DEVELOPMENT OF CORTICAL

CIRCUITS: LESSONS FROM OCULAR

DOMINANCE COLUMNS
Lawrence C. Katz and Justin C. Crowley
The development of ocular dominance columns has served as a Rosetta stone for understanding
the mechanisms that guide the construction of cortical circuits. Traditionally, the emergence of
ocular dominance columns was thought to be closely tied to the critical period, during which
columnar architecture is highly susceptible to alterations in visual input. However, recent findings in
cats, monkeys and ferrets indicate that columns develop far earlier, more rapidly and with
considerably greater precision than was previously suspected. These observations indicate that
the initial establishment of cortical functional architecture, and its subsequent plasticity during the
critical period, are distinct developmental phases that might reflect distinct mechanisms.
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R E V I E WS
Historically, neuronal development has been divided
into a sequence of events that leads from the initial spec-
ification of neuronal cell fate to the eventual emergence
of adult circuits
1
. In this formulation, many circuits
undergo a pivotal transition in which precise patterns of
synaptic connections emerge from an earlier stage of
more coarsely specified connections. Although the initial
organization of neural circuits relies on a variety of mol-
ecular cues that guide axons to generally appropriate
regions, the final specification of patterned connections
is widely held to depend on patterns of neuronal activity,
generated either by circuits intrinsic to the developing
brain or by early experience
211
. In particular, as postu-
lated by Hebb, correlations in presynaptic and post-
synaptic activity patterns strengthen and retain correct
synapses, and eliminate inappropriate connections.
In the central nervous system, and in the mam-
malian neocortex in particular, much of this prolonged
sculpting of neuronal connections is thought to occur
during critical periods, when circuits are particularly
susceptible to external sensory inputs. Such ideas orig-
inated from developmental studies of functional archi-
tecture in the mammalian visual cortex, especially the
formation of ocular dominance columns
1214
(FIG. 1).
This highly influential body of work subsequently
guided the interpretation of developmental events in
many other systems. Despite the powerful appeal of
this general model, and the experimental support that
accumulated over several decades, a number of recent
findings indicate that some of the assumptions under-
lying the conventional formulation might need to be
revised. Such revisions, in turn, indicate that alterna-
tive explanations for the patterning of connections
should be considered, and that the definition of and
evidence for activity-dependent refinement requires
greater precision.
History of theories of column development
Hubel and Wiesel initially described ocular dominance
columns in the early 1960s
15
. By making electrophysio-
logical recordings in cat primary visual cortex, they
noted that the two eyes differentially activated cortical
neurons (the physiological property of ocular domi-
nance). Cells with similar eye preference were grouped
together into columns, and eye dominance shifted
periodically across the cortex. On the basis of a few
recordings in very young, visually inexperienced cats,
Hubel and Wiesel originally argued that innate mech-
anisms determined the organization of the cortex into
ocular dominance columns and ORIENTATION COLUMNS
16
ORIENTATION COLUMNS
Orientation tuning is a property
of visual cortical neurons that
allows the detection of lines and
edges within visual scenes by
encoding their orientations.
Neurons that share the same
orientation tuning are grouped
into orientation columns.
Howard Hughes Medical
Institute and Department of
Neurobiology, Box 3209,
Duke University Medical
Center, Durham, North
Carolina 27710, USA.
Correspondence to L.C.K.
e-mail:
larry@neuro.duke.edu
DOI: 10.1038/nrn703
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A substantial alteration in this formulation occurred
when transneuronal transport of tritiated amino acids
(and later, sugars) for example,
3
H-proline made
it possible to directly visualize ocular dominance
columns
1923
. In adult monkeys
19
, injections of one eye
produced bands of transneuronally transported label
that revealed the termination patterns of one eyes rep-
resentation in the cortex, alternating with dark bands,
nearly devoid of label, which corresponded to the
other eyes thalamic input (FIG. 2a). Monocular depriva-
tion during the postnatal critical period led to a
remarkable and satisfying correspondence between the
electrophysiological loss and gain of responsiveness,
and the shrinkage and expansion of eye-specific bands
in layer 4 (REFS 2224).
The same approach was then applied to the develop-
ing visual system to determine how ocular dominance
columns first formed
22,23
. Unlike in the adult, injections
of amino acids into cats eyes before the onset of the criti-
cal period yielded a homogeneous band of label in layer 4,
regardless of which eye was injected. Beginning at about
3 weeks after birth, and continuing over the next month,
the adult pattern of segregated ocular dominance stripes
gradually appeared. The timing of the emergence of the
adult-like pattern overlapped beautifully with the period
when columns were susceptible to alterations of visual
experience
13,14,25
. Physiological evidence, based on sin-
gle-unit recordings, also indicated a higher proportion
of binocular neurons at early ages, perhaps reflecting the
greater degree of overlap of afferents representing the
two eyes
23
. In contrast to the original Hubel/Wiesel for-
mulation, these observations indicated that the precise
organization of columns in layer 4 was not innately
specified, but was gradually moulded by the same mech-
anisms that guided columnar rearrangement during
the critical period correlation-based synaptic com-
petition. Indeed, computer models based on initially
overlapping inputs and differential activity patterns can
produce columns with patterns strikingly similar to
those observed in vivo
35,8,9,2628
.
(innate was used interchangeably with genetic in their
early writings
17
). Monocular eye closure during the first
few months of life the critical period decreased
the numbers of cells activated by the closed eye and
markedly increased the number of neurons activated
exclusively by the open eye
12,13,18
. The initial descrip-
tions of the effects of eye closure during the critical
period indicated that pre-existing connections had sub-
sequently been altered, through a competitive process,
to cause the loss of cells driven by the closed eye. In
their interpretations, Hubel and Wiesel clearly distin-
guished between the innate mechanisms that guide the
initial formation of cortical functional architecture, and
the experience-dependent, competition-based mecha-
nisms responsible for their later modification during
the critical period.
Temporal
retina
LGN
Primary visual cortex layer 4 Temporal
retina
Nasal
retina
Nasal
retina
Ipsilateral
Contralateral
Ipsilateral
Contralateral
Figure 1 | Segregation of eye-specific information at the early stages of visual processing.
In mammals with binocular vision, the nasal portion of one retina encodes the same part of the
visual world as the temporal portion of the other retina. The axons of retinal ganglion cells from the
nasal portion of each retina cross the optic chiasm and project to the same lateral geniculate
nucleus (LGN) as the axons from the temporal portion of the other eye. These projections form
discrete, eye-specific LGN layers. The projection from the LGN to layer 4 of the primary visual
cortex maintains this eye-specific segregation by terminating in eye-specific patches that are the
anatomical basis for ocular dominance columns. Ocular dominance columns can therefore be
considered to correspond to an eye (left or right) or a retinal location (nasal or temporal).
Figure 2 | Early developmental organization of ocular dominance columns. Ocular dominance segregation in primates and carnivores precedes the onset of the
critical period for ocular dominance column plasticity. a | Adult-like ocular dominance segregation occurs in the macaque monkey before birth. A surface view of
radioactive proline labelling in layer 4 after injection of one eye shows clear alternating columns (alternating bright and dark bands) in an animal that had received no
visual stimulation. b | Ocular dominance column segregation in the ferret occurs by postnatal day 16 (P16). In this coronal section from a P21 ferret (equivalent to a P0
cat), labelled axons form segregated patches in layer 4 of the visual cortex (pia is at the top). Scale bar, 500 m. c,d | Ocular dominance columns form before the
critical period in cat. Intrinsic signal optical imaging (c) and improved transneuronal transport methods (d) show ocular dominance segregation at P14; a reconstruction
of the pattern in a P14 cat shows segregated columns at this early time. Part a reproduced with permission from REF. 31 1996 Society for Neuroscience; part b
reproduced with permission from REF. 58 2000 American Association for the Advancement of Science; parts c and d reproduced with permission from REF. 48
2001 John Wiley & Sons, Inc.
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R E V I E WS
waves seem to be crucial for the emergence of segregated
retinal projection patterns in the LGN itself
39
(BOX 1).
Moreover, recordings from both rodents and ferrets
show that the spontaneous patterns of activity generated
in the two eyes activate thalamic neurons, thereby poten-
tially providing signals for driving the segregation of
thalamic afferents in the cortex
4042
.
Multielectrode recordings obtained before eye open-
ing from the LGN of awake, behaving ferrets showed that
the patterns of activity generated by the two eyes pro-
duced correlational patterns, consistent with the idea that
the two eyes could act as independent oscillators. The
patterns of activity were more highly correlated at LGN
sites within the same eye-specific layer, and less well cor-
related between layers
42
. However, these recordings
uncovered unexpected differences between inputs from
the two eyes (FIG. 3). Eliminating inputs from the eye
IPSILATERAL to the recorded LGN had virtually no effect on
the pattern of spontaneous activity in both layers, indicat-
ing that the CONTRALATERAL retina alone, perhaps in concert
with cortical feedback, could activate the entire circuit. By
contrast, elimination of the contralateral input strongly
increased the correlations between eye-specific layers,
producing the same pattern of activity that was observed
in the LGN when all retinal inputs were eliminated. This
indicates that before eye opening the inputs from the two
eyes are not equivalent in their ability to activate thalamic
and cortical circuits: the contralateral eye provides much
stronger drive. A similar contralateral bias in responsive-
ness has been observed in recordings from cat cortex
shortly after eye opening and before the onset of the criti-
cal period: most neurons were initially activated exclu-
sively by the contralateral eye, and only weeks later did
responses to the ipsilateral eye appear
43
.
These observations in ferrets and cats are not consis-
tent with a strictly Hebbian-type correlation mecha-
nism for segregating ocular dominance columns
43
. If
spontaneous and evoked activities are both initially
strongly biased to one eye (the contralateral eye), these
inputs should effectively take over the entire cortex and
eliminate the much weaker ipsilateral inputs. At the very
least, there should be a substantial discrepancy in the
relative sizes of the two representations, but this is not
the case: ipsilateral and contralateral inputs normally
occupy roughly equivalent cortical territories. It would
seem, therefore, that there must be some mechanism
that prevents early imbalances in activity from being
translated into anatomical rearrangements.
Even more surprising is the finding that retinal activ-
ity does not seem to be required for ocular dominance
column formation. If both eyes are removed early in life
(P0 in the ferret), before the layers in the LGN have seg-
regated (and well before LGN afferents have reached
layer 4 of area V1), normally segregated columns of
layer-specific LGN afferents still form in the cortex.
These columns faithfully reflect the pattern of connec-
tions seen in normal animals: they have the same peri-
odicity and consist of thalamocortical projections from
what would be the same eye-specific layer in the LGN
44
.
Because ENUCLEATION does not silence the LGN
42
, this
finding does not rule out a role for correlated activity in
However, the carefully executed work of LeVay et al.
23
revealed a complication of transneuronal transport. In
young animals, anterogradely transported tracer
injected into one eye could leak into inappropriate eye-
specific layers (spillover) of the lateral geniculate
nucleus (LGN). So,
3
H-proline acted as a transneuronal,
but not necessarily as a trans-synaptic, tracer. Knowing
that spillover was more severe in younger animals,
LeVay et al. sought to compensate for the consequent
blurring of cortical columns by quantifying the extent of
spillover in the LGN. After accounting for spillover in
each animal individually, the authors concluded that
axons of the eye-specific LGN layers were intermingled
in young cats, and that segregation of geniculocortical
axons into ocular dominance columns progressed over
a period of several weeks, reaching the adult level at
about postnatal day 39 (P39).
As noted by these investigators, quantification of
spillover could be done only at the end of the experi-
ments, leaving open the possibility that more tracer was
present in inappropriate layers during the 12 weeks
required for transport of the tracer than at the comple-
tion of the experiment. So, in young animals, the pres-
ence of a continuous band of label in layer 4 might
represent either the absence of segregation as subse-
quent investigations have widely assumed or result
from extensive spillover in the LGN. On the basis of dif-
ferent labelling techniques (see below), spillover seems
to be the more likely explanation.
Early development of columns
The formation of ocular dominance columns in cats
initially seemed to coincide with the beginning of the
critical period, about 21 days after birth. As this is con-
siderably later than eye opening (around P7), it was
originally supposed that visual experience, in the form
of visually evoked patterns of action potentials, drove
ocular dominance column segregation
2224
. However,
early work in macaque monkeys strongly indicated that
thalamocortical afferents begin to segregate into stripes
before birth
29
, and are arranged into functional columns
by birth
30
. More recent experiments have shown that,
anatomically, ocular dominance column segregation in
newborn monkeys is as precise as in adults
31
. To recon-
cile these findings with previous data implicating activity-
dependent competition in column formation, a further,
non-visually driven source of activity was suggested
to provide the signals for driving segregation in the
prenatal cortex.
In postnatal animals, local correlations in the firing of
retinal ganglion cells were found even in the dark
32
. This
finding was followed by the discovery that the prenatal
retina could generate patterned activity before the differ-
entiation of photoreceptors
33,34
. Multielectrode record-
ings and calcium-imaging studies revealed the presence
of retinal waves, which are spontaneously generated,
correlated patterns of activity that course across substan-
tial areas of the neonatal retina
3538
. Because these waves
are generated independently in each eye, they could, in
theory, provide the patterns of activity necessary to seg-
regate thalamic afferents in the cortex. Indeed, these
IPSILATERAL
On the same side of the body.
CONTRALATERAL
On the opposite side of the body.
ENUCLEATION
Removal of the eyeballs.
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cleates genuine ocular dominance columns? Although
they have the right size and shape, and seem to reflect
inputs from different LGN layers, early enucleation can
severely disrupt the organization of the LGN itself
4547
.
It is possible that the patchy connections observed after
enucleation represent segregation across a modality
other than ocular dominance. The atrophy of the LGN
that is induced by binocular enucleation might also
result in a nonspecific clustering of LGN afferents.
Although intriguing, the results of these experiments
alone provide only indirect insights into the forces
guiding column formation.
Activity-based geniculocortical segregation
Despite the proposed central role for correlated neu-
ronal activity in driving the segregation of overlapping
thalamic afferents in the primary visual cortex, remark-
ably little evidence directly supports this idea. Several
experiments indicate that activity is necessary to main-
tain the segregated state, but few reveal how that state
was achieved in the first place.
the LGN of enucleated animals. However, to induce col-
umn formation, the patterns of activity in enucleated
animals should carry correlational information that is
sufficiently similar to that in normal animals. Moreover,
that information must exist even when the LGN itself
has not yet segregated into eye-specific layers.
Recordings from the LGN of young ferrets (at P25,
after columns have already formed) indicate that enu-
cleation alters the correlational structure of sponta-
neous activity
42
. After this manipulation, activity in
the two LGN layers is much more highly correlated,
leading to degradation (but not elimination) of layer-
specific correlational cues. However, similar record-
ings have not been obtained at the appropriate ages
(that is, before P16), so the patterns of spontaneous
activity in these very young animals are unknown.
The LGNcortical loop remaining after enucleation
could generate sufficient correlational information to
drive column formation.
There are other important caveats in interpreting
these findings. Are the columns that are present in enu-
Box 1 | Activity-dependent segregation of retinal axons
Current evidence for activity-based competition as a generative mechanism for ocular dominance columns relies largely on analogies with pattern
formation in other parts of the central nervous system, rather than direct tests in the developing visual cortex. Compelling evidence for activity-based
competition in the formation of segregated patterns came from work on dually innervated optic tecta in goldfish and frogs. In a normal frog, retinal
ganglion cells from each eye project to the contralateral tectum. When a third eye primordium is implanted in tadpoles, axons of retinal ganglion cells
from the ectopic eye innervate an optic tectum that also receives a normal complement of innervation from its usual source. Activity-dependent
competition between the two sets of retinal afferents results in segregated, eye-specific stripes with a striking visual similarity to ocular dominance
columns
85
(see figure; autoradiographs reproduced with permission from REF. 86 1981 Massachusetts Institute of Technology).
In goldfish, regenerating axons from the two eyes, forced to grow into the same tectum, also form clear stripes
87
. Blocking retinal activity with
tetrodotoxin (TTX) prevents stripes from forming and can desegregate existing stripes
51
. Significantly, blocking the NMDA(N-methyl-D-aspartate)
glutamate receptor, which is required in mammals for the induction of long-term potentiation in the hippocampus, also induces desegregation or blocks
segregation
88,89
. This points to an appealing model in which topographic cues intrinsic to retinal axons and the tectum guide axons from the two eyes to
similar tectal locations, where activity-based competition sorts the two populations on the basis of correlated activity
90
. The formation of stripes
represents a compromise between chemoaffinity cues guiding axons to the same locale, attractive interactions between axons with similar activity
patterns (from the same eye), and repulsive interactions between axons with dissimilar activity patterns (from the other eye). In dually innervated tecta,
it is extremely unlikely that an intrinsic stripe-like molecular cue in the tectum presages the segregation of stripes.
A strong case has also been made for a role of
correlated activity in the specification of eye-specific
layers in the cat and ferret lateral geniculate nucleus
(LGN; see REF. 91 for a recent review). Early in
development, axons from the two eyes form simple,
sparsely branched structures that form sparse synapses
throughout the undifferentiated LGN. Later, the short,
spine-like branches that synapse in the inappropriate
layer disappear, and there is a rapid and pronounced
proliferation of branches and synapses in the
appropriate eye-specific layer, leading to the formation
of segregated layers
45
. This depends on retinal activity:
blockade by either TTX or agents that block retinal
waves
39,49
prevents axons from developing their layer-
specific arborizations.
A compelling body of anatomical, electrophysiological
and pharmacological experiments substantiates all of
these findings. However, they are metaphors for ocular
dominance column formation, rather than direct tests of
the process. It will be important in future experiments to
apply some of these paradigms directly to the emergence
of ocular dominance columns, now that we have a better
idea of when the columns emerge during development.
Optic
tectum
Transplanted eye
Normal eye
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R E V I E WS
However, recent work points to a different inter-
pretation. Using improved transneuronal autoradio-
graphic techniques, together with optical imaging
of intrinsic signals, it is now clear that, in the cat,
geniculocortical afferents are already segregated by P14
(REFS 43,48; FIG. 2c,d). Taking these newer findings into
account, it is evident that Stryker and Harris
4
began
their activity blockade when LGN afferents were
already well segregated. So, rather than preventing
segregation of afferents, activity blockade probably
desegregated ocular dominance columns that were
already present. This could be a consequence of sprout-
ing or non-selective growth of axons induced by TTX
blockade, which has been observed in this system and
others
4952
. This interpretation is consistent with a
recent demonstration that neural activity is required to
maintain segregated, eye-specific axonal termination
patterns in the retinogeniculate projection. Blocking
retinal ganglion cell activity in ferrets after eye-specific
segregation has occurred results in desegregation, with
axons from both eyes mingled together in the same
region of the LGN
53
.
Although the results of Stryker and Harris
4
cannot
directly support the contention that activity is required
for the formation of ocular dominance columns, the
data do highlight the importance of ongoing activity for
normal development. Other manipulations of activity
(for example, STROBE REARING, DARK REARING, blocking corti-
cal NMDA (N-methyl-D-aspartate) receptors, or inacti-
vating the cortex through GABA (-aminobutyric acid)
receptor agonists) have been carried out during the crit-
ical period (see REF. 54 for a recent review). Therefore,
any effects on ocular dominance column segregation as
a consequence of these manipulations occur against a
background of pre-existing columns.
Critical period and thalamocortical segregation
In cats, ocular dominance column segregation is evi-
dent at P14, about a week before the onset of the critical
period. Transneuronal tracing revealed no evidence of
segregation a week earlier (P7)
48
. However, as discussed
above, transneuronal autoradiography is limited in its
ability to detect segregation in very young animals. If it
reveals segregated columns, they are certainly present, but
failure to detect columns does not necessarily confirm
their absence.
This is evident when the state of thalamocortical
axon segregation is determined by direct injections of
anterograde tracers into the developing LGN. Two
recent studies using transneuronal transport concluded
that segregation begins at P37 in the ferret
55,56
. This cor-
responds to the onset of the critical period, which is
around P35 (REF. 57). By contrast, direct injections of the
ferret thalamus showed that columns were clearly segre-
gated by P16, almost 3 weeks earlier
58
(FIG. 2b and FIG. 4).
This is roughly equivalent to an embryonic cat 5 days
before birth. Recent multielectrode recordings have
shown that correlated spontaneous activity in ferret
cortex at P22 is organized into periodic patterns that
might reflect the presence of these early columns
59
. As
the visual systems of cats and ferrets develop with
The landmark experiments of Stryker and Harris
4
were designed to test directly whether activity (either
spontaneous or evoked by sensory experience) is
required to drive segregation of overlapping afferents in
the developing cat visual cortex. They used repeated
binocular injections of TETRODOTOXIN (TTX) to block all
forms of retinal activity from P14 (before segregated
columns are visible by transneuronal transport) until
P45, when ocular dominance columns are clearly evi-
dent in normal animals. In the TTX-treated animals,
there was no evidence of segregated columns at P45.
Instead, the label in layer 4 was continuous, similar to
the pattern in P14 animals
23
. The obvious conclusion,
consistent with all of the information available at the
time, was that blocking retinal activity prevented the
normal activity-driven competition that should have
resulted in segregation by P45.
TETRODOTOXIN
A neurotoxin derived from the
Fugu, or puffer fish, which
specifically and reversibly blocks
voltage-gated sodium channels.
STROBE REARING
An experimental rearing
condition in which the only light
to which an animal is exposed is
stroboscopic (flashing). This
provides correlated stimulation
of the two eyes.
DARK REARING
An experimental condition in
which an animal is reared in
total darkness so that only
endogenous activity is present in
the developing visual system.
1 mm
Dorsal
Ventral
Posterior Anterior
P
1 8
Contra
(A)
C
On Off On Off
C Ipsi
(A1)
Control Cut i Cut i + c
F
i
r
i
n
g

r
a
t
e

(
H
z
)
100
80
85
0
60
40
20
0
Figure 3 | Contralateral bias of spontaneous activity in ferret LGN. Chronic multielectrode
array recordings show the normal pattern of bursting activity in the lateral geniculate nucleus
(LGN) of a postnatal day 27 (P27) ferret, and the greater influence of the contralateral eyes
afferents. Left: sagittal view of a ferret LGN illustrates the method used to record multiple units in
the awake ferret LGN. An array of eight electrodes spans the main eye-specific layers of the LGN.
Contra, contralateral; Ipsi, ipsilateral; P, perigeniculate. Right: the activity recorded at each
electrode is represented by one of the eight columns of pixels in each sweep; bright points
correspond to high levels of activity. A comparison of control activity and the activity pattern in the
LGN after the ipsilateral optic nerve was cut (cut i ) reveals little difference, whereas subsequently
cutting the contralateral optic nerve (cut i + c) markedly increased the correlations across eye-
specific layers. Reproduced with permission from REF. 42 1999 American Association for the
Advancement of Science.
NATURE REVIEWS | NEUROSCI ENCE VOLUME 3 | JANUARY 2002 | 39
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Overlap and segregation of thalamic afferents
Regardless of when columns form, it is important to
determine how they form. In the classical view, the
anatomical basis for the homogeneous labelling patterns
observed after transneuronal transport was overlap-
ping terminal fields of axons representing the two
eyes
2224,29,62
. In this model, well-developed but exuber-
ant arborizations of thalamocortical axons were pruned
to eliminate branches (and synapses) located in the
wrong column. An alternative view
6365
is that axons are
initially simple, and that a selective outgrowth of axon
terminals in appropriate columns, together with elimi-
nation of a small number of aberrant processes, pro-
duces mature circuits. Recent evidence supports the
latter formulation: axons initially grow to their correct
locations and generate increasingly dense arborizations,
with little evidence of overlap between adjacent
columns
58
. Early emerging columns seem to be no less
segregated initially than later, implying that once they
are established, little further refinement occurs (BOX 2).
Without evidence from real-time imaging or finer-
scale labelling, it is possible that there is ongoing elimi-
nation of errant branches or collaterals. The ideal
experiment for addressing this issue would be to visual-
ize individual thalamocortical axons in vivo, and to
determine their relationship with the emerging colum-
nar architecture (perhaps as assessed by optical imag-
ing). This is difficult for two reasons: first, it is difficult
to label individual axons, and second, it requires an
independent method to visualize the overall structure
of the nascent column. There have been heroic attempts
to relate the morphology of individual axons to the
emergence of columns
50
, but in the light of recent find-
ings on the timing of column formation, it seems that
these studies were done after the columns had formed.
Although these earlier studies attempted to find evi-
dence for segregation at the level of individual arboriza-
tions, the predominant change between P19 and P39 in
the cat is that arborizations become more elaborate.
There are indications that arborizations change the lat-
eral extent of their innervation: axons might initially
provide input to two same-eye columns, and subse-
quently reduce this to a single column. Rearrangements
that were observed might also reflect normal variation
in arborizations, and perhaps non-homogeneous
elaboration within individual columns.
Further evidence that initially supported the view
that overlapping thalamocortical axons gradually segre-
gate into discrete domains was provided by the presence
of a greater-than-expected number of binocularly acti-
vated neurons in the cortex. This was consistent with the
anatomical observations that inputs from the two eyes
were overlapping in layer 4. However, both older record-
ings and more recent work have shown that the initial
state of the cortex is, if anything, highly monocular.
Most neurons in the cat visual cortex after eye opening
are driven monocularly, rather than binocularly
66
.
Moreover, in kittens, the cortical responses before P21
are strongly dominated by the contralateral eye. Binocular
responses develop considerably later, long after ocular
dominance columns have formed
43
.
almost identical time courses
57
, this strongly indicates
that in cats, columns are present by birth, about 3 weeks
before the onset of the critical period.
In monkeys, the separability of the critical period
and thalamocortical axon segregation is perhaps even
more clear-cut. As discussed above, adult-like ocular
dominance segregation occurs before birth in the
macaque monkey
2931
, yet critical period plasticity is,
by definition, a postnatal event. It is unclear whether
activity-dependent remodelling of the macaque
geniculocortical projection could occur before birth.
However, some reports have indicated a change in V1
physiological responses and gene expression associ-
ated with the initial exposure of the visual system to
light after dark rearing
60,61
. This indicates that opening
the door to critical period plasticity might require
genuine visual stimulation, rather than spontaneous
activity alone.
Regardless of the mechanism(s) driving their initial
formation, ocular dominance columns clearly develop
considerably earlier than was believed when the
hypothesis of segregation on the basis of activity-based
competition was first formulated. As a consequence, no
pharmacological manipulations of activity have been
carried out sufficiently early to test whether activity is
required for column establishment. To test the role of
activity in column establishment, experiments would
have to begin no later than P10 in the ferret, or embry-
onic day 52 in the cat. Although monocular enucleation
shortly after column formation in the ferret does not
induce changes in the pattern of segregated input
44,58
,
this approach alone does not directly test whether pat-
terned activity is involved. However, these results do
indicate that a gross imbalance in retinal input is not, at
these early stages, translated into morphological
changes as it would be during the subsequent critical
period. It remains an open question whether more sub-
tle manipulations (such as silencing, rather than
removing an eye) can cause shifts in the patterns of
these early columns.
10
Ocular dominance
Postnatal day
LGN axons
Arrive, synapse
in layer 4
LGN injection
OD patches
MD critical period
Cortex visually responsive
Eye opening
Transneuronal OD patches
20 30 40 50 60
Figure 4 | Timeline of ferret ocular dominance column development. The emergence of
ocular dominance (OD) columns as revealed by direct lateral geniculate nucleus (LGN) injections
precedes the critical period for monocular deprivation (MD), the appearance of segregation by
transneuronal transport, the opening of the eyes and the onset of visual responses in the cortex.
The appearance of segregated columns occurs while LGN axons are arriving and forming
synapses in layer 4 of the primary visual cortex. The sequence of events in the developing cat
cortex is the same. The equivalent ages for the cat can be roughly determined by subtracting 21
days from the ferret (for example, postnatal day 21 (P21) in ferret is approximately P0 in cat; P0 is
equivalent to cat embryonic day 44). Modified with permission from REF. 58 2000 American
Association for the Advancement of Science.
40 | JANUARY 2002 | VOLUME 3 www.nature.com/reviews/neuro
R E V I E WS
mechanisms. But if the mechanisms are the same, they
must operate in substantially different cellular environ-
ments. For example, optical imaging experiments have
indicated that the response to monocular deprivation
during the critical period occurs first in the upper layers
of the cortex (layer 2/3), and is then imposed, through
intrinsic circuits, on the organization of geniculate axons
in layer 4 (REF. 68). Columns in ferrets emerge by P16,
before most upper layer neurons have migrated into
position or extended axons. So, an intrinsic circuit impli-
cated in critical period plasticity is simply absent when
columns first form.
In the ferret, the mechanism(s) that initially form
columns must be present by P16. Between E27 and P10,
LGN axons are in the cortical subplate, but have not yet
invaded layer 4 (REFS 69,70). Retinal waves are present
throughout this time
71
, and correlation-based informa-
tion could reach developing axons in the subplate.
Geniculate axons form synapses in the subplate well over
a week before they reach layer 4. Through interactions
with the postsynaptic neurons in the subplate, these
axons could acquire information about their respective
eyes of origin. In this model, specific ingrowth into layer
4 might reflect the outcome of competitive events that
take place earlier in the subplate. Ablation of the sub-
plate prevents the formation of ocular dominance
columns
72,73
, although these experiments do not explic-
itly address the relative roles of activity-dependent
or -independent cues that might be present on subplate
neurons. The presence of columnar, patterned, sponta-
neous activity in the cortex at early ages could also indi-
cate a role for local cortical circuits in the development
of columns
59
. It is not yet clear whether these patterns of
activity are involved in constructing columns or reflect
the presence of already segregated afferents.
Even after axons reach the cortex, it is not yet possi-
ble to determine how the early columns form, or how
precise (adult-like) they are. Axons are detectable as
early as P10 in layer 4, but they are so sparse that it is
unclear whether they are organized into columns
58
.
During the days after their initial ingrowth into layer 4,
competition between axons might be required to
establish appropriate territories.
The rapid, early and specific emergence of columns,
and their resistance to activity imbalances or retinal
removal, indicate that molecular cues could also guide
the initial formation of columns
44,58,74
. In the decades
after the original descriptions of ocular dominance col-
umn development, knowledge of the molecular cues
responsible for axon guidance and map formation has
exploded, providing a rich palette of plausible molecular
mechanisms that could generate the relatively simple
striped patterns of ocular dominance columns. In con-
sidering whether molecular cues might be involved, it is
important to recognize that the distinction between left
and right eye could be irrelevant. In each LGN, the eye-
specific layers receive retinal input from the nasal retina
on the contralateral side of the brain, and the temporal
retina from the ipsilateral side. The distinction between
nasal and temporal retina might be a critical feature of
column development, as ocular dominance columns can
Taken together, a picture emerges in which columns
form rapidly, well before the critical period and with lim-
ited production of exuberant projections. Furthermore,
during this initial stage of formation, ocular dominance
columns do not seem to respond to changes in activity as
predicted by simple Hebbian rules. These findings re-
inforce the idea that the critical period has both an onset
and a termination
57,67
, and that it occurs against the
background of an already differentiated system of
columns. So, activity during the critical period does not
instruct the formation of columns from a blank slate.
Rather, abnormal activity can compromise the normal
pattern. In the absence of experimental manipulations,
the main role of visual experience during the critical
period might be to reinforce and augment an already
appropriately situated set of basic connections, rather
than to instruct their de novo formation.
What guides the establishment of columns?
The observations that column establishment and the
critical period are separable developmental events do not
necessarily imply that these phenomena rely on different
BARREL
A cylindrical column of neurons
found in the rodent neocortex.
Each barrel receives sensory
input from a single whisker
follicle, and the topographical
organization of the barrels
corresponds precisely to the
arrangement of whisker follicles
on the face.
Box 2 | Activity-dependent segregation in other sensory systems
The idea that thalamocortical connections are initially highly precise, rather than
initially crude and only gradually refined, is supported by the analysis of development
in other sensory systems, most notably the representations of whiskers in the
somatosensory barrel cortex and the glomeruli of the olfactory bulb. In both cases, the
initial projections laid down during the establishment phase are remarkably precise.
Although some controversy remains, considerable evidence indicates that the initial
patterning in these segregated systems does not depend on correlated activity patterns,
whereas maintenance of the segregated state requires activity.
In the barrel cortex, ingrowing axons form precise termination patterns in layer 4
(REFS 9294; but see REF. 95). These patterns undergo little subsequent refinement, although
activity blockade can reduce their subsequent specificity, and, as in the visual cortex during
the critical period, reduces their ability to undergo rearrangement
96
. Cortical activity
blockade
97,98
does not prevent BARREL formation. Even if NMDA (N-methyl-D-aspartate)
receptors are disrupted in postsynaptic cortical neurons, thalamocortical axons segregate
into clusters, although the formation of the cellular aggregates that are characteristic of
barrels is disrupted
99
.
Perhaps the most rigorous tests of the role of activity in generating modular
organization have been accomplished in the mouse olfactory bulb. Axons of olfactory
sensory neurons bearing the same odorant receptor, which are widely distributed in the
olfactory epithelium, converge onto a few distinct glomeruli in the olfactory bulb
100102
.
This is a remarkable feat of axon sorting, given that there are about 1,000 different
receptors and a correspondingly large number of distinct axon populations. At first
glance, this would seem to be an ideal case in which correlation-based sorting could be
involved in segregating axons into discrete glomeruli, as all the axons bearing the same
receptor would presumably show highly correlated activity. However, several elegant
genetic manipulations have conclusively shown that neither spontaneous nor odorant-
evoked activity is required for the initial specification of glomeruli. Disruption of the
peripheral transduction apparatus
103,104
silences the sensory neurons, but glomeruli
form normally. Even elimination of postsynaptic neurons fails to disrupt glomerular
specificity
105
. Although activity is not required to form the map, there is considerable
evidence that its maintenance requires activity
103,106
, and that, as for ocular dominance
columns, competitive interactions can occur after map formation
107
.
The mechanisms underlying the development of visual cortical columns, barrels in
somatosensory cortex, and glomeruli in the olfactory bulb, share the same overall
features: precise, rapid establishment of initial connections that is relatively immune to
manipulations of activity, and a subsequent period of plasticity to manipulations of
activity or the sensory periphery.
NATURE REVIEWS | NEUROSCI ENCE VOLUME 3 | JANUARY 2002 | 41
R E V I E WS
powerful tools for molecular analysis transgenic and
knockout animals and commercially available gene chips
cannot be used to directly approach this issue.
The mechanisms underlying ocular dominance col-
umn segregation cannot be uncovered solely by the
standard experimental approaches of blocking neu-
ronal action potentials or postsynaptic receptors. Such
manipulations cannot distinguish between instructive
roles of activity (such as that envisioned by Hebbian
models) and permissive roles (for example, neurons
might need to be electrically active to differentiate nor-
mally). A more appropriate test for the role of activity is
to artificially change the pattern of activity while leav-
ing the relative levels unchanged. These are extraordi-
narily difficult experiments to carry out, particularly in
very young animals. However, in the case of orientation
tuning in the visual cortex, such experiments show that
the development of overall structure and pattern in ori-
entation maps is unchanged by alterations in the corre-
lational structure of retinal input, although changes are
evident in detailed receptive field properties
84
.
To unravel how, or whether, activity cues and molec-
ular patterning information interact to drive column
formation will require a leap of faith that such pattern-
ing information actually exists. If it does, then a number
of approaches that have successfully identified axon
guidance and topographic cues should yield some hints
as to their identity. Some 40 years after Hubel and Wiesel
suggested innate mechanisms for the development of
cortical functional architecture, an intriguing system of
specification remains to be fully elucidated.
be viewed as the cortical representation of this peripheral
distinction. The distinction between nasal and temporal
retina is specified early in development, and retinal axons
reaching the chiasm can choose to project either ipsilat-
erally or contralaterally, on the basis of molecular cues on
their growth cones and at the chiasm
75
. This information
can be retained at the level of the LGN (see REFS 7678). In
achiasmatic sheepdogs, for example, the normally
crossed nasal axons innervate the appropriate layers in
the LGN on the same side of the brain, indicating an
affinity between nasal and temporal axons and their
respective LGN layers
79
.
However, as there has previously been little motivation
to search for molecular correlates of ocular dominance
column formation, any hypothesis at this point is simply
speculation. Many of the molecules implicated in attrac-
tive and repulsive axon guidance are found in the cortex
at appropriate ages, but there is no evidence that any of
them are involved in column formation. Members of the
ephrin family of RECEPTOR TYROSINE KINASES are widely dis-
tributed in the prenatal monkey visual cortex
80
, but they
do not form any obvious stripe-like patterns (although
obvious patterns are not an absolute requisite for the
potential involvement of a molecule). There are interest-
ing reports of patchy distributions of various neurotrans-
mitter system components early in cortical develop-
ment
81,82
, but no evidence to directly implicate any system
in column formation. The most tractable mammalian
system for studying molecular or genetic cues the
mouse shows critical period plasticity
83
, but lacks seg-
regated ocular dominance columns. So, some of the most
RECEPTOR TYROSINE KINASES
A family of membrane
receptors, the intracellular
domains of which catalyse the
phosphorylation, by ATP, of
specific tyrosine residues on
their target proteins.
1. Cowan, W. M. in International Review of Physiology,
Neurophysiology III (ed. Porter, R.) 149191 (Univ. Park
Press, Baltimore, 1978).
2. Katz, L. C. & Shatz, C. J. Synaptic activity and the construction
of cortical circuits. Science 274, 11331138 (1996).
3. Swindale, N. V. The development of topography in the visual
cortex a review of models. Netw. Comput. Neural Syst. 7,
161247 (1996).
4. Stryker, M. P. & Harris, W. A. Binocular impulse blockade
prevents the formation of ocular dominance columns in cat
visual cortex. J. Neurosci. 6, 21172133 (1986).
The first (and only) experiments to directly test the
role of activity in the initial formation of ocular
dominance columns.
5. Erwin, E. & Miller, K. D. Correlation-based development of
ocularly matched orientation and ocular dominance maps:
determination of required input activities. J. Neurosci. 18,
98709895 (1998).
6. Sur, M. & Leamey, C. A. Development and plasticity of
cortical areas and networks. Nature Rev. Neurosci. 2,
251262 (2001).
7. Weliky, M. Correlated neuronal activity and visual cortical
development. Neuron 27, 427430 (2000).
8. Miller, K. D. in Self-Organizing Brain: from Growth Cones to
Functional Networks (eds Vanpelt, J. et al.) 303318
(Elsevier Science, Amsterdam, The Netherlands, 1994).
9. Miller, K. D., Keller, J. B. & Stryker, M. P. Ocular dominance
column development: analysis and simulation. Science 245,
605615 (1989).
10. Constantine-Paton, M., Cline, H. T. & Debski, E. Patterned
activity, synaptic convergence, and the NMDA receptor in
developing visual pathways. Annu. Rev. Neurosci. 13,
129154 (1990).
11. Wong, R. O. The role of spatio-temporal firing patterns in
neuronal development of sensory systems. Curr. Opin.
Neurobiol. 3, 595601 (1993).
12. Wiesel, T. N. & Hubel, D. H. Single cell responses in striate
cortex of kittens deprived of vision in one eye.
J. Neurophysiol. 26, 10031017 (1963).
13. Wiesel, T. N. & Hubel, D. H. Comparison of the effects of
unilateral and bilateral eye closure on cortical unit responses
in kittens. J. Neurophysiol. 28, 10291040 (1965).
14. Hubel, D. H. & Wiesel, T. N. The period of susceptibility to
the physiological effects of unilateral eye closure in kittens.
J. Physiol. (Lond.) 206, 419436 (1970).
15. Hubel, D. H. & Wiesel, T. N. Receptive fields, binocular
interaction and functional architecture in the cats visual
cortex. J. Physiol. (Lond.) 160, 106154 (1962).
16. Hubel, D. H. & Wiesel, T. N. Receptive fields of cells in striate
cortex of very young, visually inexperienced kittens.
J. Neurophysiol. 26, 9941002 (1963).
In this classic paper, Hubel and Wiesel describe the
initial state of columnar systems in the immature
striate cortex, and conclude that functional
architecture is innate.
17. Wiesel, T. N. & Hubel, D. H. Ordered arrangement of
orientation columns in monkeys lacking visual experience.
J. Comp. Neurol. 158, 307318 (1974).
18. Wiesel, T. N. & Hubel, D. H. Extent of recovery from the
effects of visual deprivation in kittens. J. Neurophysiol. 28,
10601072 (1965).
19. Wiesel, T. N., Hubel, D. H. & Lam, D. M. K. Autoradiographic
demonstration of ocular-dominance columns in the monkey
striate cortex by means of transneuronal transport. Brain
Res. 79, 273279 (1974).
20. LeVay, S., Hubel, D. H. & Wiesel, T. N. The pattern of ocular
dominance columns in macaque visual cortex revealed by a
reduced silver stain. J. Comp. Neurol. 159, 559576 (1975).
21. Hubel, D. H. & Wiesel, T. N. Ferrier lecture. Functional
architecture of the macaque monkey visual cortex. Proc. R.
Soc. Lond. B 198, 159 (1977).
22. LeVay, S., Wiesel, T. N. & Hubel, D. The development of
ocular dominance columns in normal and visually deprived
monkeys. J. Comp. Neurol. 191, 151 (1980).
23. LeVay, S., Stryker, M. P. & Shatz, C. J. Ocular dominance
columns and their development in layer IV of the cats visual
cortex: a quantitative study. J. Comp. Neurol. 179, 223244
(1978).
A seminal paper that provided the first ever view of
the pattern of developing ocular dominance columns,
and provided the experimental underpinning of most
subsequent theories of column formation.
24. Hubel, D. H., Wiesel, T. N. & LeVay, S. Plasticity of ocular
dominance columns in monkey striate cortex. Phil. Trans. R.
Soc. Lond. B 278, 377409 (1977).
25. Wiesel, T. N. & Hubel, D. H. Single cell responses in striate
cortex of kittens deprived of vision in one eye.
J. Neurophysiol. 26, 10031017 (1963).
26. Von der Malsberg, C. & Willshaw, D. J. A mechanism for
producing continuous neural mappings: ocularity
dominance stripes and ordered retino-tectal projections.
Exp. Brain Res. (Suppl. 1), 463469 (1976).
27. Swindale, N. V. A model for the formation of ocular dominance
stripes. Proc. R. Soc. Lond. B 208, 243264 (1980).
28. Jones, D. G., Van Sluyters, R. C. & Murphy, K. M.
A computational model for the overall pattern of ocular
dominance. J. Neurosci. 11, 37943808 (1991).
29. Rakic, P. Prenatal genesis of connections subserving ocular
dominance in the rhesus monkey. Nature 261, 467471
(1976).
30. Des Rosiers, M. H. et al. Functional plasticity in the immature
striate cortex of the monkey shown by the
[
14
C]deoxyglucose method. Science 200, 447449 (1978).
Using improved autoradiographic techniques, this
paper conclusively showed that ocular dominance
columns can emerge fully without visual experience.
31. Horton, J. C. & Hocking, D. R. An adult-like pattern of ocular
dominance columns in striate cortex of newborn monkeys
prior to visual experience. J. Neurosci. 16, 17911807 (1996).
32. Mastronarde, D. N. Correlated firing of cat retinal ganglion
cells. I. Spontaneously active inputs to X- and Y-cells.
J. Neurophysiol. 49, 303324 (1983).
33. Maffei, L. & Galli-Resta, L. Correlation in the discharges of
neighboring rat retinal ganglion cells during prenatal life.
Proc. Natl Acad. Sci. USA 87, 28612864 (1990).
34. Galli, L. & Maffei, L. Spontaneous impulse activity of rat retinal
ganglion cells in prenatal life. Science 242, 9091 (1988).
35. Meister, M., Wong, R. O., Baylor, D. A. & Shatz, C. J.
Synchronous bursts of action potentials in ganglion cells of
the developing mammalian retina. Science 252, 939943
(1991).
Using a technically advanced microelectrode array,
this paper revealed that spontaneous action potentials
in the previsual retina are organized into wave-like
patterns. These patterns could provide cues for
competitive interactions in the thalamus and cortex.
42 | JANUARY 2002 | VOLUME 3 www.nature.com/reviews/neuro
R E V I E WS
36. Wong, R. O., Meister, M. & Shatz, C. J. Transient period of
correlated bursting activity during development of the
mammalian retina. Neuron 11, 923938 (1993).
37. Wong, R. O. L., Chernjavsky, A., Smith, S. J. & Shatz, C. J.
Early functional neural networks in the developing retina.
Nature 374, 716718 (1995).
38. Wong, R. O. L. & Oakley, D. M. Changing patterns of
spontaneous bursting activity of on and off retinal ganglion
cells during development. Neuron 16, 10871095 (1996).
39. Penn, A. A., Riquelme, P. A., Feller, M. B. & Shatz, C. J.
Competition in retinogeniculate patterning driven by
spontaneous activity. Science 279, 21082112 (1998).
Blocking retinal waves (see reference 35) in one retina
leads to laminar rearrangements in the LGN that are
reminiscent of the effects of activity imbalances in
ocular dominance column formation.
40. Mooney, R., Penn, A. A., Gallego, R. & Shatz, C. J. Thalamic
relay of spontaneous retinal activity prior to vision. Neuron
17, 863874 (1996).
41. Mooney, R., Madison, D. V. & Shatz, C. J. Enhancement of
transmission at the developing retinogeniculate synapse.
Neuron 10, 815825 (1993).
42. Weliky, M. & Katz, L. C. Correlational structure of
spontaneous neuronal activity in the developing lateral
geniculate nucleus in vivo. Science 285, 599604 (1999).
Recordings from multielectrode arrays in the LGN of
awake ferrets revealed patterns of activity that were
better correlated within than between eyes, consistent
with the predictions of retinal recordings (see reference
35). However, significant differences were noted in the
strength of ipsilateral and contralateral retinal inputs.
43. Crair, M. C., Gillespie, D. C. & Stryker, M. P. The role of visual
experience in the development of columns in cat visual
cortex. Science 279, 566570 (1998).
Using optical and single-unit recording techniques,
the authors show that neurons in the developing
cortex are initially activated almost exclusively by the
contralateral eye, with ipsilateral eye responses
developing much later and only with visual experience.
They conclude that the intercalation of ipsilateral
responses is unlikely to reflect Hebbian competition.
44. Crowley, J. C. & Katz, L. C. Development of ocular
dominance columns in the absence of retinal input.
Nature Neurosci. 2, 11251130 (1999).
Early eye removal does not seem to prevent the
formation of segregated patterns of columns in the
cortex. The authors argue that retinal activity might
not be necessary for segregation, and propose that
activity-independent cues might be involved.
45. Sretavan, D. W. & Shatz, C. J. Prenatal development of
retinal ganglion cell axons: segregation into eye-specific
layers within the cats lateral geniculate nucleus. J. Neurosci.
6, 234251 (1986).
46. Garraghty, P. E., Shatz, C. J., Sretavan, D. W. & Sur, M.
Axon arbors of X and Y retinal ganglion cells are differentially
affected by prenatal disruption of binocular inputs. Proc. Natl
Acad. Sci. USA 85, 73617365 (1988).
47. Garraghty, P. E., Shatz, C. J. & Sur, M. Prenatal disruption of
binocular interactions creates novel lamination in the cats
lateral geniculate nucleus. Vis. Neurosci. 1, 93102 (1988).
48. Crair, M. C., Horton, J. C., Antonini, A. & Stryker, M. P.
Emergence of ocular dominance columns in cat visual cortex
by 2 weeks of age. J. Comp. Neurol. 430, 235249 (2001).
Revising earlier work (for example, see reference 23),
this paper shows that ocular dominance columns in
cats emerge before the critical period, consistent with
results in primates and ferrets.
49. Sretavan, D. W., Shatz, C. J. & Stryker, M. P. Modification of
retinal ganglion cell axon morphology by prenatal infusion of
tetrodotoxin. Nature 336, 468471 (1988).
50. Antonini, A. & Stryker, M. P. Development of individual
geniculocortical arbors in cat striate cortex and effects of
binocular impulse blockade. J. Neurosci. 13, 35493573
(1993).
51. Reh, T. A. & Constantine-Paton, M. Eye-specific segregation
requires neural activity in three-eyed Rana pipiens.
J. Neurosci. 5, 11321143 (1985).
The striking pattern of ocular dominance stripes in
frog optic tectum, induced by transplanting a third
eye, has served as a model for column development
in the cortex. This paper shows that retinal activity is
the crucial feature for inducing the segregation of
eye-specific stripes.
52. Frank, E. The influence of neuronal activity on patterns of
synaptic connections. Trends Neurosci. 10, 188190 (1989).
53. Chapman, B. Necessity for afferent activity to maintain eye-
specific segregation in ferret lateral geniculate nucleus.
Science 287, 24792482 (2000).
54. Berardi, N., Pizzorusso, T. & Maffei, L. Critical periods during
sensory development. Curr. Opin. Neurobiol. 10, 138145
(2000).
55. Finney, E. M. & Shatz, C. J. Establishment of patterned
thalamocortical connections does not require nitric oxide
synthase. J. Neurosci. 18, 88268838 (1998).
56. Ruthazer, E. S., Baker, G. E. & Stryker, M. P. Development
and organization of ocular dominance bands in primary
visual cortex of the sable ferret. J. Comp. Neurol. 407,
151165 (1999).
57. Issa, N. P., Trachtenberg, J. T., Chapman, B., Zahs, K. R. &
Stryker, M. P. The critical period for ocular dominance
plasticity in ferret visual cortex. J. Neurosci. 19, 69656978
(1999).
58. Crowley, J. C. & Katz, L. C. Early development of ocular
dominance columns. Science 290, 13211324 (2000).
By using direct injections of tracers into the
developing LGN, the authors show that ocular
dominance columns develop much earlier and much
more rapidly than was previously believed, and with a
surprising degree of specificity.
59. Chiu, C. & Weliky, M. Spontaneous activity in developing
ferret visual cortex in vivo. J. Neurosci. 21, 89068914 (2001).
60. Quinlan, E. M., Philpot, B. D., Huganir, R. L. & Bear, M. F.
Rapid, experience-dependent expression of synaptic NMDA
receptors in visual cortex in vivo. Nature Neurosci. 2,
352357 (1999).
61. Bear, M. F. & Rittenhouse, C. D. Molecular basis for induction
of ocular dominance plasticity. J. Neurobiol. 41, 8391 (1999).
62. Wiesel, T. N. Postnatal development of the visual cortex and
the influence of environment. Nature 299, 583591 (1982).
63. Purves, D. & LaMantia, A. S. Construction of modular
circuits in the mammalian brain. Cold Spring Harb. Symp.
Quant. Biol. 55, 445452 (1990).
64. Purves, D., Riddle, D. R. & LaMantia, A. S. Iterated patterns
of brain circuitry (or how the cortex gets its spots). Trends
Neurosci. 15, 362368 (1992).
65. Purves, D., White, L. E. & Riddle, D. R. Is neural development
Darwinian? Trends Neurosci. 19, 460464 (1996).
66. Fregnac, Y. & Imbert, M. Early development of visual cortical
cells in normal and dark-reared kittens: relationship between
orientation selectivity and ocular dominance. J. Physiol.
(Lond.) 278, 2744 (1978).
67. Fagiolini, M. & Hensch, T. K. Inhibitory threshold for critical-
period activation in primary visual cortex. Nature 404,
183186 (2000).
68. Trachtenberg, J. T., Trepel, C. & Stryker, M. P. Rapid
extragranular plasticity in the absence of thalamocortical
plasticity in the developing primary visual cortex. Science
287, 20292032 (2000).
69. Johnson, J. K. & Casagrande, V. A. Prenatal development of
axon outgrowth and connectivity in the ferret visual system.
Vis. Neurosci. 10, 117130 (1993).
70. Herrmann, K., Antonini, A. & Shatz, C. J. Ultrastructural
evidence for synaptic interactions between thalamocortical
axons and subplate neurons. Eur. J. Neurosci. 6,
17291742 (1994).
71. Wong, R. O. L. Retinal waves and visual system
development. Annu. Rev. Neurosci. 22, 2947 (1999).
72. Ghosh, A. Subplate neurons and the patterning of
thalamocortial connections. Ciba Found. Symp. 193,
150172; discussion 192199 (1995).
73. Ghosh, A. & Shatz, C. J. Involvement of subplate neurons in
the formation of ocular dominance columns. Science 255,
14411443 (1992).
74. Katz, L. C., Weliky, M. & Crowley, J. C. in The New Cognitive
Neurosciences (ed. Gazzaniga, M. S.) 199212 (MIT Press,
Cambridge, Massachusetts, 1999).
75. Mason, C. A. & Sretavan, D. W. Glia, neurons, and axon
pathfinding during optic chiasm development. Curr. Opin.
Neurobiol. 7, 647653 (1997).
76. Meissirel, C., Wikler, K. C., Chalupa, L. M. & Rakic, P. Early
divergence of magnocellular and parvocellular functional
subsystems in the embryonic primate visual system. Proc.
Natl Acad. Sci. USA 94, 59005905 (1997).
77. Chalupa, L. M., Meissirel, C. & Lia, B. Specificity of retinal
ganglion cell projections in the embryonic rhesus monkey.
Perspect. Dev. Neurobiol. 3, 223231 (1996).
78. Casagrande, V. A. & Condo, G. J. Is binocular competition
essential for layer formation in the lateral geniculate nucleus?
Brain Behav. Evol. 31, 198208 (1988).
79. Williams, R. W., Hogan, D. & Garraghty, P. E. Target
recognition and visual maps in the thalamus of achiasmatic
dogs. Nature 367, 637639 (1994).
80. Donoghue, M. J. & Rakic, P. Molecular gradients and
compartments in the embryonic primate cerebral cortex.
Cereb. Cortex 9, 586600 (1999).
81. Dyck, R. H. & Cynader, M. S. An interdigitated columnar
mosaic of cytochrome oxidase, zinc, and neurotransmitter-
related molecules in cat and monkey visual cortex. Proc.
Natl Acad. Sci. USA 90, 90669069 (1993).
82. Trepel, C., Duffy, K. R., Pegado, V. D. & Murphy, K. M.
Patchy distribution of NMDAR1 subunit immunoreactivity in
developing visual cortex. J. Neurosci. 18, 34043415 (1998).
83. Gordon, J. A. & Stryker, M. P. Experience-dependent
plasticity of binocular responses in the primary visual cortex
of the mouse. J. Neurosci. 16, 32743286 (1996).
84. Weliky, M. & Katz, L. C. Disruption of orientation tuning in
visual cortex by artificially correlated neuronal activity. Nature
386, 680685 (1997).
85. Constantine-Paton, M. & Law, M. I. Eye-specific termination
bands in tecta of three-eyed frogs. Science 202, 639641
(1978).
86. Constantine-Paton, M. in The Organization of the Cerebral
Cortex: Proceedings of a Neurosciences Research Program
Colloquium(eds Schmitt, F. O., Worden, F. G., Adelman, G.
& Dennis, S. G.) 4767 (MIT Press, Cambridge,
Massachusetts, 1981).
87. Boss, V. C. & Schmidt, J. T. Activity and the formation of
ocular dominance patches in dually innervated tectum of
goldfish. J. Neurosci. 4, 28912905 (1984).
88. Cline, H. T., Debski, E. A. & Constantine-Paton, M. N-methyl-
D-aspartate receptor antagonist desegregates eye-specific
stripes. Proc. Natl Acad. Sci. USA 84, 43424345 (1987).
89. Cline, H. T. & Constantine-Paton, M. NMDA receptor
antagonists disrupt the retinotectal topographic map.
Neuron 3, 413426 (1989).
90. Law, M. I. & Constantine-Paton, M. Anatomy and physiology
of experimentally produced striped tecta. J. Neurosci. 1,
741759 (1981).
91. Shatz, C. J. Emergence of order in visual system
development. Proc. Natl Acad. Sci. USA 93, 602608
(1996).
92. Catalano, S. M., Robertson, R. T. & Killackey, H. P. Rapid
alteration of thalamocortical axon morphology follows
peripheral damage in the neonatal rat. Proc. Natl Acad. Sci.
USA 92, 25492552 (1995).
93. Catalano, S. M., Robertson, R. T. & Killackey, H. P. Individual
axon morphology and thalamocortical topography in
developing rat somatosensory cortex. J. Comp. Neurol.
367, 3653 (1996).
94. Agmon, A., Yang, L. T., ODowd, D. K. & Jones, E. G.
Organized growth of thalamocortical axons from the deep
tier of terminations into layer IV of developing mouse barrel
cortex. J. Neurosci. 13, 53655382 (1993).
95. Senft, S. L. & Woolsey, T. A. Growth of thalamic afferents
into mouse barrel cortex. Cereb. Cortex 1, 308335 (1991).
96. OLeary, D. M., Borngasser, D. J., Fox, K. & Schlagger, B. L.
in Symposium on the Development of the Cerebral Cortex
No. 193 (eds Bock, G. R. & Cardew, G.) 214222
(John Wiley & Sons, Inc., New York, 1995).
97. Chiaia, N. L. et al. Postnatal blockade of cortical activity by
tetrodotoxin does not disrupt the formation of vibrissa-
related patterns in the rats somatosensory cortex. Brain
Res. Dev. Brain Res. 66, 244250 (1992).
98. Chiaia, N. L. et al. Effects of postnatal blockade of cortical
activity with tetrodotoxin upon the development and
plasticity of vibrissa-related patterns in the somatosensory
cortex of hamsters. Somatosens. Mot. Res. 11, 219228
(1994).
99. Iwasato, T. et al. Cortex-restricted disruption of NMDAR1
impairs neuronal patterns in the barrel cortex. Nature 406,
726731 (2000).
100. Vassar, R. et al. Topographic organization of sensory
projections to the olfactory bulb. Cell 79, 981991 (1994).
101. Mombaerts, P. et al. Visualizing an olfactory sensory map.
Cell 87, 675686 (1996).
102. Ressler, K. J., Sullivan, S. L. & Buck, L. B. Information
coding in the olfactory system: evidence for a stereotyped
and highly organized epitope map in the olfactory bulb.
Cell 79, 12451255 (1994).
103. Belluscio, L., Gold, G. H., Nemes, A. & Axel, R. Mice
deficient in G
olf
are anosmic. Neuron 20, 6981 (1998).
104. Lin, D. M. et al. Formation of precise connections in the
olfactory bulb occurs in the absence of odorant-evoked
neuronal activity. Neuron 26, 6980 (2000).
105. Bulfone, A. et al. An olfactory sensory map develops in the
absence of normal projection neurons or GABAergic
interneurons. Neuron 21, 12731282 (1998).
106. Zheng, C. et al. Peripheral olfactory projections are
differentially affected in mice deficient in a cyclic nucleotide-
gated channel subunit. Neuron 26, 8191 (2000).
107. Zhao, H. & Reed, R. R. X inactivation of the OCNC1 channel
gene reveals a role for activity-dependent competition in the
olfactory system. Cell 104, 651660 (2001).
Online links
FURTHER INFORMATION
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cortical barrels: maps and plasticity | cortical plasticity: use-
dependent remodelling | neural activity and the development of
brain circuits | visual system development in vertebrates
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