliocytes and glioblasts are situated to the periphery of a nucleus.Their ratio to the
neurons is 1:2 to 1:3. Along with the diffuse distribution of the macroglia the agglomerations containing up to 5-8 neu-
rons can be seen among the groups of neurons. The length of the processes of protoplasmic astrocytes, the degree of their
variability, the number of processes in the newborn rats is much lower in comparison with the 6-month old rats (P <
0.01), as well in 1-week old rats (P < 0.05). Nevertheless each astrocyte enters in the contact with a greater number of
neuron bodies. This property corresponds to the functional immaturity of the nervous control over the function of the
masticatory muscles that these nerves innervate.
The vascular loops form the straight or slightly twisted arcs with a predominantly dorsomedial directivity. It coin-
cides with the long axis of the perikarya of main population of neurons and with the course of their axons. Each loop sup-
plies 1-4 to 10-15 neurons. The angioarchitectonics has both embryonal (blood supply of the large groups of cells, ab-
sence of the contractile apparatus in the afferent vessels) and mature features of organization (the differences in microcir-
culation around the neurons with respect to neuropile appear). The general morphometric parameters are considerably
lower in comparison with the 1st week and 6 month after the birth. The maximal differences concern especially the area of
ultrafiltration of the neuron bodies (more than 3-fold), which is related to the compact arrangement of the neuronal bodies
in the nucleus. The significant differences concern the interrelation of protoplasmic astrocytes with the system of micro-
circulation as well, which appears, in particular, as a small number of contacts of one astrocyte with the vessels.
To the end of the first week of postnatal ontogenesis the nuclear cytoarchitectonics maintains as a whole the gener-
al characteristics described in a newborn. Simultaneously with the growth of populations of large and middle-size neurons
the small cell population is reduced. The arrangement of the small cells in the nucleus becomes diffuse, the number of
neurons between the capillary loops decreases. In some large neurons the rough small lumps of basophilic substance can
be observed in the cytoplasm. The arborization of dendrites increases.
The parameters of general blood supply amplify simultaneously with the constant relationship to the intensity of
vascularization of individual neurons. This results in the equalizing of the degree of general blood supply of the nucleus,
besides the pericapillary ultrafiltration diameter in one-week-old rats and in the later terms of development, with the re-
tention of significant differences in the vascular supply of individual cells.
 53
At this point of development the system of microcirculation around the large cell population is formed less in-
tensively, resulting in the differences between them and the middle-size neurons.
The relative content of neuroglia to the neurons increases. The processes of protoplasmic astrocytes elongate sig-
nificantly (the error probability for the significance of the difference between the means is of Р < 0.05), with this parame-
ter approaching to the late terms of development. The intensity of interactions of the processes of protoplasmatic astro-
cytes with the neuron bodies is sufficiently high (significantly higher in comparison with 1 or 6 months after birth).
The vascular loops are elongated, go almost straightly and supply the loci, which comprise several large neurons.
The morphology of vascular networks displays the smaller variability in different areas of nucleus in the transverse sec-
tions comparing with the later time points. The fine-loop networks are predominating. The long axes of the areas between
the adjacent blood capillaries are directed ventromedially and coincide with the predominant direction of the nerve fibers.
To the end of the first month after birth the nuclear microarchitectonics in rat is slightly different in comparison
with 6-month old animals. However, the large neurons, in contrast to the cells of mature individuals, have the smaller
number of dendrites and of their terminal ramifications, allowing distinguishing the groups of neurons having a small or a
middle number of processes (3 to 8 dendrites). The neuropil is less developed, coincidently with the larger volumetric
density of perikarya in the nucleus. The sporadic giant neurons appear. However, the general proportion of large cells in
the population does not attain the maximum, but increases significantly (P < 0.001) in comparison with the first week of
postnatal ontogenesis. The neurons having middle-diameter perikarya resemble those ones in the mature animals with
respect both to their dimensions and to the structure and number of the processes. Their amount is maintained high, dif-
fering significantly from the animals belonging to the previous and following age groups (error probability less than P <
0.05). The small neurons are morphologically similar to the neurons in the 6 month old rats, but are slightly more numer-
ous. The intensity of the blood supply corresponds to the definitive animals, with a lower ratio of the supply of individual
cells and of the nucleus as a whole (2.57 - to the end of the first month, 2.69 - at 6 months).
The length of processes of the astrocytes is generally similar to the mature animals. The types of astrocytes coin-
cide with the mature animals. The formation of the neuroglial ensembles is also analogous. Among the parameters ex-
amined the significant difference in the number of satellite cells around the neurons still persists.
The angioarchitectonics complicate considerably, approaching to the mature status. The local supply of the indi-
vidual large neurons develops, rarely does it concern the groups containing two to three cells. The shape of vascular loops
is variable (rectangular, arcadic, twisted or round). The significant polymorphism in the concentration of vessels depend-
ing on the cytoarchitectonics and myeloarchitectonics of the motor nucleus of trigeminal nerve is revealed. The base pa-
rameters of the nuclear trophic supply, the interactions with the astrocytes reach a definitive state, except for the pericapil-
lary ultrafiltration diameter of the neuron bodies, which is caused by the more compact arrangement of their bodies with
the weaker development of the neuropil (error probability less than P < 0.05).
According to the data obtained, several tendencies in the formation of the ensemble organization of nuclei which is
examined, are revealed. The early penetration of the primary capillaries into the nervous tube, which precedes the forma-
tion of the motor nucleus of trigeminal nerve anlage, is characteristic. The neuroblast maturation precedes the develop-
ment of neuroglia. In postnatal ontogenesis the processes of formation of neuronal-astrocytic-vascular ensembles actively
continue.
The anatomical region, corresponding to the level of the mesencephalic nucleus of trigeminal nerve anlage, on the
12th day of embryogenesis in rats was examined combined with the locus coeruleus; the available studies were
represented independently of the structure which was subsequently laid down in this area This statement, in spite of its
artificiality, is meaningful in the fact that the neurons both in the locus coeruleus and in the mesencephalic nucleus of tri-
geminal nerve, migrate into the zones of subsequent anatomical anlage to a small extent. The dynamics of their vascular
supply assumes the same basis which they used for the interaction during this term of development.
The cells in this area have an oval nucleus and display a high mitotic activity. Some of them produce thin
processes having the radial directivity. The vascular structures diverge into the intraorgan capillary plexus in the sub-
ependymal areas, they are tangentially directed, widely anastomose inter se and form
 54
the polygonal loops. Some embryos possess the local areas, deprived of the intraorgan vessels, where the trophic
supply is apparently provided by the vascular networks of the adjacent mesenchyma and liquor.
At this period the small number of vessels is present, which provide the diffuse supply of the large cellular associa-
tions. The blocks consist of the closely arranged, slightly differentiated, migrating cells. The general parameters of the
trophic supply are significantly less than it is both in mature animals and 15-days old embryos (Р < 0.001).
The relatively large diameter of the vessels lumen allows increasing the specific surface area of exchange of the
vessels with the anlage parenchyma, ensuring the effectiveness of microcirculation.
On the 15th day of intrauterine development the neuroblasts in the region, corresponding to the mesencephalic nuc-
leus of trigeminal nerve, are detected as small round cells, which are closely adjacent to each other. They contain several
small nucleoli. The basophilic substance of the cytoplasm, the neurofibrils are not observed. At the term investigated the
nuclear anlage is identified at the level of the pontis and is closely connected anatomically with the locus coeruleus. It is
represented as an agglomeration of closely arranged small cells with short processes, round nuclei and with the narrow
rim of cytoplasm. The overall sizes of cells grow considerably in comparison with the previous period.
The vessels converge radially to the ependyma. In the nuclear anlage and in close proximity to it the active angi-
ogenic activity appearing as the endothelial “buds” and cords can be observed. In contrast to the embryos of early terms
the significant rearrangement of the system of blood supply (its complication) is observed. The capillaceous vascular
networks form not only the plexus around the ependyma, but the “condensations”, which can be observed in the region of
the corresponding anlage of the mesencephalic nucleus of trigeminal nerve. The region, corresponding to the locus coeru-
leus and mesencephalic nucleus of trigeminal nerve anlages, is characterized by the high density of microvessels, forming
the fine-loop capillary networks which anastomose extensively between themselves, encompassing the both anlages into
the united trophic system. The capillary loops cover both anlages forming the united network. While the parameters of the
specific length of vessels and of the average dimensions of microvascular basin are considerably lower in the newborn
rats (Р < 0.001) in comparison with the mature animals, such parameters as the vessel volumetric density, the area of ex-
change surface, the pericapillary filtration diameter are equal or slightly greater at the mentioned terms than the corres-
ponding values in mature animals. This fact is due to the large capillary diameter, which increases considerably the de-
pendent parameters. The difference between the intensity of blood supply of the neurons in the anlage and the nucleus as
a whole was revealed.
The mesencephalic nucleus of trigeminal nerve in the newborn rats (Fig. 44) displayed the compact arrangement of
neurons at the level of the pontis, forming the compact agglomerations containing 8 to 10 cells, while at mesencephalic
level they are represented by the groups comprising 1 to 5 cells. In the neuronal population the round, large and middle-
size neurons which are typical for the nuclear structure can be observed, like the following periods. The small, starlike
and round cells are also present. The middle-size neurons, displaying the similar morphological features, are characterized
by the well-developed neurofibrils and the high impregnation affinity of their cytoplasm. The bright nuclei of these cells
are centrally positioned. The small neurons are the most numerous and are stained weakly argyrophilic. They do not con-
tain any neurofibrils and chromophilic substance in the cytoplasm. The intensity of the trophic supply in their perineuron-
al area is considerably poorer comparing with the corresponding values in the mature individuals (Р < 0.05 for all the ba-
sic parameters). The density of vessel distribution around the neuronal bodies increases to a much greater extent in com-
parison with the entire nucleus, suggesting the predominate vascularization of the neurons with respect to the nucleus as a
whole (the difference in the blood supply of individual neurons comparing with the nucleus as a whole is more than 2-
fold). The high value of the specific area of the most effective exchange between the microvessels and the neuronal bo-
dies is observed in the middle-size neurons in comparison with the small ones.
Macroglia is situated diffusely to the periphery of the compact neuronal agglomerations. It is characterized by the
morphological uniformity. The long processes of astrocytes, which arborize moderately or significantly, encompass one
to several neurons, forming the united conglomeration comprising the neuronal bodies and the groups of astrocytes. Ac-
cording to all the basic parameters, the protoplasmatical astrocytes differ considerably (Р < 0.001) from the corresponding
cells in the mature animals. The incompleteness of the maturing processes follows from the low intensity of the glio-
neuronal interactions, great number of neurons within the area of distribution of the processes of one astrocyte and the
low number of vessels interacting with the processes of one astrocyte.
 55
The microarchitectonics of the vascular networks retains the embryonal properties. 8-10 to 3-4 neurons encom-
pass every loop and frequently penetrate into the ventrolateral structures of the locus coeruleus, forming the united trophic
complex. The cells are closely arranged. The degree of development of the neuropil is lower in comparison with the ani-
mals at the end of the first week of postnatal ontogenesis (Р < 0.05) as well as at the subsequent terms (P < 0.001).
The mesencephalic nucleus in rats on the first week of the postnatal ontogenesis undergoes the significant architec-
tonic rearrangement, appearing as the sparser distribution of the neuron bodies. Among them the large-cell population
appears. The cells are round, have a hypochromic central nucleus and a large nucleole. The chromophilic substance of the
cytoplasm and the neurofibrils are well detected. This type of cells is surrounded by the small neurons, with a weak im-
pregnation and a low affinity for the methylene blue. The population of small neurons is characterized by the thin, short
processes (two to four in number). The trophic supply of the neuron bodies is considerably enhanced, many parameters
differ significantly from the corresponding values in the newborn rats, while being lower than in the mature animals.
The protoplasmic astrocytes do not form the differentiated system of the glio-vascular interactions, which is cha-
racteristic for the later terms of ontogenesis. The astrocytes with short processes can form the abundant terminal ramifica-
tions in immediate proximity of several neurons. The quantitative content of the gliocytes increases. They begin to pre-
dominate above the neurons. The astrocytes appear, which contact with one large neuron. The basic morphometric para-
meters have the intermediate values with respect to the previous and to the subsequent periods. Some of these parameters
(the distribution of the processes to the neuron bodies, the degree of interaction with microvessels) are nearer to the ma-
ture rats, whereas others (the number of satellite gliocytes around the body of neurons), are nearer to the newborns’ val-
ues.
As concerns the system of microcirculation, the density capillary networks increases, and the autonomy of the nuc-
lear supply with respect to the locus coeruleus augments. At these terms the compact cellular agglomerations predomi-
nate, but the areas with the scarce distribution of cells are also present. In the regions of the agglomerations of the peri-
karya the vascular networks are abundant. The structure of the latter can be considered as a transition from the embryonic
form to the mature one, which is reflected in the blood supply of the large neuronal groups, displaying the small variabili-
ty of capillary networks. This is associated with the abundance of vessels, the simple identification of the arteries and
veins (like the definitive vascular structures). While these parameters are considerably lower in comparison with the in-
tensity of the trophic supply of the bodies of neurons, the nuclear vascularization is virtually similar to the corresponding
value in the mature animal. The close-packed arrangement of cells is accompanied by the decrease of the specific diame-
ter and of the area of pericapillary filtration of the neuron bodies.
Against the end of the first month of postnatal development the general structure of the nucleus corresponds to the
mature animal. The bodies of the large neurons are situated singly of form the small groups. They have a well-defined
neurofibrillar network and the basophilic granularity. The small and middle-size neurons are situated besides the large
cells. The main population of the neurons is characterized by large or middle-diameter perikarya. The intensity of micro-
circulation around the bodies of individual neurons does not achieve the value of the 6 months, concerning particularly
the large neurons.
The protoplasmic astrocytes can be subdivided into 2 basic groups. The first group contains predominantly the as-
trocytes, which are “spread” on the surfaces of the basic population of cell, situated between their bodies and capillary
loops. They are divided according to the length of the processes and the degree of their arborization. The second group
predominantly contains the astrocytes with larger length of the processes and their relatively uniform spatial distribution.
The cells contact with several (2 to 4) adjacent large neurons. The morphometric parameters are similar to the corres-
ponding values at 6 months, except for the number of gliocytes around one neuron. The vascular network surrounds the
groups comprising one large and several middle-size and small neurons, or 2 to 4-5 large and several small neurons. Thus,
the vascularization acquires the mature pattern, except that it is accompanied by a considerably smaller proportion of the
large neurons and a greater number of cells within the microvascular basin, in comparison with the mature animals.
Thus, the formation of the neuro-glio-vascular complexes in the mesencephalic nucleus of trigeminal nerve occurs
analogously to the motor nucleus, but at the early term (15 days of intrauterine development) the intensity of the trophic
supply of the bodies of neurons is higher, in comparison with this nucleus.
At the 15th day of the prenatal development in rats the main sensitive nucleus of trigeminal nerve anlage is ob-
served as an agglomeration of slightly differentiated cells, among which
 56
the neuroblast and glioblasts identification is difficult with the use of the general methods of analysis, while after im-
pregnation the neuroblasts appear as the small cells having a small number of processes (Fig. 45). The primary capillary
networks separate some dozens or some hundreds of cells. In human, according to our results and to the literature data,
the main sensitive nucleus of trigeminal nerve is originated on the 7th week of embryogenesis (L.E. Goncharenko, 1962).
But in contrast to the rat, the location of the nucleus is very conventional, and the agglomeration of the blast cells has a
less distinct pattern.
The vessels penetrate into the anlage of main sensitive nucleus of trigeminal nerve rather regularly (with the inter-
vals of 100-150 μm) during the embryogenesis of rats on the 15th day and in human on the 7-8th week. In the mantle layer
the sparse capillary loops are observed among them, that are transversely directed with the respect to the main vessel. Be-
tween them the hundreds of neuroblasts and of glial precursors are situated. Near the ependyma the blood vessels diverge
into the capillary networks. The latter form the “condensations” in the regions of the anatomical nuclear anlages as well.
The zones of the origin of motor and of main sensitive nuclei of trigeminal nerve have a similar pattern of vascular loops.
The intensity of blood supply of individual neuroblasts and of the nucleus as a whole is equal.
To the moment of birth (Fig. 46) the group of neurons having the middle-size perikarya appears among the neurons
of the main sensitive nucleus of trigeminal nerve. The number of neurons contained in this group is much lower in com-
parison with the mature rats as well as with the animals at the first week of postnatal ontogenesis (P < 0.01 in both cases).
The mean diameter and the volume of bodies differ significantly from the corresponding values in the 2-6 months old
rats. The middle-size neurons are elongated or spindle-shape, have a strongly dispersed chromophilic substance of the
cytoplasm. The nuclei of neurons are round or oval, are centrally situated and occupy one half to one third of the cytop-
lasm area. One to two small, hyperchromic nucleoli are present. The small neurons are rounded, have a centrally located
nucleus (occupying the larger volume of the body) and 1 to 5 hyperchromatic nucleoli, several thin processes. In the cy-
toplasm of some cells the chromophilic substance appears in the form of basophilic rim. In the neurons of both popula-
tions the number and the degree of arborization of the processes goes in delay with respect to the animals of elder age.
The neuronal types are not divided according to the number of processes, which is limited to the number from 3 to 6.
The volume of distribution of the astrocytes processes and their relative concentration with respect to the neurons
is considerably lower than in the adult rats (P < 0.01), which suggests the relative immaturity of the astrocytes and of neu-
roglial interactions. The small quantity of the astrocytes, surrounding one neuron, can result from the close-packed ar-
rangement of the bodies of neurons in comparison with more adult animals.
The vessels penetrate the nucleus in the ventromedial direction. Their major portion transitorily leaves it after
forming the branches. Between the vessels from 6-7 to 10-15 neuronal bodies are present. Even the walls of the large af-
ferent vascular structures do not contain the muscular tissue, complicating their identification with respect to the veins.
The parameters of vascularization of both the middle-size and small neuron bodies are considerably lower than in com-
parison with the mature rats’ results in the low number of contacts of astrocytes with the vessels of microcirculatory sys-
tem (P < 0.001 in comparison with the mature rats and P < 0.05 in comparison with the one week-old young rats).
At the end of the first week of postnatal ontogenesis in the main sensitive nucleus of trigeminal nerve the dimen-
sions of perikarya increase, simultaneously with the increase of the number of middle-size neurons in comparison with
the small neurons. At the same time the middle-size neurons are larger than in rats of 3 to 6 months old. This can be re-
lated to the fact that at the end of the first week the middle-size population includes both the middle-size neurons per se,
as well as the growing neurons, which will enter into the large-cell population. The diameter of the largest representatives
of this population at the end of the first week (28 to 29 μm) supports this assumption, as it is lower in comparison with the
corresponding values in mature animals (33 to 38 μm).
The length of the astrocytes processes, their structural variability, the quantitative ratio to the sizes of neuron bo-
dies and the number of connections with vessels increases gradually, but it does not reach the maximum level, displaying
the significant difference from the latter. The number of capillaries, the area of their exchange surface and the pericapil-
lary ultrafiltration diameter are considerably lower in comparison with the mature animals, especially in the population of
middle-size neurons.
Against the end of the first month of postnatal ontogenesis the general structure of the nucleus and its basic mor-
phological parameters approach the corresponding values in the adult animals. While all the parameters investigated are
lower in comparison with the definitive animals,
 57
they are not significant nevertheless. The neurons are arranged more closely, resulting in the notable increase in the
diameter and area of pericapillary ultrafiltration, pertaining to the neuron bodies. This peculiarity is due to the poorer de-
velopment of neuropil in the nucleus which is associated with the smaller number of neuronal processes and the intensity
of their arborization. The subdividing of the neurons into the groups with a fine arborization and weak arborization is less
evident in comparison with the 6th month of postnatal ontogenesis. The structure of microcirculatory tree is approximating
to the finally organized. However the diameter of the microvascular basins is substantially smaller. In general, the qualita-
tive and quantitative parameters of neuro-glio-vascular co-interactions are similar to the corresponding values in 6 months
old rats.
To the 15-17th day of intrauterine development the anatomic anlage of mesencephalon and metencephalon main-
tains the features of primitive embryonic organization. At the transverse section, at the level corresponding to the locus
coeruleus, the region of this anlage is identified as an agglomeration of small, slightly differentiated cells with the single
processes. Upon the Golgi impregnation the following groups of cells can be distinguished among the neuroblasts: den-
drite-less, unipolar (having the fine single, radially directed, not arborizing process), bipolar (having fine, not arborizing
processes, situated at the antipoles of cell or arising from of one of the poles). From the 15th day of prenatal development
the first signs of noradrenergic activity appear, represented by the slight fluorescence of the nuclei. This fluorescence in-
creases to the 17th day of intrauterine development and to the moment of birth. The data of other investigators suggest the
early development and high-degree accumulation of norepinephrine and of dopamine in the brain (E.V. Loseva, 2001;
V.V. Rayevsky 1991).
At the 15th day of prenatal ontogenesis, as was earlier shown, the vessels form the united blood supply of the an-
lages of mesencephalic nuclei of trigeminal nerve and of locus coeruleus.
In infant rats the neurons of the locus coeruleus (Fig. 47) form the compact, closely arranged cellular agglomera-
tions (including 20 to 40 neuron bodies and neuroblasts). The neurons are middle-sized, oval or sometimes spindle-
shaped. The nucleus occupies less than half of the cell body area. One to two nucleoli are present. In the cytoplasm the
delicate network of neurofilaments and the fine-grained chromophilic substance are revealed. The number of processes is
equal to 2-7. They are weakly arborizing, thin, straight or have a slightly twisted course. The small neurons are triangular
or round. The nuclei are hyperchromic, centrally situated and occupy the main volume of the neuron bodies. The nucleoli
are small and hyperchromic.
The bodies of the adjacent neurons frequently closely adjoin to each other. The processes are poorly developed. At
this term the ventro-caudal region of the locus coeruleus is characterized by the larger concentration of the middle-size
neurons with respect to dorsal and cranial zones. This region joins the cells of mesencephalic nucleus of trigeminal nerve;
frequently they have a common blood supply. The processes of the protoplasmatic astrocytes can immediately adjoin to
the neuronal bodies of the both nuclei. At the moment of birth the small neurons are predominant. Their number is signif-
icantly greater in comparison with the population of middle-size neurons (P < 0.001) and differs from the mature animals
to a high degree of confidence (P < 0.01). The general dimensions of the small cells change non-significantly, as opposed
to the population having the middle-diameter perikarya. The considerable accumulation of norepinephrine in the neuron
bodies provides their intensive fluorescence. Simultaneously the adrenergic plexuses are formed around the main cerebral
vessels. The nuclei of neurogliocytes are diffusely located or form the small groups including 2 to 4 cells, when investi-
gated with the use of the conventional procedures. At the same time the cells are slightly more numerous to the periphery.
The complexity of arborization and the length of the processes of astrocytes are much lower than in the mature cells (P <
0.05). The earlier formation of a great number of the contacts of astrocytes with the neurons bodies is observed, asso-
ciated with the less concentration of these cells within the locus coeruleus (P < 0.001).
The system of capillary branching in the infant rats is similar to the embryonic system. The identification of the
small efferent and afferent vessels is hindered. Every capillary encompasses up to several dozens of cells (usually 8 to
10). The formation of the system of neurotrophic complexes is far from the completion, appearing as the identical level of
microcirculation in the nuclei and close to the bodies of the developing neurons (Р > 0.05), poor development of the glial
environment, low level of the quantitative parameters of the astrocytic-vascular interactions.
Against the end of the first week of postnatal ontogenesis the significant changes proceed in the neuroarchitecton-
ics of the central gray substance of mesencephalon. The neurons become more variable, the degree of arborization and the
number of dendrites augment, Among the neurons
 58
the main morphological types which are described in the mature rats can be identified, with a poorer development of
the dendrite tree and with the predominance of the cells with the small-diameter perikarya, in comparison with mature
animals (Р < 0.01). The representation of adrenergic nerves in the structures the stem increases.
The parameters of the trophic supply in the middle-size and small neurons in rats at the end of first week of post-
natal ontogenesis are similar. Some parameters of the intensity of vascularization of the neurons are significantly lower in
comparison with the corresponding parameters in rats at the end of the first month (the differences are significant for the
diameter of pericapillary filtration and for the area of the capillary exchange surface). The relative amount of neuroglia
with respect to the bodies of neurons increases. The changes concern both their position and cytoarchitectonics. At the
end of the first week the protoplasmic astrocytes are distributed diffusely within the nucleus. The distribution of their
processes expands. They are located between the groups of the neuron bodies, embracing them by their branches. A large
group comprise the astrocytes, having the processes which are uniformly distributed between 2 or more vessels, but the
cells which participate in the formation of the pericapillary muffs around one vascular formation are predominate (the
mean value is of 1.51).
At the end of the first week of postnatal ontogenesis the microcirculatory tree displays the thick capillary network
with a density which is not lower, but to the contrary exceeds the density in mature animals. Some embryonic features are
still present. In particular, this is manifested in the maintaining of the trophic supply of the groups of large neurons within
the limits of the proximal capillary loops. The loops are polygonal. The differences in the intensity of microcirculation of
the nucleus and of particular neurons are less expressed than 1 month after the birth. The differences in the specific length
of vessels between the nucleus as a whole and in the cellular blood supply at the end of the first week are about 1.7, at the
end of the first month – 2.35. The effectiveness of the supply of individual cells is also lower in comparison with the ma-
ture animals.
At the end of the first month after birth the basic population of neurons is morphologically similar to the mature
rats, but the proportion of the small neurons is significantly higher. The system of processes, arising from the neurons,
resembles the corresponding structure at 6 months. The cells are located singly or form the groups (including 2 to 5 neu-
rons). The predominance of the middle-diameter neurons is observed in the regions adjacent to the mesencephalic nucleus
of trigeminal nerve. The population of neurons is characterized by the significant morphological variability. Among the
middle-size neurons the triangular, starlike, round and spindle-shapes cells can be distinguished. According to the degree
of development of dendrite apparatus the poorly arborizing (3to 6 processes) and moderately arborizing (7 to 9 processes)
may be discriminated.
The small neurons are rounded or spindle-shaped and a scanty or moderately arborizing system of delicate short
processes. A number of varicose ectasia are observed. The ratio of the small and middle-size neurons is significantly bi-
ased to the small cells, even at the end of the first month, in comparison with the 6th month of postnatal ontogenesis (P <
0.01). The blood supply of the neurons and the general principles of the construction of the vascular loops in their imme-
diate environment achieve the sufficient degree of maturity. They are delayed in the degree of their development in com-
parison with the middle-size neurons (the differences for the area of the exchange surface of capillary and for the perica-
pillary ultrafiltration diameter are significant with the error probability Р < 0.05). This may indicate the continued
processes of the rearrangement of the vascular microarchitectonics around them.
Among the protoplasmic astrocytes (consisting the major body of the population of neurogliocytes in the locus
coeruleus) the cells having the uniformly distributed middle-length processes, which interact with the bodies of 1 to 6
neurons (the mean value 3.94) are predominated. The form, density and the length of the branches of astrocytes achieve a
sufficient degree of differentiation, but are not quantitatively equal to the values in the mature astrocytes, manifesting in
the less number of the satellite cells in comparison with the 6 month-old rats (P < 0.05). The neuro-glio-vascular com-
plexes generally display the high degree of differentiation.
The angioarchitectonics reaches the high degree of maturity. The fine capillary loop can be encompassed by 1-2 to
7-10 neurons. Some of them are characterized by the close vicinity to the surface of capillary. The typification of arteries
and veins does not cause difficulties. The major portion of the neurogliocytes contact with one or several vessels, distri-
buting the processes within the limits of the adjacent capillary loops (2.53 contacts with microvessel per one astrocyte on
average). The insignificant superiority of the nuclear blood supply with respect to the later age is observed, correlating
with the close-packed arrangement of the bodies of neurons and may compensate the increase of the pericapillary ultrafil-
tration diameter, corresponding to the bodies of neurons.
 59
Thus, the formation of neuro-glio-vascular complexes in the locus coeruleus occurs according to the principles
which are common for all the structures investigated. At the early periods its development is closely related with the me-
sencephalic nucleus of trigeminal nerve, manifesting in the united trophic supply of the anlages of these structures. The
signs of rather late morphological maturation of the neurons do not coincide with the manifestations of the early specific
functional activity (accumulation of specific mediator).
On the 12th day of prenatal ontogenesis the nervous tube at the level of the middle cerebral vesicle (Fig. 48) is of
small diameter. The mantle layer transforms gradually into the cortical layer. It is represented by the poorly differentiated
elongated cells. Their long axis is directed transversely to the external surface of the tube. At the level of mesencephalic
anlage at the sagittal sections 8 to 15 layers of medulloblasts are present. The morphometric data concerning these periods
of development are conventional in many instances, due to the impossibility of identification of the anatomical anlage of
the nucleus and the cells. The measurements were accomplished at the level of the middle cerebral vesicle, corresponding
to the periventricular zone.
On the 15-17th day of prenatal ontogenesis the anatomical anlage of the middle cerebral vesicle maintains the
layered structure. The region, which anatomically corresponds to the anlage of the central gray substance of mesencepha-
lon, is represented by an agglomeration of compactly lying small cells. The blasts are characterized by the short
processes, round nuclei and narrow rim of the cytoplasm. The cells-precursors of the neuroblast and glioblast array cannot
be accurately identified with the use of conventional histologic procedures. At the same time the Golgi impregnation al-
lows revealing the first bipolar forms of neuroblasts. The intensity of the blood supply of individual cells corresponds to
the trophic supply of anatomical anlage as a whole.
The vessels converge radially to the zones of the aqueduct and ependyma anlages. In the nervous tube the active
angiogenic activity in the form of the endothelial “buds” or cords can be observed, which is most obvious from the 17th
day. In contrast to the early term embryos, the significant variability in the structure of microcirculatory tree is observed.
Simultaneously, the increase of the nervous tube dimensions is delayed from the rate of formation of the vessel tree,
which is accompanied by an improvement of the blood circulation in the anlage.
The central gray substance of mesencephalon of the infant rat (Fig. 49) represents an agglomeration of uniformly
distributed small neurons and of several middle-size neurons. They can be provisionally divided into two neuronal
groups. The cells are round or polygonal, have round central nuclei that occupy about half-volume of the neurons, and
one relatively large nucleolus. The basophilic substance of the cytoplasm is revealed as the fine granularity, which some-
times interfuses with the hyaloplasm. Such cells lie singly or form the agglomerations containing two to three middle-size
and two to four small neurons. The neurons have a small diameter, fusiform, sometimes round or triangular perikarya, the
high nuclear-cytoplasmic ratio, from 1 to 3 small hyperchromic nucleoli.
Neurofibrillar structures in both types cells are not revealed with the use of the procedures employed. The neurons
have several (two to five) processes, which do not arborize or have a poor branching. The content of middle-size cells is
considerably lower in comparison with the rats at 6 months of postnatal ontogenesis. The correlation between the condi-
tions of the trophic supply of individual neurons and of the nucleus as a whole is considerably lower in comparison with
the mature animals (about 1.5 in infant rats and 2.7 - at 6 months), suggesting the relatively uniform distribution pattern
of the blood capillaries at this term. The significantly poorer blood supply of the neurons and of the nucleus as a whole is
observed (the first parameter differs much more significantly), in comparison with the mature animals and with the end of
the 1st week of postnatal ontogenesis.
The nuclear gliocytes and the neurons in the central gray substance of mesencephalon are represented in approx-
imately equal ratios, either the gliocytes can be considerably less numerous. The astrocytes lie between the groups of neu-
rons. The length of processes of protoplasmatical astrocytes, their quantitative content per one neuron are much lower in
comparison with the corresponding values at 6 months or at the end of the first week after birth. At the same time the pa-
rameter of interaction of the astrocytes with one neuron does not differ essentially. This characteristic suggests the poten-
tial importance of this parameter in the process of trophic interaction between the neurons during the ontogenetic devel-
opment, as well as the role of astrocytes as the neurogenesis integrator.
The vascular loops encompass up to 20-30 neurons, they are uniformly distributed and form the polygonal net-
works. The shape of the vascular loops, the immaturity of their wall (absence of contractile apparatus in the afferent ves-
sels)
 60
indicate the low degree of differentiation of tissue and organ components of the vessel tree. The quantitative parame-
ters of nuclear blood supply as a whole differ compared with the mature animals to a lesser degree than the qualitative
parameters of the vascularization of individual neurons. The most significant differences concern the area of pericapillary
ultrafiltration of the neuron bodies, explained by their considerably lower density at mature age and by the enlargement of
the neuropil percentage. The morphometric data concerning the formation of the ensemble organization in the central
gray substance are considerably different compared with the late terms of ontogenesis. The lesser number of contacts be-
tween the astrocytes and microvessels is revealed. To the moment of birth the intensity of blood supply of the nucleus per
se and of individual neurons increases significantly, the dimensions of the neurons enlarge, the signs of redistribution of
microvessels near the bodies of neurons are observed, manifesting in the changes of the quality parameters.
The central gray substance of mesencephalon in rats at the 1st week of postnatal ontogenesis is characterized by the
similarity of the morphological types of neurons and of their ratio to the corresponding characteristics in the infant ani-
mals. Among the neurons a comparatively small population of middle-size cells with a poor arborization is revealed, hav-
ing two to four dendrites with a straight course and poor branching. The small neurons are predominating. Like the mid-
dle-size neurons, they are characterized by round or spindle-shape perikarya, smooth contours and one to 3 - 5 dendrites,
terminating in the immediate proximity or at certain removal from perikaryon. The blood supply of individual neurons
improves significantly in comparison with the infant animals (error probability P < 0.05). This is due to the increase of
the number of the vessels in the central gray substance as a whole (P<0,01), and to a lesser degree – to the vessels concen-
tration near the neurons (the ratio between the vessels concentration in the immediate environment of neurons, in compar-
ison with the nucleus, comprises 1.65, while in infants it comprises 1.5).
The protoplasmic astrocytes have the short processes forming the uniformly distributed network. Sometimes the
maximal length of the processes is located in one of planes. The lower concentration of the processes in the nuclear struc-
ture and the less morphological variability are noted, in comparison with the later terms. The number of satellite astro-
cytes increases, supporting the stable level of interactions between each protoplasmatic astrocyte and the neuron bodies.
The following pattern is substantial during this period of development. While general parameters of nuclear blood
supply achieve the level characteristic for the mature animals, or exceeding the latter in certain values, the differences in
the vascularization of the bodies of neurons themselves are not significant while compared with the 1st or 6th months of
postnatal development. The diameter of pericapillary filtration assigned to the bodies of neurons differs considerably. The
density of contacts between the astrocytes and the vessel tree is considerably lower. Everything above-mentioned indi-
cates the insufficient morphological maturity of the formation of neurogliovascular ensembles.
The quantitative representation of the middle-size neurons gradually increases within the 1st month after birth, but
falling short of the level of the mature animals. At this time the structure of the neuronal perikarya is similar to the cor-
responding characteristics in rats at 6 months of postnatal ontogenesis, but it displays the smaller number of processes and
density of arborization. The vessels concentration reach a significant development immediately in the zones of neuronal
distribution, which results in the equalizing of the morphometric values of microcirculatory tree with the corresponding
levels in the mature population being investigated.
The relative number of the astrocytes with respect to the neurons increases, as well as the length and the degree of
morphological variability of their processes, approximating the basic morphometric parameters to the mature rats.
Thus, the angioarchitectonic pattern in the nucleus under investigation changes during the ontogenesis. This dis-
plays in the appearance of predominance of fine-loop capillary networks, in the complication of the arborization and of
the number of precapillary and postcapillary structures. The number of neurons assigned per vascular loops decreases.
The basic parameters of the ensemble organization the central gray substance of mesencephalon reach a sufficient degree
of maturity at the end of the 1st month after birth. The significant differences in the value of specific area of pericapillary
ultrafiltration of the neuron bodies and in the degree of development of the neuronal processes persist. During the ontoge-
nesis in the central gray substance of mesencephalon the less substantial dynamics of the increase in sizes of neurons and
of the decrease of the number of neuronal bodies is revealed within one capillary loop, in comparison with large-cell and
middle-cell nuclei. The increase in the number of microvessels around the perikarya of neurons proceeds probably rela-
tive to the groups of neurons rather than to the individual neuron.
 61
In view of the results obtained, several general patterns of neurogenesis in the investigated structures of mesen-
cephalon and metencephalon should be pointed out. The parallelism exists between the early development of the precur-
sors of neurons in rats and in human, while the differences are essentially temporary in their nature. According to the lite-
rature data, in both species examined the neuroblasts pass the stage of polipotent precursors with the subsequent determi-
nation. These processes, according to the opinion of a number of authors, coincide with the neuroblasts migration from
ependymal into the mantle layer of nervous tube with a simultaneous continuous proliferation. Then the neuroblasts mi-
grate in the regions of anatomical arrangement, where cellular differentiation begins (R Hardy, R Reynolds, 1993; R.B.
Norgen, R Brackenbary, 1993; O.K. Ronnekleiv, J.A. Resko, 1990). According to our investigations, the maturation of
the cellular elements occurs irregularly within the limits of the unique anatomical formation (anlages of the pontis or of
metencephalon). Thus, together with the neurons of the motor and of mesencephalic nuclei of trigeminal nerve, which
originated early and are being morphologically identifying, the neuroblasts of the locus coeruleus, of central gray sub-
stance of mesencephalon maturate much later. Within the nuclei themselves the neurons maturate asynchronously, which
is manifested in irregular increase of their sizes and of the degree of processes development. The essential difference of
the embryonic development of the anlages investigated in human, in comparison with rats, consists in the relatively earli-
er formation of the primary capillaries, in comparison with the differentiation of neuroblasts. This phenomenon can be
explained by the larger dimensions of the human nervous tube with the earlier manifestations of hypoxia, causing the pe-
netration of primary capillaries.
The processes of formation of neuron ensembles in the peripheral nervous system and, particularly, in the cervical
portion of the sympathetic the stem was examined in detail in our previous works (Iu.G. Vasilyev, 1995). It was shown
that the development of neuron ensembles in human, rabbit and rat embryos, occurs according to the similar patterns. The
differentiation of neurons since the beginning of intensive accumulation of the specific mediator coincides with the initial
terms of the fetal period in all the species examined. But there are essential features: particularly, at the moment of birth
the neurons in rat and in rabbit are comparatively small, have a poor development of the glial capsule, which corresponds
in human to the 16-20th week of prenatal ontogenesis. Furthermore, in human the microvessels in the nuclei appear a little
earlier in comparison with the neuroblasts formation (Iu. G. Vasilyev, 1995, 2001).
The translation of the data concerning the central nervous system to the peripheral nervous system should be nev-
ertheless performed carefully, even in case of the neurons having the identical mediator exchange. The identical effects
exerted upon them result in different consequences, suggesting their qualitative heterogeneity (S.Vanhatalo, S Soinila, A
Lumme, 1998). The neurons of the central nervous system having the similar mediator exchange are also heterogeneous.
Thus, the immunoreactivity of cyclooxygenase-1 is revealed in all serotoninergic neurons in mature rats, but in case of the
catecholaminergic neurons both enzyme-positive and negative cells existed. The enzyme activity varied from the high
level in the black substance and in the ventral tecta zone to low values in the locus coeruleus. The high level of tyrosine-
hydroxylase immunoreactivity existed in all regions (D Dassesse, 1997). This provides the rationale for the individual
examination of the processes of formation of neuron ensembles in central and peripheral nervous system, as well as of the
particular nuclei having the similar mediator exchange, within the central nervous system.
The relationship between the relative rates of the development of nuclei are similar in rats and in human, which can
suggest the similar patterns in the formation of the pontis and of mesencephalon during the early stages of ontogenesis in
both species.
The examination of the early stages of formation of neuro-glio-vascular complexes in rats and in human revealed
the uniformity of architectonics of the nervous tube and of the vessel tree. The anlages of mesencephalon and of the pon-
tis in human embryo at the 5-8th week of embryogenesis and in rat embryo at the 12-15th day are identical when examined
with the use of the light-optical method. Within this period of development in both species investigated the poorly diffe-
rentiated cellular elements of the anlages are revealed, forming 3 layers of the nervous tube simultaneously with the ac-
tive processes of neuroblasts migration into the regions of the anatomical nuclear anlages and of their active proliferation.
The microvessels penetrate into the nervous tube at the same time. The significant heterochronicity in the formation of
central nervous system was shown. In human the proliferation of the nerve tissue associated with the processes of neurob-
lasts migration is observed up to the 8-9th week of intrauterine development in the neopallium, up to the 6-7th week in the
spinal chord and in mesencephalon and up to the 8-10th week in the cerebellum. In rats embryos these processes are cha-
racteristic at the stages E15-17. Subsequently the mitotic index considerably reduces, the foundations of formation of in-
terneuronal
 62
associations are laid, the differentiation and the growth of processes activate (V.A. Otellin, 1992, 1999).
Thus, the development of intraorgan vessel tree in different parts of the nervous tube occurs at the different stages
of histogenesis. Consequently, the distinct importance of the embryonic angiogenesis and of endotelioblast-glioblast-
neyroblast interrelations for the neurogenesis in different areas of the nervous systems can be assumed.
The general principles of angiogenesis and of the formation of neuroglial complexes in the nervous tube as well as
on the periphery are identical and include the following stages:
1. Stage of the provision of the anlages of nervous tube on the account of the adjacent extra-organ vessels. The rap-
id development of the primary capillary network in immediate proximity to the anlages of the nervous tube is observed.
At this time the volume occupied by the capillaries is comparable with an absolute volume of the anlage of the central
nervous system. The anatomical anlage of the nervous tube appears. The determination of cells having the common pre-
cursors to the neuroblasts and glioblasts begins.
2. Embryonal angiogenesis in the nervous anlages (Fig. 29). It consists in the penetration of vasal precursors into
the nervous tube from the surrounding mesenchyma. The vasal precursors are formed of the vessels adjacent to the ori-
gins and possibly due to the differentiation of mesenchyma. At this stage the trophic supply performs at the account of
both extraorgan and intraorgan primary vascular networks. The formation of the primary vascular network in the central
nervous system proceeds long before the processes of neuroblast differentiation. At the 16-18th day of rats’ embryogene-
sis, when the primary capillaries are abundantly represented in the anlages of the nervous tube, the contact system be-
tween the neuroblasts of some nuclei of the brain stem is limited by the axonal and dendritic sprouting. An insignificant
number of immature synaptic contacts exist, simultaneously with the active growth of processes (N.N. Bogolepov, 1999).
This is confirmed by the data of K. Sato (1998), demonstrating the primitive synaptic function in the nuclei of the vagus
nerve in rats appearing not earlier than at the 15-16th day of intrauterine development.
The available data suggest that the vessels are just the main migration ways of the glial cells under the conditions
of transplantation of the embryonic nerve tissues (M.A. Aleksandrov, E.V. Loseva, I.V. Ermakova, 1993; W.J. Golden-
berg, J.J. Bernstein, 1988). There are data indicating the probability of their similar role during the ontogenesis. The high
degree of interaction is noted between the glial elements and the blood vessels during the early postnatal ontogenesis of
the central nervous system in rats. The substantial increase of the number of astrocytes and oligodendrocytes was shown
to be accompanied by the migration of their precursors and by a high degree of interactions with the adjacent vessels.
Such contacts are observed as early as at the initial stage of astrocytes differentiation. The vessels can play role in the
commitment of macroglia (M Zerlin, 1997). The high degree interactions between the astrocytes and endothelium is ob-
served, accompanied with the formation of the hollow tubes; the same exists in the tissue culture (L.R. Ment, 1997). The
precursors of neuroglia have a remarkable property of controlling the displacement and the differentiation of neuroblasts,
the growth of their processes, contributing the neuritis growth both in vivo and in vitro (YS. Caviness, Nission Jena-Paul
et al, 1991; R.D. Fetter, K Broadie, C.S. Goodman, 1995). In the cerebral cortex the neuroblasts use the fibrils of neurog-
lia, along which they move outwards to the external surface of the brain (A Faissner, M Schacher, 1995). The neuroblasts
migration performs and is regulated by the chemical interactions between them and the astrocytes precursors. Astrocytes,
in turn, possess an affinity to the vessels. It is due to the chemical (diffuse trophic and extracellular matrix molecules) and
mechanical factors (cellular surfaces). They ensure the tropism between the cells, as well as between the cells and inter-
cellular matrix (P Rakic, 1981; M.E. Hatten, 1990; B Voutsinos, L Chouaf, P Mertens et al, 1994; A. Faissner, M Schach-
er, 1995). Some researchers of the nervous systems suggest that microglia represents the derivative of monocytes, which
infiltrate the central nervous system during the development, but the mechanisms providing the penetration of these cells
into the nerve tissue, are unknown. However, the secretion of adhesive molecules in the endothelium at the stage E16-19
of rat embryos development was demonstrated. They can ensure the penetration of the microglial precursors into the
nervous tube (I Dalmau, 1997). Thus, the development of microglia is also interdependent on the intercellular and inter-
tissue interaction in the nervous tube.
3. Conversion of the primary capillary network along with the maturation of neuron and glial ensembles, either
second angiogenesis. This stage supposes the presence of several additional stages:
A. The primary capillary network becomes considerably enriched and complicated (Fig. 30), forming the so-called
“embryonic” type of blood supply of the nerve tissue. In the nervous tube
 63
the microcirculatory tree is characterized by the polygonal pattern of arborization, by the abundance of anastomoses,
by insignificant variability of architectonics in the nuclear ensembles which are morphologically and functionally differ-
ent. One loop contains the large neuron and glial groups. At this stage the intensification of the blood supply occurs due
to the absolute increase of vessels number in the whole anatomical structure. In rats in the beginning of this stage the
processes of neuroblasts proliferation continue, while at the later stages the migration and proliferation of neuroglia pro-
ceed. This stage includes the second half of intrauterine development. The rapid proliferation of neuroblasts in human,
corresponding the initial terms of development at this point, is observed up to the 6th month of intrauterine development.
Then the rapid development of glia, synapses and dendrites follows. It begins from the 25th week of embryogenesis and
continues after birth (J Dobbing, J Sands, 1975). In rats, which come up immature, the brain growth accompanied with
the predominating proliferation of neuroglia and formation of processes begins during the delivery and immediately after
the birth, according to our data and to the data of other authors (V.E. Nexdorf-Bergveilve, D Albrecht, U Heinemann,
1993). In rats during the early postnatal period the active proliferation of cells containing the acid glial fibrillar protein
continues, predominantly within the first two weeks, while the architectonics formation continues up to 2-3 weeks after
birth (J Dobbing, J Sands, 1975; V.E. Nexdorf-Bergveilve, D Albrecht, U Heinemann, 1993).
The relatively late development of neuroglia with comparison to the neurons lets to control the level of develop-
ment of neuron complexes in the central nervous system, and then stabilizes the processes of their development (S.C.
Clemens, U Klans, 1994; T.J. Sims, S.A. Gilmore, 1994). The disturbance of the rate of its maturation results in the
change of normal formation of interneuronal interactions. Such phenomenon can be observed in case of Down disease,
due to the activation of the gene, coding the protein S-100 (which accelerates the differentiation of neuroglia). The accele-
rated development neuroglia blocks the further growth of the processes of neurons, causing the neurons apoptoses and
depleting the interneuronal interactions (L.N. Korochkin, 1989). The great importance is attached to the central nervous
system effects of the large family of the evolutionarily conservative proteins, which control the cellular differentiation,
growth and morphogenetic processes during the ontogenesis (converting growth factor-beta, activin, bone morphogenetic
proteins). The superfamily of converting growth factors-beta includes more than 25 substances, revealed in the develop-
ing nervous system in mammalian, which presumably participate in the control of regionalization at the early-stage de-
velopment in mammalian. The converting growth factors, activin and the bone morphogenetic proteins cause the forma-
tion of heterooligomeric complexes in nerve tissues cultures. They can ensure the cellular cooperation during the neuro-
genesis. The last two families have the corresponding receptors on the surface of neurons and in the adult brain, which
indicates their functional significance. These tissue hormones can form the system, parallel to the neurotrophin- tyrosine
receptors, regulating the neuroplasticity and cerebral repair (T Ebendal et al, 1998).
B. The stage of formation of the definitive circulatory system in the nerve center, which is accompanied with an
active differentiation of the walls of the afferent and efferent vessels (Fig. 31, 32). It is accompanied with a variable mor-
phology of vascular networks in accordance with the nuclear structure, with an intensification of blood supply of individ-
ual cells. The vessels density per volume unit of the nucleus changes insignificantly. An increase in the number of micro-
vessels around the neuron bodies occurs via their distribution and increase in the number of neurons, immediately con-
tacting with the capillaries. The last assumption correlates with the data of the previous studies, demonstrating the maxi-
mum density of vessels in the nuclei of trigeminal complex in rats before the puberty, while the further development of
neuronal vascularization proceeds through approaching of the capillaries to the neuron bodies (E.G. Balashova, 1956).
Our results come into antagonism with the data of other investigators, demonstrating that the concentration of ves-
sels around the large neurons is higher (3-4 capillaries around the neurons in the motor nucleus, 1-2 around the perikarya
of neurons of the main sensitive nucleus of trigeminal nerve) (E.G. Balashova, 1956a). However, on closer examination
these data coincide with our results with an allowance for the volume of neurons and the number of vessels, adjoining
immediately to the neuronal bodies.
The stages of formation of the nervous tube vascularization are in accordance with the investigations of B.N. Klos-
sovsky (1949) and E.G. Balashova (1956) concerning human embryonal development. They proposed to distinguish the
following periods of trophism: liquor, liquor-hematic, vascular (at the stage of neuroblasts migration). According to their
opinion, the intense vascular networks, is visible as early as at the 3rd month of human prenatal ontogenesis. However,
there are specific contradictions with these data. Thus, in the opinion of other researchers,
 64
the vascularization of the locus coeruleus in rat embryos advances to the 8th day of development. The noradrenergic
neurons of this region are not characterized by an accelerated morphological development, but the specific fluorescence is
observed in the embryos as early as at the 12-15th day (A.M. Ten, T.I. Belova, V.V. Korolev, 1980). The differences can
result from the different approaches used in the investigation procedures and from their interpretation. In the mentioned
works the formed capillary-vascular networks in the individual anatomical structure of the nucleus were laid into founda-
tion. On the contrary, in our studies the characteristics of trophic supply of the entire anatomical region of nervous tube
within the appropriate periods were examined, rather than the particularities of an individual anlage.
The complexity of relationships between the neurons and the microvessels depends on the characteristics of distri-
bution of the vascular network, rather than on its density (E.G. Balashova, 1956). Distribution, microanatomical characte-
ristics, contacts, predominance of certain macroglial populations keep in the direct interdependence on the structure of
neuron ensembles. The processes of astrocytes closely anastomize inter se and display the specific character of interac-
tions in the different nuclei. Our opinion has something in common with the opinion on the possibility of the so-called
volume signal transmission in the nervous system, which must depend on the structural-functional role of the particular
nuclear structures in the central nervous system. This transmission can be achieved via the biologically active substances,
including the nitric oxide (S.Kh. Snaider, D.S. Bredt, 1992), the neurotrophins, the neuropeptides (M.O. Samoilov, 1999),
the neuromediators (N.B. Saulskaya, 1997). These substances can exert a diffuse effect on the neurons, which are not in-
nervated by the presynaptic terminals of an effector cell, as they diffuse to the significant distances from the secretory
site. Thus, the volume signal transmission exerts a modulating influence on the processes of the synaptic transmission
(M.O. Samoilov, 1999). Neuroglia is supposed to play the role of an important element, which actively participates in the
processing of the information arriving into the nervous system. The concept has been formulated, postulating that the dy-
namics of excitation in the central nervous system is ensured by its transmission from the neurons to macroglia, and then
to others neurons (R Galambos, 1961; S.V. Kuffler, J.C. Nichols, 1966; L Heitz, A Schousboe, 1988; A. Vernadakis,
1988).
The comparison of the stages of development and of the criteria of intensity of microcirculation of neuronal bodies
reveals the signs of significant correlation dependence (Table 35). As an example, the correlation levels between the de-
velopment of microcirculatory tree and the stages of development in rats are represented for the basic populations of neu-
rons, examined depending on their dimensions, in the motor nucleus of trigeminal nerve. The maximal correlation level is
observed between the number of vessels per neuron and the stages of development in small and middle-size neurons. It is
considerably lower in the large and very large cells. This characteristic is probably connected with the fact that the large
and particularly giant neurons are revealed at the comparatively late stages of postnatal development, while small cells are
examined beginning from the stage of neuroblasts. The specific vessel length and the other values (area of the exchange
surface of the microvessels and pericapillary ultrafiltration diameter), being its derivatives, correlate with the periods of
development similarly to the previous compared parameters. The specific area of microvessels which most effectively
exchange with the neuronal bodies in case of the giant neurons grows in parallel with the stage of development consider-
ably more rapidly, which can be caused by an increase of the neuron size. In addition, the microvessels begin to adjoin
tightly to the neuronal bodies. The distribution of the neuron populations

Table 35
Correlation between the stage of development, the microcirculation around the neuronal bodies and their rel-
ative content with respect to the whole population of the neurons of the motor nucleus of trigeminal nerve in
rats

Populations of neu- Parameters compared

rons Number of the mi- Specific length of mi- Specific area of the Relative amount with
crovessels per neuron crovessels per neuron most effective ex- the respect to the
change whole population of
neurons in the nuc-
leus
Small 0.487 ± 0.052 0.451 ± 0.054 0.431 ± 0.055 -0.612 ± 0.051
Middle-size 0.475 ± 0.047 0.428 ± 0.049 0.404 ± 0.050 -0.017 ± 0.082
Large 0.317 ± 0.062 0.242 ± 0.065 0.221 ± 0.066 0.763 ± 0.034
Giant 0.299 ± 0.077 0.201 ± 0.089 0.409 ± 0.053 0.516 ± 0.050
 65
according to their sizes indicates the existence of the inverse correlation between the stages of development and the
number of small neurons, with the positive correlation between the stages and the number of large and giant neurons.
Thus, the neurons differentiation in the course of ontogenetic development, from the early stages of prenatal ontogenesis
up to the puberty is accompanied with an increase of quantitative parameters of microcirculation, of the dimensions and
morphological variability of neurons. The importance is attached to the dynamics of changes of the level of trophic supply
of the nucleus as an integral anatomical structure during the ontogenesis (Table 36). Thus, the specific length of micro-
vessels per volume unit in the motor nucleus of trigeminal nerve correlates with the stages of prenatal and early postnatal
rats development up to the end of the 1st week of postnatal ontogenesis. This correlation is highly significant (0.801 ±
0.023). It takes an absolutely different form at the stage from the end of the 1st week to the 6th month, when the correlation
of this parameter experience an inversion and becomes negative (-0.505 ± 0.061). Thus, the absolute number of vessels at
this stage decreases, while the intensity of vascularization of the neuron bodies still increases, which is obvious both upon
examination of the absolute parameters of blood supply of the neuronal bodies and according to the correlation values in
the giant neuron population, which appear in the postnatal ontogenesis (after the 1st week of postnatal ontogenesis). This
contradiction is explained by the distribution of vessels in immediate proximity of the neuronal bodies at the late stages of
development. The density of neurons reduces accordingly, being in the inverse correlation to the stages of development.
This is caused by the increase of the neuropil volume, particularly during the postnatal development, when the growth of
the neuron bodies is considerably delayed from the degree of the processes development. During the prenatal develop-
ment these processes are mutually balanced. In ontogenesis the reduction of the area of microvascular basins occurs si-
multaneously with the reduction in their linear dimensions. The changes proceed predominantly due to the decrease of the
largest diameter of microbasin, while the smaller diameter varies less significantly, which is accompanied by the trans-
formation of microbasins shape. This process is synchronized with the reduction of neurons number in the individual mi-
crobasins, especially during the postnatal development.
Thus, the correlation analysis of the trophic supply, carried out with the motor nucleus of trigeminal nerve as an
example, demonstrates two versions of its formation during the prenatal and postnatal development. During the prenatal
ontogenesis the blood supply of neuroblasts and of neurons is improved due to an increase of vessels number within the
volume of the whole nucleus, and is accompanied by the significant dynamics of sizes and of the formation of their mi-
crovascular capillary basins. At the later stages the intensification of the blood supply proceeds by way of distribution of
the vessels in the immediate proximity to the perikarya of neurons, of the reduction of the cell number in the microvascu-
lar basins with a simultaneous significant reduction of the density of neuronal perikarya.
In other nerve center the similar changes occur. Our assumption is based on the fact that recently the ensemble or-
ganization of the structures in the central nervous system has been substantially revised. Classically, the interneuronal
interactions and the microarchitectonics of the neurons and their processes were investigated.

Table 36
Correlation between the stages of development and certain parameters of the motor nucleus of trigeminal nerve as
an integral anatomic structure in rats

Parameters Stages of development

All the stages ex- From the 10th day of From the end of the
amined ontogenesis till the 1st week till 6 months
birth
Specific length of the microvessels 0.471 ± 0.033 0.801 ± 0.023 -0.505 ± 0.061
Specific density of the neuron bodies -0.418 ± 0.039 0.064 ± 0.057 -0.679 ± 0.038
Volume of microbasin -0.419 ± 0.032 -0.727 ± 0.057 -0.228 ± 0.067
Maximal diameter of the microvascular basin -0.544 ± 0.042 -0.759 ± 0.024 -0.269 ± 0.065
Minimal diameter of the microvascular basin -0.437 ± 0.047 -0.564 ± 0.039 -0.192 ± 0.069
Number of neurons per one microbasin -0.512 ± 0.042 -0.064 ± 0.057 -0.679 ± 0.035
 66
Yet the works appeared, where, by analogy with the structure of cerebral cortex, the microensembles include not only
the neurons, but also glial and vascular elements (A.M. Antonov, 1985; L.K. Semenova, N.S. Shumeyko, 1994). These
studies relate the results of investigation of the column organization of neuron ensembles in the cerebral cortex to the an-
gioarchitectonics and glioarchitectonics. According to the authors’ data, between the agglomerations of neurons the vas-
cular collectors (arteries and veins) and the agglomerations of neuroglia are situated. These structures may separate the
columns. Contrary to our data, the results concerning the ensembles are presented by analogy with the column organiza-
tion of the ensembles in the cerebral cortex. Thus, the vascular trophic complexes are placed against the large agglomera-
tions consisting of hundreds and even thousands of neurons, the relation between these neurons, arteries, veins and large
neuroglial blocks is designated. The dynamics of ontogenesis during the formation of ensemble organization is presented.
We present the studies concerning the nuclear type centers. However the most important particularity of this ex-
amination consists in the investigation of the structures at the level of the individual microvascular basins, providing the
blood supply within the nearest capillary loops, united under the general conditions of organization. Thus, the primary
attention is given to the bodies of the individual neurons or to the small groups, rather than to their agglomerations, the
emphasis is laid not only on isolating, but also integrating properties of neuroglia, on the microarchitectonics of these
complexes at the level of individual microvascular basins.
This considerably increases the accuracy of the conclusions on examination of the physiological, pathologic and
ontogenetic problems. Based on the example of the cerebral cortex, Pfeiffer has already indicated the correlation between
the angioarchitectonic and cytoarchitectonic layers of the cerebral cortex on the basis of vertical sections after the vessels
injection (R.A. Pfeiffer, 1930). The columns of the cerebral cortex consist of the neuronal agglomerations and are
bounded with the borderline spaces 13 to 30 μm in width, occupied by the vessels and nerve fibers (vascular-fibrous cap-
sules) (L.I. Kushakovskaya, 1988). In the developing brain of the mammalian the glial cell surround the functionally ana-
logous groups of neurons, their dendrites and axons. The glial cell and the glycoconjugates (glycoproteins, glycolipids
and glycosaminoglicanes) of this environment are particularly traced in the cerebral cortex (O.S. Sotnikov, N.K. Boguta,
1994; A. Steindler Dennis, 1993). There are sporadic data concerning the participation of blood and glial sources of
supply in the ensemble organization of the morphofunctional units of the spinal cord (N.V. Novomirskaya, 1976). The
neuroglial ensembles display the individual structure. In the gifted people in the 3rd and 4th layers of the 44th and 45th cor-
tical area the percentage of the satellite neuroglia is considerably higher, as well as the total area of the glial cells, in com-
parison with the total population (N.I. Bogolepova, 1993).
The significance of the examined complexes in nuclear type centers is indirectly confirmed by the data demonstrat-
ing that even the diffuse edema of the brain develops irregularly, by the bounded areas, including the vessels, the neurons
and the glial cells. This results in a unique mosaic of the edematic and less damaged zones. The actively reacting neurog-
lia presumably performs the drainage and supporting functions (T.I. Shustova, K.G. Tikhonov, 1998). It is known that
under the pathologic conditions in the nervous system the focal withdrawal of neurons is observed, i.e., the reactions of
nerve tissue in the central nervous system are polymorphous and local (E.E. Perevozshchikova, 1999, M.B. Potanin,
1999). This mosaic structure is probably related not only to the interneuronal synaptic interactions, but also to the local
reactions of microvessels, glia and extra-synaptic intercellular contacts. The coordination of the reactions of all tissue
elements is characteristic for the central as well as peripheral nervous system (V.N. Baytmanov, 1999). According to the
opinion of N.S. Kositsyn, the activated neurons have a larger affinity to the silver nitrate, due to the spatial distribution of
protein complexes, enabling to consider the impregnation as a marker of the functionally active neurons (N.S. Kositsyn,
1999). Our studies have discovered that a substantial part of neurons and astrocytes are susceptible to the impregnation by
the local groups of cells, which is especially obvious after the experimental influences exerted. This confirms the opinion
concerning the zonal reactions of both the neurons and the astrocytes.
It was revealed, that in the areas immediately surrounding the zone of ischemia, the increase of the concentration
of the nerve growth factor two-fold or more is observed at the third day, in comparison with the control, while the signifi-
cant increase is noted as early as at the 1st day. The high level of this protein persists up to 23 days. The hormone is ad-
sorbed on the membranes of the neuron bodies and ensures their protection during the sharp phase of alteration (J.M.
Conner, S Varon, M.C. Hoener, 1996). The neurotrophic factor, produced in the astrocytes, plays an important role in the
stimulation and provision of the activity of the dopaminergic neurons (K.E. Boven Kamp, P.A. Lapehak et al, 1997).
 67
Numerous facts indicate the possibility of direct humoral interaction of the constituent elements of complexes.
The influence on the capillary-vascular structure is represented by the production of biologically active factors in the neu-
rons, which are capable to regulate the vascular tone. Thus, the neurons of the striatonigral system in rat represented the
urocortin-like immune reactivity. Urocortin is considered as an endogenous ligand, controlling the vascular tone and the
cognitive functions (V.G.Shalyapina, 1995; T Kozicz, A Arimura, H Yanaihara, 1998). The group of neurons was re-
vealed, capable of synthesizing interleukin-6, which mediates the activation of microglia and of the astrocytes under the
different influences (R Lemke, N.L. Scholz et al, 1998). The nitric oxide, known as the endothelium-secreted relaxing
factor, stimulates angiogenesis and is under the control of the substance P, endothelin-1, bradykinin, angiotensin-II, vaso-
pressin, interleukin-1, adrenaline and of other hormones (M. Ziche, 1994). It presumably exerts the mytogenic effect
through the endothelial growth factor (L Morbidelli, 1995). All these substances are produced in the neurons. In the brain
of hen embryos the proliferating neuroblasts are capable of synthesizing thrombospondin-1, while the neurons express the
thrombospondin-3 (R.T. Tuker, 1997). These tissue hormones actively participate in the processes of angiogenesis (they
possess an antiangiogenic activity) and are revealed in the brain of mice and human (N Sheibani., W.A. Frasier, P.J.
Newman, 1997). In adult persons the astrocytes possess the ability of secretion of thrombospondin, thus controlling the
intensity of vascularization (S.C. Hsu, 1996). The astrocytes absorb both the exciting and inhibitory transmitter with a
rate, which exceeds their seizure by the synaptic membranes. Simultaneously, they change as they are, the metabolic ac-
tivity under the influence of these substances (A.I. Roit-bak, 1993).
The importance is attached to the ability of neuroglia to influence the speed and degree of angiogenesis (T Shirat-
suchi, T Tokino, 1997; E.L. Lund, P.E. Kristiansen, 1998). This may show that in central nervous system there are struc-
tures, which can perform the primary homeostatic function. The motor and the mesencephalic nucleus of trigeminal nerve
are characterized by the high content of the fibroblast growth factor-9, which exerts a significant activating effect on the
growth of vessels (T Todo, K Ikeda et al, 1998).
However, the neuroblasts and differentiating neurons are certainly determining during the formation of the ensem-
ble organization. Among the factors, which play a role in the formation of the nervous systems of mammalian, the great
importance is attached to serotonin, being a key factor at some development stages. Serotonin is one of the classical neu-
rotransmitters which is expressed in the early prenatal ontogenesis in the brain anlage and provides the control over its
development, while in adults it controls the neuronal reactions. The protein S-100, glial neurotrophic factor, is postulated
to be modulated by serotonin through the A1 serotonin receptors. The inhibition of its production is accompanied by an
increase of glial acid fibrillar protein and of the protein S-100 in the experiment in comparison with the control. This can
suggest the influence of substance on the astrocytes (P Tagliaferro, 1997). The serotonin transporter is the most important
peptide, which controls the content of extracellular serotonin. At the early stages of development in different systems of
the brain the different classes mRNA of serotonin transporter is secreted (the permanent class is revealed in serotoninergic
neurons, the transitory classes - in other regions, for example, in the nuclei of trigeminal nerve). There are data indicating
that the effect of serotonin in the different periods of ontogenesis is different (S.R. Hansson, B.J. Hoffman, E Mezey,
1998). It was shown that the monoaminergic hypothalamic systems during the prenatal ontogenesis develop synchronous-
ly with the formation of serotoninergic structures (M.T. Ugryumov, 1997). The representation of adrenergic receptors in
the vascular plexuses and in neurons increases dynamically during the ontogenesis, according to their differentiation. Ac-
cording to the opinion of the authors, this can play the leading role in angiogenesis and in noradrenalin mediation (U.H.
Winzen-Serhan, F.M. Leslie, 1997). The cholinergic and GABA-ergic neurons of the cerebral cortex are capable of ex-
pressing interleukin-6 that plays an essential role in the early process of inflammation and stimulating the astrocytes or
microglia (R Lemke, R Schliebs, V Bigl et al, 1998).
Upon the microinjection of acetylcholinesterase the specific activation of the protein metabolism is observed in the
neurons of the locus coeruleus in rats, which is accompanied by excitation of astrocytes and microgliocytes. The inten-
sively functioning neurons are supposed to form the local signals, which cause the reactive changes in the adjacent neu-
roglia. They are manifested in the local immunohistochemical reactions of astrocytes for one hour after the influence on
the neurons. Microglia changes significantly
 68
within 4 - 8 hours (L.A. Zimmer, M Ennis, M.T. Shiplay, 1997).
Endothelium is capable of exhibiting the hormonal activity through the release of substances, which control the
vascular tone (prostaglandins, endothelins, nitric oxide), and of the growth factors (epidermal growth factor EGF/NGFb,
converting growth factor, vascular endothelial growth factor, monobutyrin and trombospondin). The class of endothelins
is remarkable in this respect. The expressed vasoconstrictor effect of the endothelins 1 and 3 is known (G.W. Haynes,
F.E. Strachan, D.J. Webb, 1994). There is a connection between the group of endothelins from one part and angiotensin,
kinins and prostacyclins from the other. Endothelin 1 stimulates the gene of cerebral natriuretic peptide and adrenomodu-
lin, exerting a great modulating influence in the central nervous system (O.A. Gomazakov, 1996). Endothelins can control
the proliferation and migration of the endothelium per se (L Morbidelli, 1995). With the use of immunohistochemical me-
thods it was revealed, that the bodies of neurons in adult rats are characterized by the high content of class A receptors to
endothelin in many regions of brain, including the tectum of the pontis, the locus coeruleus, the lateral mesencephalic pe-
riventricular region of the rostral area. The low level of susceptibility is revealed in the mesencephalic nucleus of trige-
minal nerve. This receptor is predominantly characteristic for the catecholaminergic neurons (K Kurokawa, 1997).
The high plasticity of the nervous systems was revealed, manifesting in the change of synaptic architectonics and
of the structure of neurons (N.N. Bogolepov, 1996; B Budzynska, A Zerebska, 1996; R. d'Ascanio, O Pompeiano, P Ar-
righi, 1998). The dynamics concerns both the synaptic and the non-specific interneuronal contacts (N.N. Bogolepov,
1979; N.N. Bogolepov, I.I. Pavlovskaya, N.I. Iakovlev, 1979; A.P. Novozhilova, 1993). The morphological change in
these contacts is accompanied by the variable functional activity of neurons and leads to the change of the neuron ensem-
bles developments during the ontogenesis (Y Chen, M Herrera-Martshitz, k. Anderson et al, 1997). It was revealed that
neurons possess the receptors to the neurotrophic factors, while the type of receptors depends on their structure and spe-
cialization, which was shown on the mature rats in the ventral nucleus of auditory nerve (A Burette, 1997). The dynamics
of extra-synaptic contacts in the central nervous system they are manifested in their quantitative changes (increase of the
dendro-dendritic, dendro-somatical and dendro-glial contacts). The local ectasia, the disturbance of the congruence in the
membranes lead, the aggregation of organelles and the increase of the number of areas displaying the intensive osmiophil-
ity are observed (A.P. Novozhilova, 1993).
The reasons of genetic impairment in case of the hereditary damages of the brain and the structure of nuclei in
these diseases are actively investigated (V Plante-Berdeneuve, D Taussing, F Thomas, G Said, 1997). At each level of
organization of mammalian brain during the ontogenesis the influence of both rigidly fixed genetic and probabilistic pro-
vision of development is characteristic. The plastic rearrangements are inherent not only at the intracellular level, but in
the macro-ensembles, which is manifested in a change of their cellular, fibrous and vascular structure (L.I. Korochkin,
1991; O.S. Adrianov, 1995; M.E..R. Hallonet, N Le ' Douarin, 1993; M.E. Hallonet, 1993). The spectrum of the genetic
programs is present, which in joint interaction determine the architectonics of the nervous systems. In this spectrum both
the neuronal programs and the genetic influence exerting at other levels, including the organism level, are of importance.
The process of neuronal differentiation is universal and reaches the irreversible state in the stage of differentiation (L.I.
Korochkin, 1991). The changes of neuro-glio-vascular interrelation occur upon a change of the age and of the functional
state (N.A. Mezhibrovskaya, 1987).
 69
CHAPTER IV. TRANSFER OF SUBSTANCES IN THE BRAIN

After the supravital injection of Evans blue and trypan blue under normal conditions in mature animals the transfer
of these substances through the hematoencephalic barrier was considerably hindered, but the barrier could be surpassed
with the use of the high doses of dye. We considered the creation of the conditions of artificial hypothermia to be a more
appropriate method for the breakthrough of the barrier; in this case the distinct focal impairment of the barrier properties
of endothelium in the cerebral vessels was observed. This phenomenon was most obvious from the 1st to the 4th hour after
the performed procedures. Having carried out the preliminary studies we stopped at the injection of the dye one hour after
the creation of artificial hypothermia of cerebral tissue. The dye diffusion was manifested in the staining of specific cere-
bral tissue structures. The process of diffusion after the injection of methylene blue and neutral red was facilitated. The
tracers easily penetrated through the barrier structures of the brain.
The data concerning the substances with the low penetrating power seem to be the most curious. Under the condi-
tions of the preserved barrier the Evans blue and trypan blue are located in the lumina of the vessels investigated, fre-
quently forming the fine granularity. Trypan blue stains the erythrocytes dark blue. Frequently the weak staining of endo-
thelial lining could be observed, but the preparation did not move further forward. The similar phenomena were observed
after the slaughter of the animals 1 minute after the injection of the dye (Fig. 33). In case of breaking the barrier both try-
pan blue and Evans blue diffuse to the astrocytes processes and penetrate the perivascular muffs that they form, enabling
to stain the terminal branches of their processes. The ways of the dye transfer move apparently along the course of the
processes of gliocytes, resulting in the formation of the cords, containing the dye which is dispersed in the form of the
finest granularity. The pattern of these cords resembles the architectonics of the astrocytes processes, obtained after the
Golgi -Bübenet staining. The dye does not penetrate into the bodies and the processes of neurons, leaving the cytoplasm
unaffected. The single cases of the neurons staining are observed. Thus, the importance of macrogliocytes and of the as-
trocytes in particular could be supposed for the ensuring of barrier functions. The extensive area of the contact surface of
these cells can provide the seizure of some substances, preventing their immediate effect upon the structures of neurons.
In 3 to 5 minutes the diffusion of Evans blue reaches 6 to 15 μm from the surface of vessel (on the average 7.18 ±
0.15 μm in 3 min. and 11.63 ± 0.19 μm in 5 min). The methylene blue penetrates relatively uniformly, staining diffusely
the structures of cerebral tissue as early as in 1 minute, achieves the maximum concentration in 15 minutes and is consi-
derably reduced 30 min and 1 hour after the injection. It is predominantly accumulated in the nuclei of every cell and in
the cytoplasm of neurons (Fig. 34, 35).
The significant interest is attached to the peculiarities of substances transfer through the barrier structures. Thus,
the diffusion of Evans blue proceeds more easily in comparison with the trypan blue, resulting in the rich staining of the
astrocytes processes. It should be noted that the dye does not penetrate all over, but rather in some zones along the course
of the vascular wall. It is especially obvious in the large vascular structures. The process of diffusion is characteristic not
only for the microcirculatory tree, but for the arteries and the veins as well. It develops most actively in the postcapilla-
ries. The presence of the developed glial muffs around the postcapillaries, in spite of the increased permeability of the
latter, is not accompanied by the breaking of barrier, due to the active capture of the dye in the astrocytes processes. The
diffusion of dye is limited within 15 to 30 μm (on the average 19.17 ± 0.27 μm in 10 min. and 21.47 ± 0.42 μm in 30 min)
from the boundary of the endothelial lining. The brightness of the staining of the cerebral structures decreases considera-
bly one hour after the injection; but the single weakly-stained zones are visible. The distribution of the dye is limited
within the distances which are observed 15-30 minutes after the injection of a substance (on the average 22.14 ± 0.35
μm). The dye does not virtually penetrate in the structures of pericapillary cells, which could suggest their low activity in
the processes of the transfer of high-molecular organic substances.
The diffusion of Evans blue in the system of microcirculatory tree proceeds non-homogeneously; after the breaking
of the hematoencephalic barrier it stains the tissue irregularly, forming the separate areas, it results in a mosaic picture
which can be observed, when both the zones absorbing the dye and free from it are encountered in one nucleus. The stain-
ing performs in parallel with the microbasins, which were examined earlier. If we examine the cross section of the vessel,
the traffic streams are uniform in all directions, diminishing from the lumen of the vessel to its periphery. Thus, the break-
ing of the hematoencephalic barrier is accompanied by the focality of the lesion, in accordance with neuro-glio-vascular
conglomerates.
The functional heterogeneity of the substances transfer along the course of individual vessels was revealed,
 70
which is manifested in different penetration of the tracer along the vessels. The structures having the significant and
weak absorption of the dye can be encountered.
The investigations in rabbit and in rats showed similar results. We should note less stable data with the use of the
Evans blue in rabbit under the conditions of hypothermia at the level of the brain stem, whereas in cerebral hemispheres
the breaking of the barrier properties in rabbits and in rats occurs analogously. This could indicate a certain imperfection
of the method of hypothermia that we used in larger animals. The degree of penetration of the substances into the brain
tissues and the particularities of the traffic stream within the same time range are similar to the corresponding values ob-
served in rats. However, the absolute analogy appears artificial, since after the rats slaughter and the isolation of the stem
structures with the cold fixation of the dye 1 to 1.2 minutes could pass, whereas in rabbit this process occupied 5 to 7 mi-
nutes, resulting in the significant changes of the substances diffusion. Thus, the processes of the transfer in the brain can
be more conveniently examined in small animals (rat, mouse).
During the examination of the characteristics of the barrier impairment in the experimental conditions it was re-
vealed that the focal staining of the dorsolateral area of the locus coeruleus and of the ventral structures of the pontis (nuc-
leus pontis) is observed most frequently. The transfer of substances into the tissue structures of the brain performs irregu-
larly in different vessels, which is most obvious under the pathologic conditions. The depth of diffusion is limited within
20 to 25 μm. During the examination of the vascular cross sections, taking into account the heterogeneity of the traffic
streams along the different vessels and even within the different zones of one vessel, the tracers were revealed to pene-
trate uniformly in all directions. Somewhat different results were obtained during the investigations with the use of me-
thylene blue. According to the available data, it easily undergoes the transcapillary transfer process in the brain stem,
which results in the diffuse penetration of the substance 3 to 5 minute after the injection. It is associated with a weak and
irregular staining of cerebral tissue structures. The nuclei of neuroglia appear to be most intensely stained. The bodies of
neurons have a weak blue color. Some of them are stained somewhat more intensely in comparison with the adjacent
cells. The nuclei of certain neurons are visible. The structures of neuropil are not identified in consequence of the uniform
penetration of the dye into the heteromorphic structures. The different intensity of staining of the white and grey sub-
stance and of the separate zones of the nuclei is observed. The variability in the content of dye is most obvious in the me-
sencephalic nucleus and in the zones having the focal distribution of neuronal bodies in the main sensitive and motor nuc-
lei of trigeminal nerve. In the central gray substance of mesencephalon, in the locus coeruleus, in the areas characterizing
by the diffuse distribution of neurons in the main sensitive nucleus of trigeminal nerve the tracer was distributed more
uniformly. At 10-15th minute the decrease of the tracer concentration in the parenchyma and in blood flow is observed,
more markedly at the 30th minute. This can indicate the reverse process of the dye diffusion into the vessels. The tracer
persists longer in the cellular nuclei, especially in the gliocytes.
Thus, the diverse versions of substances distribution in the nerve tissue are discovered, depending on their alkalini-
ty or acidity, intensity of the tracer binding with the molecular and macromolecular complexes of the cell and of the inter-
cellular substance. In the cases examined the preparations were used, which are not utilized or are weakly utilized by the
tissue structures of the brain, enabling to examine the traffic streams of the substances irrespective of their metabolism in
the cerebral tissues. Within the limits of the vessels cross section the diffusion of dye performs uniformly, while the dif-
ferences concern the longitudinal transfer. This provides an experimental confirmation of the possibility of using the pro-
posed parameter of the specific surface area of the most effective exchange of microvessels with the body of neuron for
the substances having the low-degree or uniform metabolism in the cerebral parenchyma. It appears appropriate in case of
the relatively uniform distribution of neurons, when the traffic streams within the capillaries weakly differ from the nor-
mal line and when there is no need for the differential examination of the alternate vectors of diffusion in the individual
structures of the vessel. However in the case when the diffusion streams are considered as deflecting from the normal line,
the probability of the substance diffusion in the direction of the neuron bodies will decrease exponentially in parallel with
the increase of the angular distance from the median, connecting the vessel under examination and the body of neuron.
The area of the exchange surface of neuron and mutually dependent parameters of the shape, size, number of neuron
processes are of great importance in the metabolic processes, especially including the elements of active transfer. The sig-
nificant concentration of vessels, revealed especially around the bodies of neurons in the mesencephalic nucleus of trige-
minal nerve, can be caused not only by the level of activity of energetic processes, but by the small surface area of neu-
rons, which are round-shape and have a small number of processes. This can hamper the supply of some substances which
are actively absorbed and metabolized within the cell, particularly of the monosaccharides; we have demonstrated this
phenomenon in the process of the mathematical modeling of glucose transfer.
 71
CHAPTER V. MATHEMATICAL MODELLING OF THE TRANSPORTATION FLOW
IN THE CENTRAL NERVOUS SYSTEM

V.1. Mathematical analysis of the diffusion flows of the oxygen and carbon dioxide

Thus far the available data concerning the mathematical analysis of gas diffusion, in particular of oxygen, at the
level of the system of microcirculatory tree are insufficient.
The previously used mathematical models attempted to examine the gas exchange within the volume of the brain
as a whole or within the limits of simulated vascular cylinder. The most interesting Russian model having a potential of
the further utilization during the investigations of brain is the model of K.P. Ivanov and Iu.Ia. Kislyakov (1979). Unfortu-
nately, the superfluous formalization of this model represents one of its important defaults. The limitations of the pro-
posed modeling method consist in the artificial distribution of vessels, strict boundaries of the microvascular basins, rigid
determination of the number of vessels around a neuron and of the number of neurons in environment of one capillary.
The represented version of modeling proposes to investigate the dynamics of gas diffusion in the real micro-
objects, preliminarily rebuilt with the use of stereo reconstruction of the sections.
The model build-up is preceded by the detailed investigation of an object with selection of typical or atypical struc-
tures, according to the need of the author, used for the subsequent reconstruction of the range of sections. The series re-
constructions were accompanied by the recording of data concerning the characteristics of microarchitectonics in the sec-
tion. The analysis of the sections was performed at intervals of 5 μm.
When the reconstructions were performed, the data concerning the object of investigation characterizing by the
unit dimensions of 125 μm3, were recorded into the computer. The size of a unit has no fundamental value and can vary
according to the purposes of the researcher. Our results confirm the sufficient degree of informativity even with the unit
dimensions mentioned above.
According to this model, the type of each microvessel was identified. For this purpose the characteristics of the
muscular wall and the angles of microvascular arborization were traced along the movement of the preparation.
Accept the normal hydrostatic pressure in the arteriolar part equal to 35 mm Hg, in the venular part - 20 mm Hg.
The resistance in each of the portions examined is described by the formula:

8 ⋅ hk ⋅ L k
Rk = (5.1.)
π ⋅ rk4
where Rk – resistance in the microvessel examined (Pa/mm3), hk – coefficient of the apparent viscosity of the blood within
the microvessel (Pa*sec), Lk – length of the microvessel (mm), rk – average radius of the microvessel (mm), π - pi charac-
ter.
The coefficient of the apparent viscosity of blood within the microvessel, which is used in the formula 5.1, is intro-
duced for each microvessel separately. In case of the vessels 2 to 10 μm in radius the viscosity coefficient is introduced
according to the Faraday-Lindsquist effect for the hematocrite value of 40 to 50%, described by the formula:
hk = 0.001 ⋅ (1.4 + 0.045 ⋅ rk ) (5.2)
where rk – average radius of the microvessel in μm, while hk – is presented in the units of N/mm3*sec. The total re-
sistance R was determined separately for each sequence of microvessels according to the first Kirchhoff's law. It is equal
to:
R = R1 + R2 + ... + Rk (5.3)
Thus, the volume velocity of blood circulation in the system of microvessels investigated is equal to:
ΔP ΔP ΔP
W= = = (5.4)
R R1 + R2 + ... + Rk 8 ⋅ h1 ⋅ L1 + 8 ⋅ h2 ⋅ L2 + ... 8 ⋅ hk ⋅ Lk
π ⋅ r14 π ⋅ r24 π ⋅ rk4
where ΔР – pressure gradient between the arterial and venous parts of microvessels (Pa).
The linear blood flow velocity in the terminal capillaries - vk (mm/sec) is equal to:
W
vk = (5.5)
π ⋅ rk2
The linear blood flow velocity in the afferent and efferent microvessels - vs (mm/sec) – was calculated while taking
into account the sum of the volume velocities
 72
of blood flow of the arising or converging vessels. Each portion between the new ramifications was analyzed indivi-
dually. The formula for the portion of two converging vessels assumes the following aspect:
W1 + W2
vs = (5.6)
π ⋅ rs2
If the terminal parts of the capillaries do not fall within the limits of the model examined, then their length in human is
taken equal to 0.7 mm, in dogs -0.64 mm, as this length is considered their average length, according to the experimental
data, which are confirmed in our own investigations.
During the modeling of the changes of oxygen content (ΔК) along the blood vessel we proceeded from the follow-
ing formula:
Δl ⋅ (π ⋅ Mt ⋅ L ⋅ ( R 2 − r 2 ) + (Vk1 ⋅ ( Mk1 − Mt ) + ... + (Vk k ⋅ ( Mk k − Mt )
ΔK = Ka − (5.7)
π ⋅r2 ⋅v⋅ L
where Ka – concentration of the oxygen in the arterial part of the vessel (mlО2/mm3); Δ/ - difference of the length of the
portion of vessel (mm); Mt- specific oxygen uptake in the neuropil (mlО2/mm3•sec); Mkk – specific oxygen uptake in the
neuron body (mlО2/mm3•sec); R – radius of the vascular cylinder (mm); Vkk – volumes of neurons, which are supplied by
the given vessel (mm3).
The proportions of the neurons volume, supplied by the vessel under investigation, were found with the use of the
following formula:
Vk1g ⋅ L1
Vk 1= (5.8)
∑ Lk
where Vk1g – total cell volume; L1 – length of the first vessel at a distance less than 25 μm of the neuron body; ∑ Lk -
sum of lengths of all vessels, situated at a distance less than 25 μm of the neuron body.
For the portion of vessel, situated at a distance of more than 25 μm of the nearest neurons, the gradient of the oxy-
gen concentration was calculated according to the equation:
Δl ⋅ π ⋅ Mt ⋅ L ⋅ R 2
ΔK = Ka − (5.9)
π ⋅r2 ⋅v⋅ L
The oxygen concentration in the arterial part of the vessel was calculated as follows. The partial oxygen content in
the proximal part of the arteriole or of the artery, which was determined at the reconstruction, was taken equal to 0.2
mlO2/mm3 - the value, which is confirmed in the number of literature sources. In case the origin of the arterial part of the
capillary steps over the bounds of the model examined, the microarteriole had to be found in the preparation, which gave
rise to the microvessel, and the initial maximal oxygen concentration was calculated taking into account the length of the
portion preceding the model beginning from the site of influx of the afferent microvessel.
In every case Ка in each subsequent portion was calculated from the oxygen concentration in the distal end of the
preceding portion. In case of converging the venous ends of blood vessels the oxygen concentration was averaged on tak-
ing into account its concentrations in the both converging portions of the microvessels and the volume blood flow veloci-
ty in them. Thus, the general formula is the following:
Q1 ⋅ Kv1 Q2 ⋅ Kv 2 Q ⋅ Kv k
Ка = + + ... + k (5.10)
∑ Qg ∑ Qg ∑ Qg
where Kvk – partial oxygen concentration in the venous end of the converging vessel (mlО2/mm3); Qk – volume
blood flow velocity in the converging vessel (mm3/sec); ∑
Qg - sum of the volume blood flow velocities of all converg-
ing vessels in the portion examined (mm3/sec). Since in the structures under investigation two vessels were converging in
each portion, the formula for these cases had a simplified aspect:
Q1 ⋅ Kv1 Q2 ⋅ Kv 2
Ка = + (5.11)
∑ Qg ∑ Qg
The dynamics of the gradients of partial pressure, of the degree of dilatation of the blood vessels is immediately related
with the differences in the pulse wave, which is most obvious in the afferent vessels, meanwhile, at the level of the cere-
bral vessels these differences are not so significant; so, they were not taken into account in process of modeling the blood
movement in the system. After the calculation of the oxygen concentration along the vessel its partial pressure can be de-
termined in mm Hg or in Pa. In our work we preferred to use the first measurement unit (mm Hg) as most usual for a bi-
ologists; in addition, these results can be easily converted into Pascals (via multiplying by 133.3), thus it is not crucial.
The partial oxygen pressure within the vessel is determined from its concentration and the dissociation curve of hemoglo-
bin. The last value depends both on the oxygen concentration
 73
in the vessel and on the partial pressure of the carbon dioxide which is dissolved in it. When the carbon dioxide partial
pressure (Рсо2) = 40 mm HG, the dissociation curve of oxygen can be described, according to the method of R.V. Shu-
mikhin, Iu.V. Vasiliev (2002), with the following formula:
Po2 = 0.2439 − 912.0018 ⋅ Ko2 + 299865.8167 ⋅ Ko22 − 2.1945 ⋅ 10−7 ⋅ Ko23 + 7.7622 ⋅ 10−8 ⋅ Ko24 −
− 1.5523 ⋅ 10−10 ⋅ Ko25 + 1.8745 ⋅ 10−11 ⋅ Ko26 − 1.3937 ⋅ 10−12 ⋅ Ko27 + 6.237 ⋅ 10 −12 ⋅ Ko28 − (5.12)
−13 −13
− 1.5410 ⋅ 10 ⋅ Ko + 1.6141
9
2 ⋅ Ko10
2
The oxygen concentration can be calculated taking into account the experimental dissociation curves of oxyhemog-
lobin with different Рсо2. The given procedure of determining the oxygen concentration is described in detail in the work
of K.P. Ivanov, Iu.Ia. Kisliakov (1979). After the Ро2 along each blood vessel was determined, the Ро2 in the tissues has
been modeled, particularly in the neurons bodies, taking into account their specific oxygen intake. According to the rec-
ommendations of Iu.Ia. Kislyakov, I.K.Breslav (1988), in line with the laws of substances diffusion by the concentration
gradient and taking into account the partial intake of this substance in the cerebral tissues, the partial oxygen pressure in
the tissues of the brain was calculated as follows:
δ 2 Po2 δ 2 Po2 δ 2 Po2 Mt ( x , y , z )
+ + − =0 (5.13)
δ x2 δ y2 δ z2 Dt ⋅ αt
where Dt – coefficient of oxygen diffusion in the nervous tissue, which is equal to 1.7•10-3 mm2/sec; αt – coefficient of
the oxygen dissolubility in the tissues of the brain, which is equal to 3•10-8 mlО2/mm3•mm Hg. (G. Thews, 1960).
While examining the partial oxygen pressure in the individual units the differential equations can be replaced by
the incremental equations:
mi , j , k Po 2i −1, j ,k − 2 Po 21, j ,k + Po 2i +1, j ,k Po2i , j −1,k − 2 Po 21, j ,k + Po2i , j +1,k
= + +
Dt ⋅ αt h2 h2
(5.14)
Po2i , j ,k −1 − 2 Po 21, j ,k + Po2i , j ,k +1
+
h2
where Ро2i,j,k – partial oxygen pressure in the given unit (it is nominally supposed to be uniformly distributed within the
volume of a unit, but shows in substance the pressure in the central part of the unit); h2 – area of contact of the adjacent
units (in our model it was equal to 25• 10-6 mm2); mi , j ,k - oxygen uptake in the given unit (mlО2/mm3-sec). After reduc-
ing the formula to a simplified aspect we obtain, according to the data of Iu.Ia. Kislyakov, I.S.Breslav (1988) the follow-
ing equation:
mi , j , k ⋅ h 2
Po2i −1, j ,k + Po2i +1, j ,k + Po2i , j −1,k + Po2i , j +1,k + Po2i , j ,k −1 + Po2i , j ,k +1 −
Po21, j ,k = Dt ⋅ αt (5.15)
6

The model investigated arises from some assumptions, that are probably important, but thus far poorly developed by
the physiologists and requiring further investigation. The irregularity of the oxygen intake and of the carbon dioxide pro-
duction in the neuropil is the example of such parameters. We understand that the bodies of astrocytes, oligodendrocytes,
the processes of neurons and the synapses can significantly differ in the mentioned parameters. Unfortunately, in availa-
ble literature these data are lacking; in addition, the mutual distribution and the relative volume of each cellular and sub-
cellular compartment cannot be determined simultaneously in the same structure of the brain. Moreover the metabolism
of oxygen and of carbon dioxide in the neuropil, according to the data of physiological studies, is of one order lower in
comparison with the bodies of neurons, determining the primary attention paid to the bodies of neurons. Furthermore, the
somewhat different pattern of oxygen and carbon dioxide diffusion through the intercellular spaces and other structures
can be supposed; however, taking into account the extremely complex nature of the intercellular space of nerve tissue, it
is impossible thus far to represent clearly the nature of its distribution and of preferred directivity. We proceeded from the
assumption about the random nature of intercellular spaces and the possibility of relatively uniform distribution of this
substance in the space of neuropil, enabling to examine the area between the neuron bodies as mathematically isomorph-
ous, having the similar possibilities of diffusion and of the level of consumption. It would be interesting to solve the given
problems in the subsequent studies.
The study of carbon dioxide diffusion has a number of differences with respect to the oxygen. If in case of oxygen the
characteristics of its diffusion and uptake in different tissue compartments must be considered, the transfer of carbon dio-
xide is caused both by the
 74
gas dissolved in the biological medium and by the diffusion of the carbon acid salts, as well as of the related substances
(particularly, hemoglobin). Thus, the concentration of free carbon dioxide per se comprises but a small bit of its deriva-
tives in the tissue structures of the body. It is necessary to keep in mind that the expansion of monosubstituted and bi-
substituted anions of carbon acid in the cellular compartments and in intercellular substance can perform relatively inde-
pendently and is controlled due to the permeability of ionic channels. At the same time the diffusion of carbon dioxide
through the diaphragm structures of the cell is accomplished freely by the concentration gradient. The relationship be-
tween the carbon acid and the dissolved carbon dioxide is a sufficiently constant value under conditions of the permanent
composition of the basic components of the liquid and of the united temperature regimen. Thus, the partial pressure of
carbon dioxide can serve an indirect, but sufficiently significant parameter of the acid-base balance status and of the gen-
eral content of free and conjugated CO2.
According to the opinion of a number of authors, the partial pressure of the dissolved carbon dioxide in the arterial
blood (PaCO2) is equal to 40 mm Hg. The partial pressure of carbon dioxide in the venous blood Pvco2 has a value of 46-
48 mm Hg. The partial pressure in the blood PKco2 is described by the formula:
HbO2 Hbo2
Pkco2 = 0.01 ⋅ (0.1148 + 0.41 ⋅ ) ⋅ Kco2 ⋅ (2.68 − 0.31 ⋅ ) (5.16)
100 100
In the brain the respiratory coefficient is taken equal to 1. The coefficient of dissolubulity in the cerebral tissues is
equal to otfCO2 = 5.6 mlСО2/mm3 MPa = 7.47• 10-4 mlО2/mm3 mm Hg, i.e. much higher than in case of oxygen, taking
into account the formation of other substances from the carbon dioxide. For the blood иксо2 = 5.06 mlСО2/mm3 •MPa =
6.74•10-4 mlО2/mm3 mm Hg. Dk - coefficient of oxygen diffusion in the blood which is equal to 2.5 • 10-3 mm2/sec.

V.2. Results obtained during the analysis of the oxygen diffusion flows using the mathematical model

As an example we represent the analysis of one reconstructed object: the mesencephalic nucleus of trigeminal
nerve in dogs (Fig. 57). We shall examine the model under the conditions of normal oxygen and carbon dioxide parame-
ters, normal system arterial pressure. We shall proceed from the assumption that the oxygen concentration in the arterioles
is equal to 0.2•10-3 mlO2/mm3 which corresponds to oxygen concentration of 95.8 mm Hg. According to the data of other
authors, at the level of arterioles and of the precapillaries this pressure is equal to 94 mm Hg (U Cleichmann et al, 1962).
The Расо2 value = 40 mm Hg, pH in the arterial blood was taken equal to 7.4.
With a normal system arterial pressure the average velocity of the blood flow in the capillaries, obtained experi-
mentally in the internal organs, is equal to 0.5 mm/sec, with the average length of blood capillaries of 0.67 mm (YR Ma et
al, 1974). According to the results of our morphometric analysis, the length of vessels in the structures of the brain nerve
center examined varied from 0.1 to 1 mm. During the mathematical analysis of the dynamics of vessels movements, tak-
ing into account their length and diameter, it was determined that the blood flow velocity in the capillaries (according to
the calculations) varied from 0.2 to 1 mm/sec. In each capillary in the given model the linear blood flow velocity was
considered. Each portion which was formed as a result of confluence or branching of the microvessels, was examined in-
dividually. The difference of systolic and diastolic pressure in the arterioles was not taken into account, due to the insigni-
ficant pressure differences in microcirculatory system inside the brain.
The oxygen intake in the body of neuron was taken equal to 6.0•10-6 mlО2/mm3sec, in the neuropil – 0.167• 10-6
mlО2/mm3sec (Fig. 58), which after conversion of the measurement units that we utilized, corresponds to the data of K.P.
Ivanov, M.K. Kalinina (1972), H. Hyden., P.W. Lange (1965). It appeared that the value of partial oxygen pressure in the
vein leaving from the model approaches the average value, given in various literature sources concerning the extraorgan
cerebral veins and comprising 37 mm Hg. However, the oxygen content along the small efferent vessels is to a great de-
gree nonuniform. There are areas inside the venules, where the partial pressure falls to the sufficiently low values: - 23-25
mm Hg. One zone in the model examined which is characterized by a significant decrease of oxygen content precedes the
region of merging of the venule with a short capillary, where the oxygen loss is not significant. Due to the blood mixing
the partial pressure rises again up to 50 mm Hg. Actually, this capillary is similar to a semi-bypass. Due to a small length
of the vessel and a low value
 75
of resistance, it performs the blood regurgitation, restoring the pressure level of oxygen in the efferent vessel. There are
versions of the confluence of larger postcapillary structures, having the similar levels of partial oxygen pressure. The
presence of the short length capillaries suggests the possible mechanisms of their formation. As can be seen from the ma-
thematical model, the areas of significant reduction of oxygen concentration correspond to the zones of brain, functioning
under conditions of local hypoxia. This could result in the formation of the vascular “buds”, which restore the conditions
of adequate vascular supply after the confluence with the adjacent arterioles. This is in accordance with the opinion of a
number of authors, giving evidence that hypoxia and the products of metabolism arising under this condition represent the
factors of the most active stimulation of angiogenesis. The astrocytes, in agreement with the energy needs, are capable to
control specifically the vascular tone, dilating if necessary the regional arteries (S Murphy, G Rich, K.L. Orgren, 1994).
The stimulation of the astrocytes can induce the synthesis of the vasoactive substances in these cells: prostaglandins,
platelet activation factor, nitric oxide (S Murphy, R.L. Minor, G Welk, D.G. Harrison, 1991; S Murphy, G Bruner, M.L.
Simmons, 1992; B Pearce, G.P. Wilkin, 1995). Neuroglia exerts its effect on the processes of angiogenesis as well (M
Assimakopoulou, I Varakis, N Papadakis, 1997), secreting, among other, the endothelial growth factor (K.H. Plate et al,
1994, 1997; S.Y. Cheng, 1997; L.R. Ment, 1997 A). This hormone exerts a powerful stimulating effect on the angiogene-
sis in the zones of damage and takes part in the mediation of impairment of the hematoencephalic barrier (S Nag, 1997).
The endothelial growth factor is important in the formation of blood circulation in the central nervous system, and it is
intensely secreted in the astrocytes under conditions of insufficient oxygenation (L.R. Ment et al, 1997 b) and functions
locally through the appropriate receptors (flk-1). These receptors are expressed most actively in the conditions of the tu-
mor growth (K.N. Plate, 1994). The substantial increase of the production of converting growth factor near the necrotic
foci of brain lesion was discovered. It is secreted most actively in the astrocytes and was also revealed in the macrophag-
es, neurons, endothelium. In damages the expression of the receptors for this factor in all cells outlined is activated (A K
Ata, Y Olsson, K Funa, 1997).
At the same time, the brain is very sensitive to hyperoxia. The possible influence of hyperoxia can be connected
with the formation of the radicals, which exert a neurotoxic effect (I.T. Demchenko, etc., 1999). Even in the long capilla-
ries, passing through the structures of the white substance and neuropil, the oxygen loss along their course are less signifi-
cant compared with the areas spatially close to the bodies of neurons. The capillaries that go from the white substance of
brain, even having penetrated through a great distance, contain the blood sufficiently oxygen-enriched. This concentration
of oxygen rapidly decreases when the microvessel approximates the regions, which surround the bodies of neurons im-
mediately.
During the analysis of oxygen distribution in the tissue structures of the brain it is evident that the concentration of
the dissolved gas in the neuropil is rapidly reduced at first, in parallel with the removal from the blood vessel. Within 10
μm from the arterial part of the microvessel the partial oxygen pressure falls by 15-20 mm Hg (by 8-10 mm Hg at the in-
tervals of 5 μm), while at a distance of 30 μm it decreases by 38-45 μm. Then the concentration begins to decrease gradu-
ally by 0.3-2 mm Hg every 5 μm. The further from the microvessels, the more gradually the decrease of partial pressure
proceeds. If the body of neuron lies immediately adjacent to the vessels, the dynamics of decreasing of the partial oxygen
pressure has somewhat different nature. The decrease of partial pressure occurs within 5 μm from 13 to 21 mm Hg, while
at the distance of 10 μm - by 20-28 mm Hg. In the spaces, occupied by the bodies of neurons, the decrease of partial oxy-
gen pressure occurs much more rapidly than in the neuropil: from 4 to 1 mm Hg at a distance of 5 μm. The regions, occu-
pied by the bodies of neurons, form the valleys on the curves, which reflect the level of Ро2, especially in the central
zones of the large perikarya. The central areas of the bodies of large neurons are characterized by the decrease of reduc-
tion Ро2 if the uptake is assumed at the level 6 • 10-6 ml О2/mm3 • s to 19 and 23 mm Hg).
The results of analysis of the model examined show that the adjacent areas of the microbasins, even in studies of
the regions of neuropil, which are devoid of the bodies of neurons, are significantly different in the intensity of gas ex-
change. There are zones containing the high concentration of oxygen in the microbasin, in the zone of neuropil: up to 45-
55 mm Hg. In the regions of microbasins which are supplied poorly there are areas with low concentration of oxygen (up
to 34-35 mm Hg). The differences are much more expressed during the comparative analysis of the bodies of neurons.
They become considerably more obvious from the large to the small neurons. Moreover, the large neurons exist in the
conditions of hindered gas exchange, even
 76
when high concentration of microvessels are present around them. While the central regions of bodies of large-size
neurons are characterized by the reduction of the level of Ро2 to 20 mm Hg, then in the small neurons the level of Ро2 is
approximately 40-45 mm Hg . However this is not the whole story. In the case examined the decrease of Ро2 value in the
bodies of large neurons comprised from 19 to 23 mm Hg, i.e. its variability was not too wide. At the same time, the small
neurons in different microbasins have very different conditions of gas exchange. It depends on the degree of proximity to
the capillary, by the level of oxygen saturation and by the gas exchange conditions in the microbasin examined as a
whole. As a result the differences in O2 saturation among small neurons vary from 30 to 46 mm Hg, i.e. 1.5-fold, even
with the assumption of identical intensity of their metabolism. It is important that even if the body of small neuron is lo-
cated at “crucial” distance from the nearest vessels of microcirculatory tree (25 μm), its concentration falls to 30 mm Hg
under the conditions of the average neuron oxygen intake.
Thus, the high vessel density in the gray substance, especially near the bodies of large neurons for the most part is de-
tected during the morphometric analysis of specimen, during the modeling of O2 exchange, suggests that this concentra-
tion only compensates a notable increase of perikarya oxygen requirements, but does not indicate at all the improvement
in their supply. While the large neurons having the average value of oxygen intake in the model examined were characte-
rized by the close values of oxygen concentration, neuropil and small neurons were characterized by a substantial varia-
bility of this parameter. These differences depended on the capillary-limited zones, suggesting the existence of the trophic
microbasins. Similar microbasins, as has already been indicated during the morphological analysis, are encompassed by
the astrocytes processes. In this model one can see that most processes are distributed in the space characterized by the
analogous conditions of oxygen concentration and, in the essence, are directed along the main flows of oxygen diffusion
in the neuropil. The interesting characteristic of astrocytes consists in its connection with the adjacent arteriole, capillaries
and postcapillary, which suggests the possibility of controlling by this cell the conditions of trophic supply within the
considered microbasin.
In the proposed model let us change the intake of oxygen in the neuron bodies to the level of maximum requirement –
6.8• 10-6 mlO2/mm3•sek, in the neuropil - to 0.23•10-6 mlO2/mm3•sek, (Fig. 59), characteristic for the physiological condi-
tions, according to the data of K.P. Ivanov, Iu.Ia. Kislyakov (1979). The parameters of oxygen and carbon dioxide partial
pressure, of hemodynamics, of the acid-base equilibrium in the system of inflow will maintain at the initial level. In this
case the intensity of gas exchange in the bodies of large neurons in the given model decreases to 13 and 18 mm Hg, for
the small neurons - to 27, 36 and 38 mm Hg. The most “ischemic” neuropil zones, remote from the neuron bodies are
characterized by the reduction of Ро2 to 32 mm Hg, while in several regions this parameter is non-significantly reduced.
This activation of О2 consumption in the neuron bodies is usually accompanied by the increase in the neuropil activity,
which can increase the oxygen requirement to 0.205•10-6 mlО2/mm3-sec. The increase in activity of astrocytes and oligo-
dendrocytes in the zones containing activated neurons, according to the data of a number of authors, obtained with the use
of biochemical and physiological methods, points in favor of this assumption. The increase in neuronal activity is accom-
panied by the analogous processes of synaptic transfer. All these changes are revealed with the use of electron microsco-
py as the increase of the volume density of mitochondria in the synapses and in the bodies of gliocytes. To start with we
will not vary the parameters of microcirculation. This situation is virtually improbable, but one should remember that in
this model we use all the vessels that could be revealed, some of which are resting and do not play a significant role in the
gas exchange. The introduction of this new parameter changed very significantly the value of oxygen partial pressure in
the intercellular substance and partially in the vessel tree. Ро2 value decreases considerably in the large neurons and in
their central part (to 11 and 15 mm Hg.); in the small neurons to 22, 31 and 34 mm Hg. In the vein under investigation the
reduction of this parameter at output to 35.5 mm Hg is observed. Significant fluctuations of partial oxygen pressure from
26 to 50 mm Hg are observed in the areas of neuropil that are removed from the bodies of neurons more than 10 μm. The
regions of significant oxygen concentration decrease in the neuropil are characterized by the more expressed fall of its
concentration in parallel with the activation of metabolism. The regions characterized by more favorable conditions of
supply display a considerably less expressed reaction. However, in the most energy-dependent and least stable areas of
neuronal bodies the reduction of Ро2 proportional to the metabolism activation proceeds in parallel with the reduction of
its concentration in the tissue structures. This enables us to draw a conclusion
 77
that under uniform conditions of blood circulation and with a simultaneous increase of the energy uptake, the hypoxic
disturbances in the tissue structures of the brain are local in their nature and are restricted within the microbasins, that are
formed by the adjoining microvessels with the zones of neuropil and the neuron bodies which can lie among them. As
may be inferred from the available morphological data, such zones are integrated by the areas of astrocytes expansion,
covering the adjacent constituent structures of microcirculatory tree. Thus, just the astrocytes can regulate the level of gas
exchange in the individual microbasin, due to the ability of dilatation of afferent vessels, assigned to them. It may result
in a change of the pressure gradient between the arterial and venous capillary ends, in determining the capillary diameter
and the linear blood flow velocity. The oxygen concentration in the tissue structures around the vessels falls more sudden-
ly in comparison with the mean level of consumption. At the distance of 10 μm from the arterial part of the capillary the
decrease of Ро2 is equal to 20 - 30 mm Hg, while in the capillaries, surrounding immediately the neuron, this decease
comprises 35 - 40 mm Hg. At a distance of 30 μm occurs the fall off the Ро2 by 35 - 55 mm Hg is observed, that may re-
duce considerably the compensation abilities of such zones of neuropil for the gas exchange
Let us examine the case of significant activation of energy consumption and of the gas exchange, correspondingly,
in certain locus of the brain, for instance, in the zone of central microbasin in the model investigated. Assume the oxygen
requirement in the neuronal bodies increase to 7 • 10-6 mlO2/mm3 • sec and in the neuropil respectively to 0.24•10-6
mlO2/mm3• sec. Assume the hemodynamic and the arterial blood parameters remain constant, (Fig. 60). This phenomenon
can occur more or less probably after the specific irritation of the neuron. In the mesencephalic nucleus of trigeminal
nerve this situation could evolve after the local irritation of the peripheral receptor of neurons, lying in the parodontium.
In the case investigated the significant reduction of oxygen partial pressure (to 5.6 mm Hg.) in the central zones of large
neurons is revealed (thus far it was equal to 11 mm Hg according to the requirement of 6.8• 10-6 mlO2/mm3• sec). In
smaller neurons it decreased to 31 mm Hg (from the initial value of 34 mm Hg). Thus, the decrease of partial pressure in
larger neurons proceeds much more rapidly than in the small neurons. The effect on the adjacent zones is minimal. In the
adjacent large neuron Ро2 was maintained within 15 mm Hg. The small neurons and neuropil are characterized by the de-
crease of Ро2 value by 0.3 – 0.1 mm Hg, while in neuropil of the active zone Ро2 decreased by 4 mm Hg (from 26 to 22
mm Hg in the areas most remote from the vessels).
Thus, a local increase of activity in the individual neuron can result in a significant reduction of the reserve- com-
pensating abilities of a zone, formed by the small microbasin, which are limited by the adjacent capillary loops. Consider
the possible reaction of an astrocyte and its possible reciprocal influences with the microvessels, that it surrounds with its
processes. As may be inferred from the reconstruction, the concerned gliocyte encompasses with its processes an arteri-
ole, 3 capillaries and one postcapillary. The possibility of influence on the arteriole and the ability to relax its smooth
myocytes, which results in the dilatation of the lumen, are most significant in this situation, on account of decreasing the
resistance and of increasing the pressure gradient between the capillaries. Assume the arteriole lumen increases 1.5-fold.
Then the corresponding change in the width of the vessel’s lumen and the increase of the partial pressure gradient result
in 1.4 to 2.2-fold change of the linear blood flow velocity in that microbasin under examination and in 3-fold increase of
volume blood flow velocity.
The increase of linear and volume blood flow velocity result in non-significant variations of gas exchange in the
microensemble examined. Ро2 in the most ischemic zone of large neuron was equal to 7 mm Hg instead of 5 mm Hg,
while in the small neurons it was equal to 2 mm Hg instead of 31 mm Hg. Ро2 value in the neuropil increased from 22 to
24 mm Hg in the most ischemic zone. The variations of gas exchange conditions in the neighboring microensembles are
insignificant, except ones which immediately adjoin the reactive vessels, where the decline amounts to 1-3 mm Hg. Thus,
the intensification of the linear and volume blood flow velocity in the area being simulated, so long as the number of the
functioning microvessels remains stable, exerts a very moderate compensating effect on the characteristics of gas ex-
change. The similar dynamics can represent one of the important conditions necessary for the maintaining of the adequate
level of gas exchange, which adapts the local variations of requirements in the separate microbasin to its blood flow level.
The modeling of different situations in the area examined suggests the presence of quite different characteristics of
the gas exchange in the local zones of the brain and significant differences within the limits of adjacent neuroglio-
vascular ensembles. The boundaries of these ensembles can be conventionally defined by the limits of adjacent capillary
loops. These ensembles are characterized by relatively similar conditions of gas exchange and probably - of the trophic
supply.
 78
The adjacent microbasins represent relatively autonomous gas exchange characteristics; the variation of the
conditions of oxygen diffusion due to the dynamics in one of microbasins does not exert a substantial effect on the adja-
cent trophic ensembles. Possibly, this could explain the small-focal withdrawal of neurons in case of the general damage
of the brain (arterial or venous hypertension, hypothermia and sun stroke, concussion etc.). Thus, the information about
the average sizes of neurons, the overall level of microcirculation in the nerve center as a whole and about many other
average parameters cannot adequately reflect the cerebral status and the level of the spare and compensation abilities of
its trophic supply, even by the simple parameter of the gas exchange. From this point of view the extreme parameters are
considerably more interesting than the averaged ones, as they suggest the probable level from which the withdrawal of the
individual neuron groups, most sensitive to a particular effect, can be observed.
The indirect morphofunctional confirmation of probable active compensation of glucose deficit in the central nerv-
ous system on account of the astrocytes consists in the fact that astrocytes are capable to the rhythmical contraction with
the duration of 90 sec and the period of relaxation of 240 sec. The average frequency of such contractions is equal to 2 -
20 hours. The important feature of the contraction consists in the fact that, according to authors’ opinion, the processes
swell, but do not shorten (B.I. Tkachenko, 1994). The increase of the processes thickness, considering the possibility of
the transport of substances and of glucose in particular, can ensure the significant increase of the exchange area and facili-
tates the transfer to the surface of neurons bodies.
The factor of the volume increase of the intercellular space after the brain damage accompanied with the presence
of edema is considered significant. On the one hand, the edema worsens the status of the brain as a whole, nevertheless, it
can facilitate the diffusion of organic matter, and of glucose particularly, through the increase of the exchange area.
In contrast to the basic model, proposed by K.P. Ivanov, Iu.Ia. Kislyakov (1979), our data indicate significant spare
and compensation abilities of cerebral tissue and the sufficient ability of the blood flow to ensure an increase of the neu-
rons’ gas exchange requirements. The large neurons (both according to our data and to the results of the mentioned au-
thors) lie in the worse gas exchange conditions, which increases significantly their sensitivity to hypoxia. But in these
neurons the potential of the vascular system is also sufficient for the compensation of the oxygen need.
At the same time the data obtained in rats studies with the use of the platinum polarographic microelectrodes (Ie.P.
Vovenko, I.B. Sokolova, 2001) suggest the fact that under the conditions of hypoxia the considerable reduction of blood
oxygenation along the course of arteries occurs. During the inhalation of the gas mixture containing 12% of oxygen, 3%
of carbon dioxide and 85% of nitrogen the oxygen concentration in the system arterial blood was equal to 83% of So2,
while in the 8-10 μm arterioles it was equal to 57% of So2. Under these conditions Ро2 was described through the authors’
formula
Po2 = 0.106 ⋅ D + 37 (5.17)
where D - diameter of arteriole (μm). In venules 10-260 μm in diameter this relation is represented by the following for-
mula:
Po2 = 0.048 ⋅ D + 16,9 (5.18)
The results obtained with the use of mathematical modeling of the partial pressure along the course of microves-
sels, correlate with the results of the authors’ experimental examinations, confirming our mathematical model.

V. 3. Carbon dioxide diffusion flows, obtained using mathematical modeling

The simulation study of the mathematical Рсо2 model in the tissue structures of the brain and in the blood vessels
revealed the following characteristics of distribution. When the initial value of Расо2 in the blood is equal to 40 mm Hg,
the carbon-dioxide content in the venous blood increases to the value of Рvсо2 equal to 48 mm Hg. Such results are in
accordance with the authors’ data, obtained experimentally in the main arteries and veins of the brain (N.V. Sudakov,
2000). Meanwhile, the distribution of carbon dioxide in the model under investigation is considerably more uniform, than
in the case of oxygen. Thus, in the structures of neuropil the variation of Рсо2 is not more than 3 to 6 mm Hg. When the
oxygen requirement in the body of neuron is equal to 6.0•10-6 mlО2/mm3 sec and in neuropil – 0.167• 10-6 mlО2/mm3 sec
(Fig. 61), Рсо2 in the neuropil was equal to 43 mm Hg in the most oxygenized areas of neuropil to 49 mm Hg in the areas
most remote from capillaries. The variations in the level of Рсо2 between the adjacent cells are rather not substantial and
do not exceed 0.005 – 0.1 mm Hg the level. The value of Рсо2 in the neurons is higher than in neuropil, but the pressure
gradient between the central zones of neurons and the neuropil amounts to 2-5 mm Hg. It is most obvious in the large
neurons. In the small neurons the gradient pressure between the central zones and the boundaries of neuronal body and of
neuropil does not exceed 1 - 3 mm Hg. In the bodies of large neurons under examination the increase of the partial pres-
sure of carbon dioxide was revealed,
 79
amounting to 52 and 52.5 mm Hg, while in small neurons this pressure comprised 49, 49 and 49,7 mm Hg. Thus, under
the conditions of mean consumption the partial pressure of carbon dioxide in the brain tissues varies from 43 to 52 mm
Hg, which agrees with the experimental data, obtained by other researchers indicating the average value of Рсо2 in the
brain tissues as equal to 40 - 60 mm Hg. Iu.Ia. Kislyakov, I.K. Breslav (1988) indirectly confirm these results, that we
obtained with the use of mathematical simulation. The most intensive change of the concentration of carbon-dioxide is
present in the region of its preferred synthesis (neurons) and in the perivascular spaces. The intensive decrease of the par-
tial pressure of carbon dioxide occurs within 10 μm from the capillaries (from their arterial parts especially), while the
increase is present on the boundary between the body of neuron and the neuropil. Within 10 μm from the arterial parts of
capillaries the pressure gradient can be equal to 2 to 6 mm Hg, and on the boundaries of neurons it comprises 0.5 to 3 mm
Hg.
The moderate variability of the parameters of carbon dioxide partial pressure is probably explained by a high ab-
sorptive power of the biological fluids, where but a non-insignificant proportion of CO2 is dissolved in a free state, which
influences significantly the characteristic of its distribution in the tissue structures of the brain. Thus, the diffusion of car-
bon dioxide in the central nervous system does not manifest any tendency toward the dependence on the individual mi-
crobasins, in contrast to oxygen, and any signs of accumulation in a certain locus of nerve tissue. Another tendency would
be possibly present in case of modeling the distribution of carbonate and hydrocarbonate, but, unfortunately, the mathe-
matical calculation of these parameters is very complex. No empirical coefficients are available for the transmembrane
transport of monosubstituted and bi-substituted carbonate ions in the neurons and in neuroglia.
When the partial pressure of carbon dioxide in the afferent vessels increases, the change of its concentration in the
nerve tissue is non-significant and does not exceed 1 to 3 mm Hg, thus, the basic characteristics of carbon dioxide distri-
bution in the tissue structures remains unchanged.

V. 4. Modeling of the glucose transportation flow in the nervous system

In contrast to the simulation of oxygen and carbon dioxide diffusion, that are passively achieved, in the direction of
minimal concentration, in case of the glucose transport it is important to consider the membrane organization of the neu-
rons and of neuropil. During the analysis of the distribution of oxygen and free carbon dioxide in the brain tissue this as-
pect is not meaningful. This is due to the fact that their diffusion through the membranes differs little in the hydrophilic
cellular and extracellular medium of the brain. Glucose penetrates through the endothelium of capillaries via the active
transport. In the brain tissues the passive diffusion of glucose can be supposed, preferably through the intercellular matrix,
while in case of the neuron bodies and other cells glucose penetrates actively, after which it diffuses in the intracellular
substance. The latter moment is least studied. It is not clear whether glucose moves passively according to the concentra-
tion gradient and whether the intracellular cyclosis does change the rate of this diffusion, via facilitating its expansion
within the cell.
According to literature data and to the morphometric analysis of electronograms (based on our own and available
literary sources), the intercellular substance of the nerve tissue amounts to 10% to 12% of the neuropil as a whole. We
considered it as the volume, where the distribution of glucose in the brain proceeds. Here the distribution of glucose is
accomplished passively according to the concentration gradient, with a gradual decrease of the glucose concentration in
parallel with its consumption by the tissue structures of the brain.
90% of glucose metabolism in the brain is performed via aerobic phosphorylation, while 10% - via anaerobic gly-
colysis. According to the literature data, anaerobic glycolysis is characteristic for neuroglia (first of all, astrocytes and to a
certain degree microgliocytes and oligodendrocytes). In the model under investigation both versions may be anticipated.
On a first approximation we forego the examination of anaerobic glycolysis. The respiratory coefficient for glucose in the
brain is equal to 1.0. The ratio between the glucose metabolism and the oxygen intake can be calculated mathematically.
It is known that the utilization of 1.0 g or 0.84 L of oxygen is equivalent to the utilization of 0.937 g of glucose (G Lusk,
1931). Apply this ratio to oxygen intake, after transferring the intake of oxygen in ml into grams. In case of neuropil the
glucose consumption via aerobic glycolysis is equal to 0.232•10-9 g of glucose/mm3•sec when the value of oxygen utiliza-
tion is of 0.167•10-6 mlО2/mm3•sec. If the consumption in the body of neurons is equal to 6.000• 10-6 mlO2/mm3•sec, then
the glucose consumption in the neuropil comprises 8.346• 10-9 g of glucose/mm3• sec. Thus, let us formulate the equation
for the glucose concentration in the bodies of neurons. It is simplest among the system of
 80
the values under investigation. The glucose concentration in 1 mm3 of the neuronal body is equal to:
1 ⎛ l ⋅ V ⋅ mi , j , k ⎞
Pkgi , j , k = ⋅ ⎜⎜ Pkgi −1, j , k + Pkgi +1, j , k + Pkgi , j −1, k + Pkgi , j +1, k + Pkgi , j , k −1 + Pkgi , j , k +1 − ⎟⎟ (5.19)
6 ⎝ Dk ⋅h 2 ⎠
where Pkg – glucose concentration in the cell (g of glucose/mm3); l – length of a unit (5•10-3 mm); V -(unit volume, which
is equal in our case to 125•10-9 mm3); mi,j,k - glucose uptake in the given unit (g of glucose/mm3•sec); Dk – glucose diffu-
sion coefficient in the nerve tissue (mm2/sec); h2 – contact surface of neighboring units (in our particular model it was
equal to 25•10-6 mm2). The value of Dk in the hyaloplasm and in the neuron’s nucleus is unknown, the diffusion coeffi-
cient in the biological tissue media is only available which is equal to 5•10-7 mm2/sec (K.Groebe, 1986) and which was
taken as the basis for the calculation, in the absence of another value.
However, the glucose transport into the cells is performed actively. The dependence of the flow F through the
membrane, under the conditions of the absence of transmembrane potential, on the concentration of transport ATP-ase
and on the ions concentration on both sides of the membrane [S]1 and [S]2, is described with the equation:
c 0 ⋅ P ⎛ [S ]1 [S ]2 ⎞
F= ⋅⎜ − ⎟⎟ (5.20)
2 ⎜⎝ K 1 + [S ]1 K 2 + [S ]2 ⎠
where с0 – concentration of the transport enzyme on the membrane, Р –coefficient of membrane permeability for the
complex of transporter with the enzyme, К1 и К2 – dissociation constants of the complex of the transported substance and
the carrier by both sides of the membrane.
The transport of a substance (S) with the use of a transporter (С) through any membrane can be simply represented
in the form of two processes: diffusion of the complex (CS) through the membrane in one direction and diffusion of the
free transporter in the inverse direction. Membrane itself serves as the main barrier for the substance being transported.
Thus, it may be assumed that on both sides of the membrane the balance of the substance with the carrier is rapidly estab-
lished; as a sequence,
[S ]1 ⋅ [C ]1 = K1 [CS ]1 ;
[S ]2 ⋅ [C ]2 = K 2 [CS ]2 (5.21)
In case of the active transport of substance К1 is not equal to К2. If the total concentration of the carrier in the
membrane in all its forms is symbolized as с0, then this parameter is described with the following formula:
[C ]1 + [CS ]1 + [C ]2 + [CS ]2 = c0 (5.22)
Since the rate of the total process of transport depends on the rate of the complex diffusion through the membrane,
the density of the summary substance flow through the membrane can be defined as:
F = P ⋅ ([CS ]1 − [CS ]2 ) (5.23)
where P = D / l (5.24)
and where P – coefficient of solute permeability for the complex, D – coefficient of the complex diffusion in the mem-
brane, l- membrane thickness. In the stationary state the flow of the complex in one direction is equal to the carrier flow
in the inverse direction and is described as follows:
Dc
F = Pc ⋅ ([C ]2 − [C ]1 ) = ⋅ ([C ]2 − [C ]1 ) (5.25)
l
where Pс – coefficient of the solute permeability for the free carrier, Dс – diffusion coefficient of the carrier.
The size of the transporter molecule is much larger in comparison with the glucose molecule. Thus, it can be assumed
that the diffusion coefficients of the complex and of the transporter in the membrane are equal, so Р = Pс, and the formula
acquires the following form
[C ]1 + [CS ]1 = [C ]2 + [CS ]2 = c0 (5.26)
2
The rate of transfer J (product of the flow by the surface area of the membrane). Under condition of different val-
ues of [S]1 1/J is plotted as a function l/[S] 1. The right line is produced (Lainuiver-Berk plot), described with the formula:
1 1 K 1
= + 1⋅ (5.27)
J Jm Jm [S ]1
where Jm – maximum rate of transport, which is equal to the product of Fм and the surface area of the membrane.

The maximum rate of transport, other factors being equal, depends on glucose concentration on the external sur-
face of the membrane.
 81
However, the decrease of Jm can result from the reduction of the surface area of the membrane, of the concen-
tration of the carrier or of the rate of diffusion of the complex through the membrane. The coefficient of the transmem-
brane transport through the unit of the surface of cellular membrane is thus dependent on many parameters, including the
surface area, the number of carrier molecules, the glucose concentration on the outside of the cell and inside it. Generaliz-
ing the formula, let us introduce the coefficient of the transmembrane glucose transfer through the membrane of neurons -
Dl. The specific value of this coefficient under conditions of the different glucose concentration on the outside of the neu-
rons and of the different level of neuronal functional activity is unknown until today. But when the equilibrium between
the glucose absorption and the rate of its diffusion in the extracellular matrix is achieved, this coefficient cannot be higher
than rate of compensation of the glucose utilization in the perineural space. Thus, it can be easily calculated mathemati-
cally according to the threshold, when the concentration of glucose immediately near the surface of the membrane of neu-
ron tends to zero. If this coefficient is calculated for different glucose concentrations in the nerve tissue it varies depen-
dent on the concentration of glucose in the intercellular space from 14•10-10 (when the concentration of glucose exceeds
6-fold its concentration in plasma) to the values tending to zero (in parallel to the reduction of glucose concentration).
Since the absorption of glucose proceeds actively, its concentration in the peripheral zones of cytolemma of neu-
rons is defined both by the passive diffusion processes and by the contact area of the surface of the unit under investiga-
tion with neuronal cytolemma and by the coefficient of the transmembrane glucose transport through the cellular mem-
brane. Thus, the formula for the extreme units acquires a more complex aspect and has the following form:
1
Pkgi , j , k =
⋅ ( Pkgi −1, j , k + Pkgi +1, j , k + Pkgi , j −1, k + Pkgi , j +1, k + Pkgi , j , k −1 +
6
(5.28)
Dl ⋅ S l ⋅ V ⋅ mi , j , k
+ − )
V Dk ⋅ h 2

where DI - coefficient of the transmembrane glucose absorption in the neuron from the intercellular substance (g/mm2); S
- area of the contact surface of neuronal membrane (mm2). If two or three sides interact with the surface instead of one,
thereafter we use the coefficient of absorption with respect to two or three surfaces of a unit. The greatest complexities
concern the interpretation of the coefficient of absorption (concentrating abilities of the cellular membrane). The high de-
gree of its lability can be assumed, depending on the physiological state of neurons and on the concentration of glucose in
the intercellular matrix and inside the cell. For the concentrations achieved in the intercellular substance within this par-
ticular model, this coefficient varies from 12 • 10-10 to 0.5 • 10-10 g/mm2. With an increase of the coefficients in the partic-
ular zones of the membrane of neurons the glucose concentration in the adjacent area of the neuronal membrane com-
pletely depletes. The value of this parameter is defined by means of the mathematical analysis and depends on the con-
centration of glucose in the intercellular matrix and in the perimembrane space of neurons as a result of the absorption
processes, by the optimum level of glucose concentration inside the neurons. If the integrated parameter of absorption of
the neuron throughout its total area is applied, a very interesting pattern can be revealed. The expressed glucose deficit
was observed in the perimembrane space around the cell, or within the neuron itself. Thus, the obtained parameter for the
neuron proved to be unstable, and its variability was determined by the degree of compensation of the glucose absorption
through the membrane of the body of neuron, by the glucose diffusion through the intercellular substance of the neuropil.
The formula is considerably different while defining the processes of glucose diffusion in the neuropil. We de-
scribed the diffusion of glucose relative to the volume of intercellular substance (12.5•10-12 mm3) rather than to the entire
volume of the unit (125• 10-12 mm3). Accordingly, the exchange area between two units decreases to 2.5• 10-8 mm2, while
the distance of the “transfer” of glucose molecule along the unit composes the value, which is about 1.3 – 1.5-fold larger
in comparison with the length of the unit. This is connected with the complex configuration of intercellular fissures, form-
ing the complex labyrinth where glucose is transferred. The results of the morphometric analysis of electronograms sug-
gest the increase of the distance in the neuropil precisely by the mentioned value. Thus, the concentration of glucose in
the intercellular substance of neuropil can be described using the following formula:
 82
1
Ptg i , j ,k = ⋅ ( Ptg i −1, j ,k + Ptg i +1, j ,k + Ptg i , j −1,k + Ptg i , j +1,k +
6
(5.29)
lt ⋅ Vkn ⋅ mkni , j ,k
+ Ptg i , j ,k −1 + Ptg i , j ,k +1 − )
Dkn ⋅ h 2
where Ptg - glucose concentration in the intercellular substance of the neuropil (g of glucose/mm3); lt- length of the unit
(taken equal to 7.5• 10-3 mm, considering an about 50% increase of the distance that glucose passes through the intercel-
lular fissures in the nerve tissue).; Vkn – volume occupied by the cells and their processes in the neuropil of a unit, in our
case it is equal to 112.5• 10-9 mm3).; mkn,i,j,k - glucose consumption in the given unit utilized via the aerobic phosphoryla-
tion (g of glucose/mm3•sec); Dkn – diffusion coefficient of glucose in the intercellular substance of the nerve tissue, taken
equal to 5 • 10-7 mm2/sec; h2 – contact surface area of the intercellular matrix of the neighboring units (in this particular
model it was equal to 2.5 •10-6 mm2).
However, in the perivasculary units of the neuropil, in the unit adjacent to endothelium the active glucose transport
through the endothelial membrane is performed. Due to this the formula for these units must take into account the coeffi-
cient of the concentration ability of the endothelium (absorption coefficient) and the area of the contact surface between
the unit and the endothelium. Thus, the formula acquires the following appearance:
1
Ptg i , j ,k = ⋅ ( Ptg i −1, j ,k + Ptg i +1, j ,k + Ptg i , j −1,k + Ptg i , j +1,k +
6
(5.30)
lt ⋅ Vkn ⋅ mkni , j ,k
+ Ptg i , j ,k −1 + Dle ⋅ Ppg − )
Dkn ⋅ h 2
where Dle – ratio between the rate of glucose absorption in the endothelium and the passive diffusion in the intercellular
substance ; Se – area of the contact surface of neurons (mm2); Vn – volume of the intercellular substance of neuropil of
the unit – in our case this value is equal to 112.5• 10-9 mm3). Ppg – plasma glucose concentration (g of glucose/mm3). Ac-
cording to the literature data (К.V. Sudakov, 2000), the ratio between the rate of glucose diffusion through the endothe-
lium is 6-fold higher in comparison with the rate of glucose diffusion in the intercellular substance, that results in the ac-
cumulation of glucose under the condition of the usual consumption equal to 2.5 – 3.5 • 10-6 g glucose/mm3 (or 0.25 –
0.35%), according to the data of mathematical simulation of this process.
However, this formula does not represent the change of the glucose concentration in the immediate proximity to
the body of neuron. The formula must acquire the following appearance:
1
Pkg i , j ,k = ⋅ ( Pkg i −1, j ,k + Pkg i +1, j ,k + Pkg i , j −1,k + Pkg i , j +1,k +
6
(5.31)
Dl ⋅ S lt ⋅ V ⋅ mkni , j ,k
+ Pkg i , j ,k −1 − − )
V Dkn ⋅ h 2
The negative value obtained on the side of the unit which interacts with the membrane of the body of neuron, is due
to the active neuron absorption leading in any case to the decrease of glucose concentration in the intercellular substance.
While describing the changes of the glucose concentration in the intercellular substance the processes of anaerobic
glycolysis must be taken in account, besides the consumption via the aerobic phosphorylation. Considering the literature
data suggesting that neuroglia rather than neurons is capable to the anaerobic glycolysis as the final step of the glucose ca-
tabolism, the formula for the neuropil has an appearance:
1
Ptgi , j , k = ⋅ ( Ptgi −1, j , k + Ptgi +1, j , k + Ptg i , j −1, k + Ptg i , j +1, k +
6
(5.32)
lt ⋅ Vkn ⋅ (mkni , j , k + mkngi , j , k )
+ Ptg i , j , k −1 + Ptgi , j , k +1 − )
Dkn ⋅ h 2
where mkni,j,k - glucose consumption in the given unit via the anaerobic glycolysis and for other needs (g of glu-
cose/mm3-sec). The values in all the other formulas change accordingly.
Let us examine several other important factors, which can be of value in describing the glucose metabolism in the
brain structures. One of such factors may consist in the capability of glucose accumulation in the gliocytes in the form of
glycogen, but this factor under the conditions of physiological equilibrium-state
 83
and in the absence of the signs of glucose deficit does not have a vital importance, whereas under the conditions of in-
sufficient blood circulation it is of importance during the time interval until the moment of glycogen depletion. In this case
the time variable should be considered aside from the parameters mentioned in the previous formulas. When the new level
of equilibrium is achieved, the glycogen degradation and synthesis processes are equalized and keep in complete accor-
dance with the previous formula, as the part of the coefficient ткпi,j,k.
Perhaps, the possibility of the transmembrane glucose transfer into the cell through the neuron processes in spite of
the neuron bodies appears more meaningful, with a subsequent diffusion of glucose according to the concentration gradient
from the distal parts of processes to the bodies of neurons. This parameter is most significant for the proximal zones of
dendrites and axons. The problem of description of diffusion transportation flows for these regions, especially in the thick
processes (up to 5 μm – the size of the examined unit), can be considered more appropriately if in reconstructions these
parts of processes could be assumed as the continuation of the bodies of neurons and included maximally in the descrip-
tion. In this case no new formulas would be required. The much different problem concerns the characteristics of the diffu-
sion with regard to the aggregate of dendritic tree. In this case the approximate description of diffusion flows should con-
sider the area of the contact surface between the units, not only with respect to the intercellular substance, but also for
processes of neurons (h2 + hd2), where hd2 - area of the contact surface between the cells, which refers to the processes of
neurons (mm2). However, in this case the glucose transport through the intercellular substance and along the course of the
processes of neurons should be taken into consideration discretely. While the diffusion in the intercellular substance occurs
according to the concentration gradient and is equally probable in all directions, this assumption would be incorrect with
respect to the processes of neurons. Mathematically, the direction of glucose diffusion flows for the constellation of the
processes is such a complicate value that its description appears thus far inaccessible. On the other hand, such description is
probably meaningless. The inflow of the own processes is more important for the individual body of neuron than the inflow
in the whole aggregate of the processes. Thus, the value of glucose influx per unit of the surface of neuron can be formu-
lated by means of the following parameter:
Dl ⋅ S Sd
Pkg i , j , k = + Pkdi , j , k +1 ⋅ i , j2, k +1 (5.33)
V h
where Pkd – average glucose concentration in the processes of the neuron under investigation in the adjacent unit (g of
glucose/mm3) Sd - cross-section area of the processes, confluent with the bodies of neurons (mm2). Accordingly, the
amendments must be introduced into the formula earlier quoted.
1
Pkgi , j , k =
⋅ ( Pkgi −1, j , k + Pkgi +1, j , k + Pkgi , j −1, k + Pkgi , j +1, k + Pkgi , j , k −1 +
6
(5.34)
Dl ⋅ S Sd l ⋅ V ⋅ mi , j , k
+ Pkdi , j , k +1 ⋅ i , j2, k +1 − )
V h Dk ⋅ h 2
The changes of glucose concentration, being important for the neurons under consideration, in this case are equal to
the following values:
1 Dl ⋅ S lt ⋅ Vkn ⋅ (mkni , j , k + mkngi , j , k )
Ptg i , j , k = ⋅ ( Ptg i −1, j , k + ... + Ptg i , j , k =1 + − +
6 V Dkn ⋅ h 2
(5.35)
Sd lt ⋅ Vkn ⋅ (mkni , j , k + mkngi , j , k )
+ ( Sd i −1, j , k Ptd i −1, j , k + ... + Pkdi , j , k +1 ⋅ i , j2, k +1 − )
h Dkn

V. 5. Results obtained using the analysis of the mathematical model of the glucose transportation

During the study of glucose concentration and its transport in the brain of mammalians the high variability of its
concentration is revealed. This acquires a special complexity while taking into account the assumption about the predo-
minant diffusion of glucose through the intercellular substance in accordance with the concentration gradient. If we as-
sume this mechanism of transport in the brain as a singularly possible,
 84
then the following patterns of glucose concentration in the brain can be observed.
Under the assumption about the fact that glucose metabolism in the brain is preeminently limited by aerobic phos-
phorylation and by the probability of 10% metabolism via the anaerobic glycolysis, the value of glucose utilization in the
blood plasma from the arteriole to the venule is equal to 26%. Assuming the content of glucose in the arteries equal to 1 •
of 10-6 g/mm3, according to literature data for the dogs (A.A. Bogomoletz, 1941), being the model of brain that we ex-
amine, the concentration of glucose in the blood of the efferent vessel would be equal to 0.74•10-6 g/mm3. But if the level
of glucose was equal to 1.2•10-6 g/mm3 (the upper normal limit), then the decrease in glucose concentration from the ar-
tery to the vein would comprise 21%. According to the opinion of a number of authors, the average glucose concentration
in the venous blood plasma in dogs is 13% lower than in the arteries (Lepine, 1941); although these data do not coincide
with our theoretical calculations, they are comparable, taking into account the high degree of glucose consumption in the
brain, in comparison with other organs. In order to confirm or to refute our results we analyzed the glucose concentration
in 5 narcotized dogs. In the general carotid artery the concentration of glucose was equal on average to (1.07 + 0.06) * 10-
6
g/mm3, in the internal jugular vein - (0.78 + 0.08) * 10-6 g/mm3, which is close to the theoretical results.
The glucose concentration in the neuropil was examined only for the intercellular substance. In this case the para-
meters considered have a high variability when the glucose concentration is compared both between the adjacent micro-
basins and inside every microbasin. The high glucose requirements in the perikaryon of neuron are of great importance in
these differences.
Let us examine the level of glucose concentration when its consumption in the body of neuron is 8.346• 10-9 g of
glucose/mm3 * sec, with the value of oxygen utilization equal to 6.0• 10-6 mlO2/mm3*sec. The consumption in the neuro-
pil is taken equal to 0.232• 10-9 g of glucose/mm3*sec, that corresponds to the oxygen requirement of 0.167 • 10-6
mlO2/mm3•sec (Fig. 62). Under these conditions glucose concentration in the intercellular substance of neuropil achieves
its maximum within the adjacent 5 μm and varies within the limits of 2.5 – 3.5• 10-6 g of glucose/mm3. At the distance of
10 μm its content decreases to 1.8 - 2• 10-6 g of glucose/mm3. The analysis of glucose accumulation in the structures of
the white substance and of zones gray substance, which do not contain the neuron bodies in the immediate proximity, re-
vealed a gradual decrease of concentration of glucose to the value of 0.5 – 0.3• 10-6 g of glucose/mm3. But the substantial
part of the zones are characterized by the level glucose in the intercellular substance corresponding to 1.1 – 0.8• 10-6 g of
glucose/mm3, which is close to the parameters of the blood plasma. The zones examined are characterized by a gradual
decrease of the level of glucose by 0.001 – 0.003•10-6 g of glucose/mm3 every 5 μm. Even at significant distance from the
microvessels the level of glucose in the intercellular substance of the white substance itself does not reach a critical level,
being 2 – 2.5-fold lower in comparison with the level in the plasma, which is in agreement with the literature data (Siegel,
1921).
The dynamics of changes of glucose concentration in the zones, which are immediately adjacent to the body of a
neuron, is considerably more complicated. The zones under examination are characterized by a sudden fall of the concen-
tration of glucose. In the immediate proximity around the body of neurons the decrease of the glucose concentration
comprises 0.3 – 1.0• 10-6 g of glucose/mm3 every 5 μm. This decline is not compensated by the diffusion from the adja-
cent spaces of neuropil, under the conditions of the uniform high level of glucose absorption by the membrane of neuron.
Such phenomenon can be explained by a relatively low glucose diffusion coefficient in comparison with the gases dis-
solved and by the limited volume of the intercellular substance, accompanied with a proportional reduction of the ex-
change area between the adjacent units and with the increase of the distance the molecules of glucose overpass in the in-
tercellular substance of the brain due its complex form. The signs of the downfall of glucose concentration are most ex-
plicit at the distance of 25 to 30 μm. The impairment of the compensation results in the impossibility of the uniform ac-
tive absorption of a significant volume of glucose at this distance and in the ineffectiveness of the active pumping func-
tion of neuronal cellular membrane. Taking into account the fact that in this model the possibility of negative values was
envisaged, they allow estimating the degree of deficit under conditions of the identical level of absorption over the whole
surface of a cell. As can be seen in the sections, this deficit does not appear in the negative values but in the immediate
proximity to the neurons, but is rapidly compensated just at a distance of 5 to 10 μm from the body of neuron. Thus, 25
μm corresponds to the critical distance, on the basis of our mathematical model, not for the gas exchange, but for the ab-
sorption of glucose.
Thus, the rate of glucose absorption by the bodies of neurons is unequal in different zones and is in direct propor-
tion to the concentration of glucose in the intercellular substance.
 85
This feature is followed by a significant complication of glucose diffusion in the nerve tissue, taking into ac-
count its concentration in the intercellular space. Due to this, the simulation of glucose transport through the membrane
of neurons, which exceeds approximately two-fold the rate of its diffusion in the intercellular substance, was performed,.
With the use of this combination the balance between the consumption of glucose, its concentration in the cytoplasm of
neurons and the concentration in the intercellular space is maintained. When the absorption value is 2.5 – 3-fold larger,
the unbalance is observed, resulting in the depletion of glucose in the neuropil, whereas the decrease of absorption results
in the deficiency of glucose in the bodies of neurons.
The following distribution of glucose in the neuron can be thus obtained. In the cytoplasm and in the karyoplasms
of the largest neurons in the model examined the level corresponds to 0.24•10-6 to 0.10 • 10-6 g of glucose/mm3, which
can be sufficient for 10 seconds or more with the level of glucose consumption equal to 8.346•10-9 g of glucose/mm3•
10-6 sec. The similar tendency is observed in the neurons with a small diameter, lying near the vessels. At the same time
in small neurons, removed from the vessel, the concentration of glucose in some areas decreases to 0.04 – 0.05• 10-6 g of
glucose/mm3, which decreases considerably the compensation abilities of neurons, with their consumption reserve not
exceeding 4 - 5 seconds, in case of the blocked entry. Thus, the zones of neuropil, which are adjacent to these regions,
have also the extremely low concentration of glucose in the neuropil, up to 0.003 – 0.01 • 10-6 g of glucose/mm3. The
similar decrease of the level of glucose in the immediate proximity to the neuron bodies can be observed at the distance
of 20 - 30 μm from a microvessel as well. If the distance exceeds 30 μm, this pattern becomes predominant, which de-
creases considerably the compensation abilities of the neurons to absorb glucose under condition of a sudden increase of
its consumption.
The importance is attached to the fact that even in well blood-supplied bodies of large neurons the regions re-
moved from microvessels exist, where the concentration of glucose is reduced significantly. For example, there are poles,
where glucose concentration can descend to 0.05 to 0.08• 10-6 g of glucose/mm3. Probably, the deficiency of glucose in
these areas serves in some degree as the cause of the phenomenon of mitochondrial and nuclear polarization of a cell
which is well-known in the morphology, especially under condition of a sudden increase of its consumption.
It is noteworthy that the level of oxygen and of glucose can differ. The most significant reduction of oxygen con-
centration is observed in the central zones of the neuronal bodies, whereas the glucose concentration sharply decreases in
the areas that are most removed from vessels. Such a decrease can occur in the limited regions of the close contact be-
tween the neuron bodies as well. The small neurons, even when they are remote (up to 20 μm) from the microvessels, are
not characterized by an extremely low oxygen level, compared with the large neurons. The completely different situation
exists in case of glucose. Its concentration is reduced most substantially in these cells, as we have stated already.
The comparative analysis of the variety of concentration of glucose, oxygen and carbon dioxide revealed that the
concentration of glucose is most labile. This may hamper the compensation abilities under the conditions of glucose defi-
cit considerably. Probably, the possibility of its accumulation in the form of glycogen enables to compensate these differ-
ences. If the balance of glycogen is maintained at a certain level, it is extremely significant under the conditions of the
changing consumption, while it cannot play a significant role in the transport processes in view of the compensation of its
degradation and synthesis. Probably glycogen provides the attenuation of glucose deficit in the zones with a sudden in-
crease of the energy requirements of neurons.
On the basis of the obtained results of simulation, it could be assumed that not only the body and the processes of
neurons could participate in the transport of glucose, but the astrocytes and oligodendrocytes as well. This assumption
allows for inclusion of considerably larger volume in this transportation system in comparison with the intercellular sub-
stance. According to the literature data and to the results of the direct morphometry of electronograms of the nerve tissue,
the bodies and the processes of neuroglia occupy 6 to 8% of neuropil. We shall try to examine the characteristics of glu-
cose transport flows upon consideration of the possibility of its transport through the macroglia, with a probable active
transport into the intercellular spaces of neuropil. It should be noted that such assumption is speculative in many respects
and is not experimentally confirmed thus far. However, the possibility of glycogen accumulation in the macrogliocytes is
proved. This allows for the indirect assumption of the possibility of its transport after glycogenolysis under the conditions
of glucose deficit. Although it is not improbable that astrocytes and oligodendrocytes just compensate their own require-
ments in such a way. The data concerning the accumulation in the neurons
 86
of type 1 lactate-dehydrogenase (cardiac form), revealed with the use of monoclonal antibodies, may serve another
proof, while in the astrocytes type 5 lactate-dehydrogenase was discovered. This directly indicates the existence astrocyt-
ic-neuronal metabolic cycle, where the lactate is produced in the astrocytes, and is degraded in the neurons (L Pellerin,
P.J. Magistretti, 1994). The reverse capture of some exciting mediators (glutamate) from the zone of synaptic contact was
revealed in the astrocytes. This results in the activation of Na+/K-ATPase in the astrocytes, in the glucose uptake and in
the synthesis of lactate (L Pellerin, P.J. Magistretti, 1994). Two last statements can indirectly confirm our assumption.
The problem consists in the absence of definite information concerning the rate of lactate diffusion and the rate of its me-
tabolism in the cytoplasm of the astrocyte, as well as the coefficient of the transmembrane transport through the mem-
brane of neurons. Theoretically, the consideration of this factor would not much complicate the formula, and if the men-
tioned coefficient were known, it could be used. At present we just simplified the formula, assuming that glucose itself is
transported rather than glucose and its metabolic products.
The contractile ability revealed in the astrocytes in the central nervous system which has a selective pattern de-
pending on the functional state of neurons, testifies favorably the role of the astrocytes in the transportation flows in the
neuropil. In the supraoptic hypothalamic nuclei in rats the specific contraction of the astrocytes processes under the con-
ditions of dehydration and their restoration after rehydration were discovered, not observed under the similar conditions
in the other parts of the brain, which are less active functionally and secretory in comparison with the neurons of supraop-
tic nucleus, releasing the antidiuretic hormone. The physiological role of spatial variations of the processes configuration
is probably connected with the extrusion of neuronal axoplasm and with the effect exerted on the fluids flow in the inter-
cellular space or with the supply of functionally active neurons (B.I. Tkachenko, 1994; N Hawrylak Et Al, 1998).
Taking into account the possibility of glucose transport through the processes and bodies of macroglia, besides the
processes of every neuron, and assuming the compensation of the glucose deficit due to this mechanism, the mathemati-
cal analysis revealed the high concentration of glucose in the zones of the neuropil, in comparison with the case of its
possible transport through the intercellular spaces solely. The concentration of glucose in the intercellular substance
grows in this case to 2.7 – 1.1 • 10-6 g of glucose/mm3 near the vessels; while in the areas of neuropil, which are most re-
mote from microvessels, it is maintained at the level of 0.77 – 0.96• 10-6 g of glucose/mm3. The glucose concentration
gradually decreases proportional to the removal from the microvessel.
These effects cannot completely compensate for the high degree of absorption of neuronal membrane as far as at
the distance of 30 - 35 μm from the capillaries. The tendency for the low level glucose in the immediate proximity to the
cytomembrane of the body of neurons persists. All these factors result in a very interesting tendency. The areas in large
neurons with a good glucose supply are characterized by a substantial increase of glucose concentration. The value of
glucose concentration in their hyaloplasm and karyoplasm varies from 0.35•10-6 to 0.20• 10-6 g of glucose/mm3. Howev-
er, the zones of neurons with the low concentration of glucose change insignificantly the level glucose, whereas their
area decreases. In theses zones the glucose concentration is maintained within the limits of 0.05 to 0.09 • of 10-6 g of glu-
cose/mm3. In the model examined this is most characteristic for the small neurons, remote from the capillaries, or for the
weakly vascularized areas around the large neurons.
Thus, a clear tendency persists for the dependence of the level of glucose intake on the distance to the microvessel,
which is independent on the sizes of neuron. The limitation of the distance sufficient for the active intake of the large vo-
lume of glucose increases, but non-significantly (to 30-35 μm).
If the concentration of glucose in the plasma decreases to the level of 0.5• 10-6 g of glucose/mm3 (fig 63), which is
known as the level triggering the excitation of animal with activation of feeding behavior, then under condition of the
constant endothelial concentration ability (six-fold), that is considered maximal, the concentration of glucose in the brain
undergoes substantial changes.
The decrease of glucose concentration in the plasma to 38% in comparison with the average standard can play a
significant role in this process.
Even after taking into account all the possible mechanisms of glucose transport into the body of neuron, namely -
active transmembrane transport, passive diffusion through the neuronal processes, possible active transport through the
neuroglial cytomembranes and passive diffusion through neuroglial processes - the following changes are observed. The
ability of intercellular substance for the absorption of glucose molecules from its surface is considerably reduced. Glu-
cose deficit in the intercellular fissures is revealed as early as at a distance of 15 to 20 μm from the adjacent microvessels.
The diameters of the zones in the bodies of neurons increase 1.5 - 2-fold, while the concentration of glucose declines to
the level of 0.06 – 0.04• 10-6 g of glucose/mm3.
 87
In the considered model the bodies of neurons, which are removed to the distance of 20 μm from the capillaries
are characterized by a significant reduction of the concentration of glucose to the level of 0.02 – 0.04• 10-6 g of glu-
cose/mm3, providing the neuron supply with glucose after the breakdown of blood flow but for 1 to 2 seconds.
The degree of active glucose absorption, which can be performed in the membrane of neurons, without complete
depletion of glucose concentration in the intercellular substance is limited by the coefficient corresponding to 7*10-10 -
0.3• 10-10 g/mm2; with the increase of this parameter the concentration of glucose in the intercellular substance declines to
zero. The further absorption becomes physically impossible. Even under these values that are obviously decreased in
comparison with the standard parameters, the concentration of glucose in the perimembrane space of the neurons is 2- to
4-times higher in comparison with the adjacent intermembrane space.
The data obtained suggest the opinion that the mentioned reactions can increase the concentration ability of endo-
thelium and probably can compensate the glucose variations in the nerve tissue. The level of the concentration ability of
endothelium must increase 1.5- to 1.8-times, according to the calculations, i.e. endothelium must absorb the glucose 9 –
10-times more actively in comparison with its passive diffusion. However, even under the conditions of six-fold concen-
tration ability of endothelial lining the glucose concentration becomes marginal, while it does not result in its absolute
depletion and can be compensated, particularly via glycogenolysis in the astrocytes.
The further aggravation of hypoglycemia achieving the level of 0.4•10-6 g of glucose/mm3 (Fig. 64), which results
indeed in a coarse disorganization of the cerebral functions, to the extent of the coma, is accompanied by the following
changes in the model under investigation. In the plasma of venous blood its concentration declines to 0.11 • 10-6 g of glu-
cose/mm3, which results in a critically hindered absorption, due to the glucose ability of binding with the high-molecular
plasma compounds.
As early as in the pericapillary space the glucose concentration declines to 1.1 – 0.4•10-6 g of glucose/mm3, rapidly
depleting at the distance of 10-15 μm.
The glucose concentration in the neuropil varies from 0.085 – 0.09• 10-6 g of glucose/mm3 in the zones with a poor
supply to 0.19 – 0.12 • 10-6 g of glucose/mm3 in the zones of relatively satisfactory supply. In the zones of neuropil, that
are 10 - 30 μm removed from the surface of neuron, the level of glucose in the intercellular substance is equal to 0.02 to
0.09 • to 10-6 g of glucose/mm3.
The degree of glucose absorption by the membrane of neurons from the intercellular substance decreases from 4•
10-10 to 0.03• 10-10 g/mm2. Under the conditions of the insignificant activation of absorption the concentration of glucose
in the extreme units of the intercellular substance is absolutely depleted around the membrane, preventing higher intensi-
ty of transmembrane transport.
However, such intensity of glucose concentration in the membrane of neuron results in significant reduction of its
concentration in the cytoplasm and karyoplasm. Thus, in the zones of the neuron bodies which are poorly glucose sup-
plied, the glucose concentration declines to 0.02 – 0.006• 10-6 g of glucose/mm3. Assuming the consumption equal to
8.346•10-9 g of glucose/mm3•sec, its content must be absolutely depleted in 0.75 sec. However, such concentration is not
apparently sufficient to provide the effective energy production in the neurons. It should be noted that in the model pro-
posed the most favorable possibility is considered, when the activity of neurons is similar to the usual and the transport
proceeds both through the intercellular fissures and through the processes of neurons and of neuroglia.
However, the following characteristic of hypoglycemic coma should be taken into consideration. It is known that
under the conditions of hypoglycemia, before the coma develops, the extraexcitation of the central nervous system oc-
curs. According to this, the activity of neurons and of neuropil must increase achieving the glucose metabolism corres-
ponding to 9.496•10-9 g of glucose/mm3•sec in the bodies of neurons and to 0.696• 10-9 g of glucose/mm3•sec in the neu-
ropil, which matches to the upper limits of oxygen intake, equal to 6.667•10-6 mlО2/mm3•sec and 0.334•10-6
mlО2/mm3*sec, respectively. After the introduction of such coefficients of glucose consumption the following data were
obtained.
There are areas in the neuropil having 30 - 150 μm in diameter with a deficit of glucose, where its concentration
falls to the level of the minimal values from 0 to 0.05 – 0.06• 10-6 g of glucose/mm3. The average glucose concentration
in the neuropil varies from 0.11 to 0.28 * 10-6 g of glucose/mm3.
In the zones adjacent to the neuron bodies, especially in those 15 - 25 μm removed from the microvessels, the de-
crease in glucose level is equal to 0.004 – 0.07• 10-6 g of glucose/mm3. The active transport from such deficiency zones
of neuropil becomes virtually impossible. The glucose level is sufficiently high barely within 10-15 μm from the micro-
vessels. The neurons, remote from the microvessels more than 15 μm, appear under the conditions of a total deficiency of
this carbohydrate. The decline of glucose concentration in the cytoplasm achieves 0.003 – 0.0005• 10-6 g of glucose/mm3,
that may
 88
result in the impossibility of ensuring the functioning of the neurons at such level of energy consumption. Actually,
these conditions would result in an absolute depletion of glucose resources within 1/3 to 1/20 sec after the cessation of
blood flow.
These processes result in a defensive inhibition of neuronal activity, their partial damage and unconsciousness. The
neurons pass into the lowered metabolic activity at the level of 4.748• 10-9 g of glucose/mm3 • sec. in the bodies of neu-
rons and of 0.464 • 10-9 g of glucose/mm3 • sec in the neuropil, corresponding the lower limits of oxygen intake equal to
3.334 • 10-6 mlO2/mm3•sec and to 0.167•10-6 mlО2/mm3-sec, respectively. Such decrease of the level of glucose con-
sumption allows to equalize the parameters and is accompanied with the increase of glucose concentration in the neuropil
and in the bodies of neurons to the values, that are achieved with the decrease of plasma glucose level to 0.6•10-9 g of
glucose/mm3. Thus, the glucose deficit is significantly reduced, while is not eliminated.
However if we refuse the assumption of the possibility of glucose transport through neuroglia (Fig. 65), the simu-
lation of glucose concentration even under condition of the critical decrease of its consumption when the decrease of glu-
cose concentration in the arteries achieves 0.4•10-6 g of glucose/mm3 reveals in the nerve tissue the broad areas characte-
rized by the complete absence of glucose in the neuropil and in the bodies of neurons. This virtually interrupts the surviv-
al of these parts of the brain, while the negative values reflect the deficit of glucose, which must be compensated by other
substances.
Thus, the mathematical simulation of glucose transport in the cerebral tissue reveals several important features. So
that a certain portion of the surface of neurons could perform the transport of glucose in a sufficient way, they must lie
not more than 25 μm from the nearest microvessel. In this case even insignificant decrease of the level of glucose, i.e. to
0.7• 10-6 g of glucose/mm3, is accompanied with the formation of the zones inside the neurons, which experience the glu-
cose deficiency. The role of such local zones can be not too significant, while the consequences of the deficit may be li-
quidated by means of redistribution of the mitochondria into the zones with a high glucose concentration.
When the blood glucose concentration decreases to 0.4• 10-6 g of glucose/mm3, its deficiency becomes so signifi-
cant, that a certain portion of neuropil and individual neurons appear under the conditions of a very substantial reduction
of glucose concentration. This results in the impossibility of their functioning at high level of energy consumption and in
the deep functional impairment. The data of mathematical modeling are in absolute agreement with the clinical informa-
tion.
The results of mathematical simulation suggest the active role of neuroglia in the transport of glucose, at least un-
der the conditions of its deficiency. When the glucose concentration is sufficiently high, such a transport is not so signifi-
cant, if it takes place at all, since the glucose requirement is completely compensated due to its diffusion through the in-
tercellular spaces. At the same time, in case of the deep deficiency of glucose, which results in coma or praecoma, but not
in death, the neglect of this parameter suggests the impossibility of the brain functioning in general, in disagreement with
the clinical data. However, the increase of glucose diffusion can proceed due to the increase of the relative volume of in-
tercellular substance as well, that is known to occur in case of the brain edema. Thus, the edema can exert a protective
and compensatory function, increasing the area of glucose exchange. Indeed, in this case the distance from the microves-
sel to the body of neurons grows, but the distance increases proportionally in the linear progression, while the area in-
creases in the quadratic dependence.

V.6. Oxygen distribution modeling in the anlage of the posterior cerebral vesicle

The principles of the mathematical simulation of oxygen diffusion in the micro-objects of the mammalian embryos
were not developed thus far. The calculation was performed in accordance with the procedure earlier described. The ini-
tial oxygen concentration, taken equal to 62 mm Hg in the afferent vessels (J.O. Davis, 1965, Young Maureen, 1963),
whereas it can be considerably lower (40 - 45 mm Hg.); carbon dioxide concentration equal to 46 mm Hg or more; the
curves of oxygen dissociation, taking into account the predominance of fetal hemoglobin and the dynamics of its changes
in accordance with the given blood pH and with blood concentration of carbon dioxide, represented the particular fea-
tures of these calculations. The linear blood flow velocity was determined separately for each vessel with calculation of
the resistance, considering blood viscosity variations, and of the pressure gradients. During the calculations the pressure
in afferent vessels in rats during the prenatal ontogenesis was taken equal to 20 - 25 mm Hg (Young Maureen, 1963),
while the pressure gradient in the precapillaries was taken equal to 4 to 8 mm Hg.
 89
In rat embryo on the 12th day of intrauterine development the middle cerebral vesicle represents a hollow struc-
ture with the wall thickness of 150 to 27-30 μm, consisting of several layers of the matrix cells forming its nuclei.
The anatomical anlages of the nuclear centers within the given periods cannot be identified. At the level of the an-
lage of the middle cerebral vesicle the nervous tube consists of 6 to 12 layers of medulloblasts. The mantle and ependym-
al layers cannot be visually defined. The cells in the region under investigation are poorly differentiated, have the oval
nuclei and are characterized by a high mitotic activity in the ependymal layer and by the small sizes. The identification of
the direction of their future differentiation with the use of the methods at our disposal is difficult.
The region of the mesenchyma, which lies in immediate proximity to the cerebral vesicle, is characterized by nu-
merous primary capillary networks having large diameter and irregular contours. They form the abundant anastomoses
and can be directed both longitudinally and transversely. The first vessels penetrate from them into the depth of the nerv-
ous tube, breaking through the external terminal membrane. The vasal precursors are oriented radially or transversely and
lie virtually perpendicularly to the external surface of the cerebral vesicle. The course of the perforating efferent and affe-
rent structures is nearly straight-line. The wall of the primary capillaries is formed only with the endothelial lining. This
is impossible to isolate the afferent and efferent vessels in accordance to their morphology and with the use of the con-
ventional examination procedures, upon the direct observation of the individual sections, and the inhering of the vessels
to the anlages of veins and arteries is defined by means of their tracing in the series of preparations to the sites of obtain-
ing the anlages of the main vessels. Some of extraorgan vessels form the cellular cords, not containing the erythrocytes,
which represent the probable areas of capillarogenesis. Some microvessels in the nervous tube contain the erythrocytes.
Thus, the process of the primary angiogenesis in the nervous tube sufficiently being rather early, coincides with the
rapid proliferation of matrix cells and with the beginning of neuroblasts migration processes, preceding the formation of
the definitive nuclear centers, and results in the formation of the systems of primary capillary networks. The possibility of
the active influence of microvessels on the formation of the nervous system in embryogenesis can be due to several mo-
ments: the change in the gradients of the nutrients supply (first of all, glucose and amino acids), the variations in the gas
exchange, the contact and humoral interactions between the endotheliocytes (endothelioblasts) and the differentiating tis-
sue structures of the nervous tube, the absence of hematoencephalic barrier. The absence of the barrier properties in the
vascular wall provides the diffusion of a number of biological substances into the brain, whose content is substantially
increased in the most vascularized zones, creating the gradient for the further neuroblasts development, which is in
agreement with the opinion of other researchers. The early penetration of vessels into the nervous tube contributes such
effects.
However the dynamics of the processes of gas exchange and metabotropic reciprocal effects in the nervous tube
are not clarified thus far. The complexity of direct examination of these processes is related with the significant technical
problems and high costs of the experimental direct observation of such phenomena. The mathematical simulation of these
processes could play a certain role in the solution of this problem. The conventional models are unfortunately too forma-
lized and cannot describe the process dynamics while taking into account the local variations, creating the impression of
inapplicability of mathematical methods in the course of description of the biological processes; however, upon consider-
ation of morphological structure, at least in connection with the diffusion and simple metabotropic phenomena these me-
thods are very effective for the purpose of clarifying a number of phenomena.
We shall examine as an example the diffusion properties in the volume reconstruction of a portion of the nervous
tube. The volume reconstruction was performed with the use of a sample 6.25 х 106 μm3 in volume, thus the volume of an
elementary unit in the course of the mathematical calculations was equal to 125 μm3. The calculations were performed
while taking into account the variety of parameters: oxygen intake, oxygen concentration in the afferent vessels (from the
maximal level of 62 mm Hg to 40 mm Hg), diffusion of oxygen through the cavity of the ventricle, variations of oxygen
dissociation curves depending on the levels of pH and Рсо2, with different pressure gradients in the microvessels. Such
calculations can be easily performed and take several hours, but they are very succinct upon their interpretation and expo-
sition. As an example, we shall examine the optimal version of development of the nervous tube (Fig. 66), when Ро2 in
the arterial blood is equal to 62 mm Hg, Рсо2 in the arteries is equal to 46 mm Hg, pH is equal to 7.4, the pressure gra-
dient between the anlages of the arteries and veins (within the considered limitations of the model) corresponds 8 mm
Hg. The blood flow velocity under the condition of introduction of the considered gradient was equal to 0.2 to 0.5
mm/sec.
 90
In such conditions, with the assigned parameters of oxygen intake in the tissues, its content in the efferent mi-
crovessels of the model descended to 7 - 12 mm Hg, whereas further retardation of the blood flow achieving the value of
0.05 - 0.2 mm/sec was accompanied by the nearly absolute oxygen depletion, which is practically quite improbable and,
on the contrary, confirms the assumption about more rapid flow of blood in the embryonic microvessels. The possibility
of oxygen diffusion through the cavity of the cerebral vesicle was examined with application of the model parameters
given above. In the present case it was taken within the limits of 20 mm Hg, that are assumed as maximal level, while
taking into account the data of other researchers (B. Frolkov, E. Nile, 1976). .
When partial oxygen pressure in the arteries is equal to 62 mm Hg, the maximal consumption level in the epen-
dymal and mantle layers of the nervous tube is limited by 3.4 mlO2/100 g per 1 min, while its metabolism in the mesen-
chyma is equal to 0.6 ml O2/100 g per 1 min. Such value of the consumption corresponds approximately to the consump-
tion of the mature human brain in general, but is at least two times lower than the requirement of the gray substance at
rest. Further increase of the consumption is accompanied with the formation of large zones in the nervous tube, which are
practically oxygen-deprived. The comparative analysis of oxygen distribution in the thickness of the anlage of the middle
cerebral vesicle revealed the lowest values in the depth of its walls, but the concentration of the dissolved gas is very ir-
regular. Thus, besides the zones characterized by rather high oxygen concentration, which are located near the vasal pre-
cursors, that penetrate into the nervous anlage, there are zones, where Рсо2 level appears critical. The areas in the nerv-
ous anlage with a high oxygen level are characterized by larger thickness and high values of mitotic activity of medullob-
lasts (difference between the areas correspond to 1.4). Such a phenomenon suggests the possibility of high metabolism
and the rate of development of the vascularized zones that may in turn appear as one of determining factors of heteroch-
rony in the course of the nervous tube ontogenesis and of the formation of its anatomical characteristics. The decrease of
oxygen value in the arterial blood to 45 mm Hg, when Рсо2 is equal to 50 mm Hg, is accompanied with the necessity of
significant reduction of oxygen intake in the embryonic tissues of the ependymal and mantle layers of nervous tube to 1.2
ml O2/100 g per 1 min, and in the mesenchyma - to 0.15 ml O2/100 g per 1 min. In this situation the possibility of tran-
scavitary diffusion through the cerebral vesicles becomes very significant. The essential differences in the trophic supply
in different sections of the anlage are maintained, which are similar to the changes earlier examined, indicating the stabil-
ity of the patterns of nervous system formation, that is revealed even with taking into account the incompleteness of the
data concerning the physiological organization of metabolism and of microcirculation during the early stages of ontoge-
nesis in mammalian. On the other side, the acquaintance with one of the parameters allows for approximation of these
data to the calculation of all the other parameters.
Thus, the development of microcirculatory system and the penetration of the endothelial channels into the anlage
of the nervous systems play the fundamental role in the formation of mesencephalon at early stages of ontogenesis, which
is accompanied with the correlation between the development of the brain structures and their vascularization. The in-
formation obtained in the course of the morphological analysis, is supplemented by the mathematical modeling, which
revealed the nonuniformity in the trophic supply of the anlage of cerebral vesicle, which can be of importance in process
of the determination and differentiation of tissue elements of the central nervous system.
 91
CONCLUSION

Our data and the results available in the literature reveal the complex neurotrophic interactions existing in the cen-
tral nervous system. The structure of neurogliovascular ensembles varies in the different portions of the nervous systems
and is related with their evolutionary, ontogenetic, morphological and functional with characteristics. Both the variability
of the neuron complexes and of glial environment, as well as the allomorphism of the vascular structures is essential.
The interdependence is revealed between the degree of blood supply of the neuron bodies and their sizes. The
small neurons are supplied with smaller absolute quantity of vessels, independently of the functions of nucleus and the
species investigated. This absolute parameter is to a considerable degree leveled by an increase of the volume of perineu-
ronal space around the neurons. Thus, without taking into account the sizes of neurons, the absolute number of capillaries
around the body of neuron is not correct. New quantitative specific parameters of blood supply of the neurons bodies that
we proposed are considerably more reliable. This statement is confirmed by the opinion that the central nervous system is
characterized by an expressed variability of microcirculation even in the adjacent zones (P.A. Motavkina, V.M. Chertok,
1980). The differences concern not only the gray and white substance, but the certain structural elements of the gray sub-
stance as well. The more intensive is the exchange in the structure, the thicker are the capillary networks and the smaller
size have the loops (P.A. Motavkina, A.V. Lomakin, V.M. Chertok, 1983; I.V. Gannushkina, A.P. Shafranova, T.R. Rya-
sina, 1977). The local reactions of the vascular elements are regional and are limited by the areas of individual microba-
sins. The independent variations of blood flow in the brain, according to the literature, proceed within the volumes cor-
responding to 1/10 mm3 and even smaller (G.I. Mchedlishvali, 1986). Our results of mathematical simulation show that
the processes of diffusion and the levels of oxygen and glucose concentration can differ markedly in even smaller volume
areas (within the microbasins, delimited by the adjacent capillary loops). The processes of macromolecules diffusion after
the breakthrough of barrier, the penetration of low-molecular tracers without impairment of hematoencephalic barrier,
which are experimentally obtained, also confirm such tendencies. Thus, the significant difference of the processes of
trophic supply and their control may be assumed at the level of the neuro-glio-vascular complexes that are investigated in
this research, which are limited by the adjacent capillary loops and united with the use of the processes of neuroglia dis-
tributed between them (primarily astrocytes).
The vessels length in the particular zones of vascularization varies in different types of neurons even within the
limits of the unique morphological formation (B.N. Klosovsky, E.N. Kostomarskaya, L.M. Bakhitova, 1968; Iu.G. Vasi-
lyev, 1995). The blood supply of neurons reflects the metabolic intensity (Iu.I. Zhabotinsky, 1965). The heterogeneity of
vascular reactions could explain the focality of the damages of the zones of the brain under conditions of hypoxia (B
Budzynska, A Zerebska, 1996), as well as the evolutionarily developed compensatory reactions, which enable to control
the degree of blood flow in the brain, including the pathological situations. The data of mathematical analysis confirm the
authors’ opinion; however, the similar changes can appear under conditions of hypoglycemia.
The general averaged parameter of the vascularization of nucleus reflects the level of its intrinsic trophic supply
but approximately. The study of microcirculation in the constituent morphological structures instead of large anatomical
formations of the nervous systems appears the most correct. Thus, under the conditions of pathologic processes the ex-
amination of the conditions of trophic supply of the separate neuronal populations possessing the different types of func-
tional reactions in response to a certain action is considered more convenient; this is possible due to the method of mor-
phometric and statistic analysis, which is proposed in this work. However, even in this case the averaged parameters can-
not completely reflect the real threshold levels, which can cause damages in the individual populations of neurons; in this
case on the contrary, the extreme parameters are more reliable than the mean values.
The dynamic parameter of specific surface area, which is characterized by the most effective exchange
 92
between the capillary and the body of neuron, is in the correlation dependence on the sizes of neurons. Several me-
thods of solution of the problem concerning the most effective blood supply of neuron bodies can be observed. These me-
thods include the concentration of vessels around the neuron bodies with the decrease of their density in the neuropil re-
gion, the close arrangement in immediate proximity to the microvessels and to their arborization zones, the thick distribu-
tion of vessels in animals having smaller capillary diameter and the poorly developed neuropil (rat and rabbit). The last
statement can be due to the interspecies differences in hemodynamics, in the tissue exchange, in cytoarchitectonics and
myeloarchitectonics.
The elements of the glial environment in the gray substance of mesencephalon and metencephalon include the pro-
toplasmic astrocytes, microglia, in certain degree - fibrous astrocytes, oligodendrocytes, in some nuclei investigated (the
central gray substance of mesencephalon and the locus coeruleus) - the processes of ependymocytes as well. The detailed
examination of their structure with the astrocytes as an example revealed, that they represent a rather variable group of
cells, which are distinguished according to the pattern of arborization and to the length of processes, to the arrangement
with respect to vessels of microcirculatory system, to the bodies and processes of neurons. The distribution of the
processes of astrocytic glia has a tendency for the most effective provision of transportation processes in the systems in-
vestigated. The results of mathematical simulation suggest the necessity for their active participation in the transportation
processes (for example, glucose transport, especially under the conditions of its deficit).
At the same time the significant differences in the distribution of macroglial processes in the central nervous sys-
tem can result in significant changes of a so-called volume signal transmission. Thus, while in the large-cell nuclei the
astrocytes and oligodendrocytes encompass the bodies of one or two neurons, the activation of the given gliocyte can ex-
ert a modulatory effect within those limits, considering that the signal transmission in the neuroglia attenuates at a dis-
tance of 50 μm. In the small-cell nuclei one astrocyte distributes its processes in the immediate proximity to several neu-
rons at once. Moreover they are located within the unique microvascular basin, therefore - under the close to similar con-
ditions of supply. Thus, the extrasynaptic influences in such nuclei encompass most frequently the group of cells instead
of a single cell. The differences of the trophic supply, of glial environment can result in the particularities of extrasynap-
tic modulatory influences on the function of neurons in the nerve center and in the different level of compensation abili-
ties in the given centers.
The estimation of degree of morphological maturity of the nerve tissue can be obtained by means of the analysis of
individual constituent elements (quantitative and qualitative characteristics of the neuron bodies, synaptic contacts, con-
centration of the mediators), or with the use of the integrated assessment method, which includes the investigation of the
conditions of neurons, neuroglia, and vessels. The complex method appears to be the most correct. The data of our inves-
tigations demonstrate that the signs of differentiation of the individual neurons do not implicate the maturing of the nerve
center as an integral structure. This is especially important upon consideration of increase of the data concerning the role
of neuroglia and of microvessels (particularly, of the endothelium) in the functioning of the nervous system. The insuffi-
cient maturity of the glial-vascular component along with the high degree of variability of the morphofunctional characte-
ristics of neuron complexes can represent the factors, which ensure the chain of so-called “random” external influences,
resulting in the formation of the structural particularities of the central nervous system, characteristic for the high mam-
malian.
The obtained results can serve as the basis for the construction of mathematical models for the purposes of clarifi-
cation of the characteristics of the nerve centers trophic supply, after the examinations of physiological constants of dif-
fusion and metabolism of the substance under investigation. In this regard for describing the early stages of ontogenesis
(before the birth) the modification of Krogh tissue model appears the most appropriate (A Krogh, 1936). For the postnatal
development the modifications of the model of Iu.Ia Kislyakov et al.(1988) are promising. In the latter case, the above-
described model of the oxygen diffusion needs the essential updating and represents the particular case of the neurotroph-
ic interrelations. In such model, as our studies revealed, the examination of the possibilities of the transportation flows’
deviation from the normal and the correction for the different sizes of microvascular basins and the structure of neuron
ensembles are necessary.
In the course of ontogenetic development several stages of formation of the neuroglio-vascular ensembles are ob-
served: primarily, the relatively isomorphous compartments, consisting of the agglomerations of neuroblasts and gliob-
lasts, contain the poorly differentiated microvessels; then the transition into the uniform trophic supply of the anatomical
structures of nuclei and ganglia on the account of the intraorgan vascular plexuses occurs, the vessels of microcirculatory
tree are formed
 93
at the juvenile period, and are more expressed at the moment of puberty; the neuro-glio-vascular complexes
acquire a clear organ specificity. However, as early as during the first stages of development the formation
of microcirculation system results in the qualitatively different conditions of the trophic supply and of the
influences of substances, which penetrate from the blood, in the neuroblasts that lie adjacent to the capilla-
ries. These gradients of substances distribution (in particular, of oxygen and glucose) can influence the total
subsequent development of the nervous system.
The stages of vascularization of the neuron bodies correlate with the periods of the organism devel-
opment; the intensification of the trophic supply of the nerve center occurs both due to the absolute increase
of the vessels quantity and due to the pattern of their distribution within the nucleus. While at the early stag-
es of ontogenesis the increase of the parameters of microcirculation occurs predominantly due to the in-
crease of total number of the blood vessels in the nerve center, after birth the high concentration of micro-
vessels around the neuron bodies comes to the fore.
Our principle of the quantitative assessment of blood supply can be recommended for the use in the
investigation both of the nervous systems and of other heteromorphic biological systems, with the correction
for their structural-functional characteristics.

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