Thalamic Networks for Relay and Modulation: Pergamon Studies in Neuroscience

RUSTIONI

Part I

Evolution and Development

Outline

Chapter 1: Parallel Pathways and Fibre Size

Chapter 2: Interneurons in the Mammalian Thalamus: A Marker of Species?

Chapter 3: Thalamocortical-Corticothalamic Reciprocals and the Evolutionary Origin of Medial Geniculate

Chapter 4: The Development of Trigeminothalamic Projections

Chapter 5: Disrupting the Establishment of Thalamo-Cortical Circuits: Effects of Prenatal Exposure to Ethanol

1

Parallel Pathways and Fibre Size

I.T. DIAMOND,     Departments of Experimental Psychology and Neurobiology, Duke University, Durham, NC, USA

Publisher Summary

This chapter explores the tecto-pulvinar path to visual cortex and thalamic projections to superficial layers of striate cortex. It discusses that the key to understanding the thalamus lies in the classification of nuclei. There are four classes—(A) The first class consists of the principal sensory nuclei each one of which projects to a single area of koniocortex; (B) The second class is a group of nuclei that project diffusely to several, and probably many, cortical areas; and (C) nuclei in third and fourth classes project more intensely to one area and less intensely to a second or third area. The experiments are made by injecting WGA-HRP into the caudal extremity of the pulvinar nucleus with the result that the entire ventral region below MT is filled with terminals. Thus, almost the entire visual cortex is a pulvinar target in the Galago; and the striate cortex stands alone with an absence of terminals in layer IV. The chapter also discusses the significance of large and small cells in a single sensory relay nuclei and the reason of projection of large cells to layer IV and small cells to the superficial layers of koniocortex.

Historical Introduction

The key to understanding the thalamus lies in the classification of nuclei. It was entirely appropriate then that Macchi (1983) introduced the first volume in the series with a description of four classes: 1) The first class consists of the principal sensory nuclei each one of which projects to a single area of koniocortex; 2) The second class is a group of nuclei (including the intralaminar nuclei) that project diffusely to several, and probably many, cortical areas; and finally, 3) Nuclei in classes 3 and 4 project more intensely to one area and less intensely to a second or third area. Such a useful picture has depended on new methods for tracing pathways to the thalamus and from the thalamus to cortex and corpus striatum.

I would like to go back in history because the early methods underscore the significance of new methods and earlier results set the stage for later results. Cajal was the first to draw the three main sensory pathways that are relayed to the koniocortex by the GL, GM and VP (see list of Abbreviations for this chapter).

Relying chiefly on cytoarchitecture, Le Gros Clark (1932) later divided the mammal thalamus into two groups: The principal nuclei and the intralaminar nuclei. The intralaminar nuclei comprise the peripheral zones of the adjacent principal nuclei … [and] their cells are usually small and fusiform (Le Gros Clark, 1932). Small and fusiform relay cells are also found within the principal nuclei and I will argue later that their function is distinct and different from the large relay cells.

The role of the intralaminar nuclei took a giant step forward when, in the early 1940′s, Dempsey and Morison discovered the cortical recruiting response (Morison and Dempsey, 1942; Dempsey and Morison 1943). Whether the intralaminar nuclei are indeed the controlling influence upon the rhythmic electrical activity of the entire cortex was hotly debated in back-to-back papers (Jasper, 1949; Moruzzi and Magoun, 1949; Rose and Woolsey, 1949). Taking one side, Rose and Woolsey argued that the intralaminar nuclei do not project to the cortex at all, let alone to the whole of it. The grounds for their conviction was the failure to find retrograde degeneration in the intralaminar nuclei after widely separate cortical lesions.

Rose and Woolsey then divided the rest of the thalamus (i.e. the principal nuclei) into the sensory relay nuclei and a second class which depends on the first class for sensory impulses. This idea was accepted for many years by all of us. For example, in 1959 George Bishop (see References) recorded visual responses in the pulvinar nucleus following stimulation of the optic nerve. The latency of response suggested a synapse and Bishop immediately assumed the synapse had to be in GL. We now know that the synapse was in the SC.

Tecto-Pulvinar Path to Visual Cortex

The pulvinar nucleus became the focus of my attention when a complete destruction of striate cortex in the tree shrew failed to produce deficits in the animal’s capacity to follow moving objects or to distinguish patterns, colour or shape (Snyder and Diamond, 1968; Diamond and Hall, 1969). The striate cortex is easily identified in the tree shrew and layer IV of the striate area is especially conspicuous. The preservation of vision in the absence of GL and the striate cortex requires a visual path to extrastriate cortex in parallel to the path to striate cortex; and the pulvinar nucleus was the best candidate. It turned out that the pulvinar nucleus is the target of the superficial layers of SC and projects to an extensive area of cortex—area 18, and most of the temporal cortex. It is not surprising when the caudal half of the neocortex is ablated, the tree shrew’s vision is decimated.

A general picture of the mammal pulvinar nucleus cannot, however, be settled by the tree shrew alone, and we looked next at a prosimian primate, Galago senegalensis and Galago crassicaudatus. Once again, a robust projection from the SC to the pulvinar nucleus was identified (Raczkowski and Diamond, 1981).

The major target of SC was found in the caudal division of the pulvinar nucleus, but in a recent study a second pathway was found from SC to Pbg and from Pbg to a more rostral area of the pulvinar nucleus. This rostral region of the pulvinar nucleus is divided by the zero vertical meridian into dorsal and ventral subdivisions and both receive fibres from Pbg (Diamond et al., 1992). Figure 1 shows a large injection of WGA-HRP into the pulvinar nucleus close to the zero vertical meridian. Cells labelled by retrograde transport are depicted by large dots and terminals by fine dots. Note first the labelled cells in the Pbg, SGS, LDT and the superficial layers of SC. In addition to the projections from tectum and brain stem to the pulvinar nucleus, there are also descending projections from the cortex; in the striate cortex, the labelled cells are in layer V; in areas 18 and MT, the labelled cells are in layer VI. The terminals of pulvinar projections to the cortex reveal the striking differences between the striate area and the extrastriate visual areas: there are no terminals in layer IV of striate cortex. Case 2755 shows only a part of the entire cortical field receiving pulvinar projections.

FIG. 1 An injection in the rostral half of Pul S is depicted by black spot. In cortex layer IV is full of terminals in area 18 and MT, but layer IV is devoid of terminals in area 17. Retrograde transport (depicted by large dots) is found in Pbg, SGS and layer V in striate cortex.

Further experiments were made by injecting WGA-HRP into the caudal extremity of the pulvinar nucleus with the result that the entire ventral region below MT was filled with terminals (see Figure 2). Thus almost all of the visual cortex is a pulvinar target in the Galago; and the striate cortex stands alone with an absence of terminals in layer IV.

FIG. 2 A more caudal injection shows projections to temporal lobe—Tv and Tp. Note large dots in SGS depict cell bodies labelled by retrograde transport.

Thalamic Projections to Superficial Layers of Striate Cortex

The pulvinar nucleus is not the only source of visual projections to the superficial layers of the striate cortex. In 1979, Carey, Fitzpatrick and I restricted HRP to the superficial layers of the striate cortex with the following results: 1) Continuous curved columns of cells labelled by retrograde transport were found in the pulvinar nucleus; 2) Retrogradely labelled cells were densely distributed in clumps in layers 4 and 5 of GL. These are the layers with small fusiform cell bodies and they are just the layers that receive fibres from SC; 3) Much to our surprise, a dense population of cells labelled by retrograde transport was found in the claustrum; 4) Finally, cell bodies were labelled in the midline and intralaminar nuclei, notably the central and paracentral nuclei (Carey et al., 1979).

For the present purpose, the most important finding was the projection from GL layers 4 and 5 to layers I and II of striate cortex (see Figure 3). GL layers 4 and 5 are the target of SC so there is a pathway from SC to superficial striate via GL layers 4 and 5 and the pulvinar nucleus (Carey et al., 1979; Diamond et al., 1985). We also found in tree shrew that certain GL layers (layers 3 and 6) receive SC projections and send fibres to the superficial layers of the striate cortex. The lateral geniculate nucleus is unique among thalamic nuclei in having a prominent laminated organisation. The layers are usually different in cell size and the Galago is special in having three different-sized matched pairs of layers (Carey et al., 1979; see Figure 4a). Layers 1 and 2 have very large cells (mean soma area 402 microns), whereas layers 4 and 5 contain small cells (mean soma area 284 microns), cells in layers 3 and 6 are intermediate in size.

FIG. 3 Sagittal section of Galago GL after injection of HRP into superficial layers of striate cortex. Upper figure shows labelled cells in layers 4 and 5. Lower figure shows higher power in dark field.

FIG. 4a Nissl stain of GL in Galago. The largest cells are in layers 1 and 2. The smallest in 4 and 5, while cells in 3 and 6 are intermediate.

It seems that the relation between layers 4 and 5 and the rest of GL might be similar to the relation between large and small relay cells in VP nucleus. Penny et al. (1982), using the cat as subject, tried to restrict HRP either to layer IV or to the superficial layers of cortical area SI. After injections in layers IV and III, labelled cells were, on average, about twice as large as cells labelled by superficial injections. This is a conservative estimate of the actual difference between the two populations of thalamic cells inasmuch as the deeper injection could have labelled thalamic cells that project to the superficial layers.

Calcium Binding Proteins Mark Large and Small Cells of the Thalamus

A novel and creative way of identifying, in a single nucleus, small fusiform cells that project to superficial cortical layers, and large cells that project to layer IV, was taken by Jones and his collaborators, Hendry and Rausell (Rausell and Avendano, 1985; Jones and Hendry, 1989; Rausell and Jones, 1991a,b). This team also showed that the clusters of large cells in monkey VPM (called rods), as well as the surrounding neuropil, were stained by antibodies to parvalbumin; the small cells in the matrix, on the other hand, were pale after the parvalbumin stain but were positive after staining with an antibody to calbindin. We were able to replicate these experiments in VP of Galago and tree shrew. It was also possible to exploit the method of identifying calbindin and parvalbumin in GL of Galago (Diamond et al., 1993). A picture of the results is shown in Figure 4b.

FIG. 4b (a) To show a photograph of a section through GL in Galago where the stain results from the antibody to the protein parvalbumin. (b) To show a photograph of an adjacent section through GL where the stain results from the antibody to the protein calbindin.

Significance of Large and Small Cells in Single Sensory Relay Nuclei

The final questions for discussion are: What is the significance of large and small cells in a single sensory relay nuclei? And why do large cells project to layer IV and small cells to the superficial layers of koniocortex? The best clues can be found in Bishop’s 1959 paper on fibre size and modality (see References). Bishop argued that parallel pathways relayed to cortex by a single nucleus reflect stages of evolution. The small fibre path is the oldest in evolution as revealed by projections to the tectum and other centres found in lower vertebrates. With the evolution of telencephalon and diencephalon, the old pathways find targets in the thalamus and the end result is an increasing number of synaptic stations. The newer and larger-fibre pathways bypass the old centres so that fewer synapses and faster conduction rates produce an earlier arrival to the sensory cortex. Projection to superficial layers of koniocortex would fit Bishop’s phylogenetic scheme since the reptile cortex has just two layers—layer I receives thalamic projections and layer II consists of pyramidal cells with descending axons. This could be the organisation in a reptile-like mammal ancestor.

It now remains to show the size of optic tract fibres projecting to two of the three layers in a set. The last figure illustrates a large fibre projecting to layer 2 and a small fibre projecting to layer 5 (Conley et al., 1987; see Figure 5). Fibres to layers 3 and 6 are intermediate in size. Since GL layer 5 projects to superficial layers of striate, there is a small fibre pathway beginning with the retina and terminating in the superficial layers of cortex.

FIG. 5a Optic tract fibre terminating in layer 2 to show the large size of the fibre.

FIG. 5b Optic tract fibre to layer 5 is very small in comparison to the large fibre to layer 2. Note that the fibre appears to go beyond layer 5 but then returns.

Postscript

If wishes were appropriate in science, I would hope that some clear order will ultimately come from the issues raised here. There are small thalamic cells that project to superficial layers of visual koniocortex and receive fibres from SC and these have different functions from the large cells that seem highly specialised and are very sensitive to certain parameters of the stimulus. One might have expected the large and medium cell layers in GL would have similar functions in various species but, as it turns out, there are not the slightest similarities from one species to the next. Thus, one pair of layers in tree shrew is ON-centre and a second pair is OFF-centre, while one pair of layers in monkey may be colour and a second pair may be sensitive to motion. Once the conduction to layer IV is achieved there is further integration between pathways in the superficial layers of striate cortex. The opportunity still remains to test whether the function of the small cells projecting directly to superficial layers are similar for every species. At the present, it is not even clear whether there is a function common to all the thalamic cells that project to superficial striate; this would include cells in CL, the pulvinar and lateral nuclei. There is even a source of projection from the claustrum—but the role of the centres outside the thalamus goes beyond the present goals. If there is a common function, it is likely to be very broad such as modulation or integration. The superficial layers are also the sites of convergence from many cortical areas and the net effect of convergence is a strong influence on the motor cells in the deeper layers, especially layer V. While there is no reason to challenge the concept of a nucleus as the functional unit, there is good evidence that small cells at the periphery of a nucleus (recall Le Gros Clark’s distribution of intralaminar cells) project to the superficial layers of koniocortex. For example, VP in Galago consists of a middle region of large cells and bands of small cells above and below the middle band. In the rat the population of small cells adjacent to VPM is considered a different nucleus, POm. POm projects to superficial layers of the barrel cortex including the cortex intercalated between barrels. A paper presented at this meeting has shown that the POm pathway mediates spread of activity between cortical barrels and is in a position to strengthen or weaken the links between barrels—taking it a step further then, links between whiskers (see chapter entitled Parallel Somatic Sensory Pathways through the Rat Thalamus by M. E. Diamond in this volume). These findings might offer clues to the function of the projections to superficial layers in other koniocortical areas.

Acknowledgements

I want to thank everyone who has contributed to this meeting, the third, and perhaps the last of its kind. The honor I have received from my friends and colleagues is the highest possible award.

We owe the success of these conferences and publications to a number of people: Marina Bentivoglio, Roberto Spreafico, Aldo Rustioni, Diego Minciacchi, Marco Molinari and especially to Giorgio Macchi, whose leadership has led to this unique sequence of events. The settings in Milano, Verona, and Rome, and the diverse contributors from many countries have created an atmosphere that will never be replicated.

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