Thalamocortical synaptic relations: A review with emphasis on the projections of specific thalamic nuclei to the primary sensory areas of the neocortex

Bruin Research Reviews, 1 (1979) 275-3 11 0 Elsevier/North-Holland Biomedical Press

THALAMOCORTICAL EMPHASIS

SYNAPTIC

ON THE

TO THE

PRIMARY

EDWARD

L. WHITE

275

RELATIONS:

PROJECTIONS SENSORY

A REVIEW

OF SPECIFIC

AREAS

OF THE

THALAMIC

WITH NUCLEI

NEOCORTEX

Departwent of Anatomy, Boston University School of‘ Medicine, Bostm, Muss. 02118 (U.S.A.

J

(Accepted September 4th, 1979) Key worrl~ :

thalamocortex - synapse electron microscopy

-

neocortex

-

somatosensory

cortex

-

CONTENTS

.................................

1. Introduction 2. Retrograde

cell degeneration

3. Marchi method

275

..........................

277

........

.......................

4. Reduced silver impregnation

methods

......................

281

tracing methods ........................

5. Autoradiographic

6. The HRP retrograde

284

transport method ......................

286

7. The identity of neurons which receive input from the thalamus

...........

8. Electron microscopic elucidation of thalamocortical

synapses .............

9. Theoretical implications of widespread functional units ................................

input:

IO. Hierarchical

vs parallel processing

11. A concept of thalamocortical 12. Questions to be answered. Acknowledgements References

thalamic

......................

...........................

................................

....................................

Appendix A references.

thalamic

287 288

selection of cortical 295

........................

relations

281

..............................

Appendix B references ...............................

295 296 300 301 301 310 311

1. INTRODUCTION

In the latter half of the 19th centrury, new techniques for preserving, sestioning and staining nervous tissue revolutionized neuroanatomical investigations by enabling

the light microscopic processes*.

visualization

The application

tions soon led to the realization which project

of some of the finer details of nerve cells and their

of these new methods

topologically

to the study of thalamocortical

that the thalamus to particular

contains

regions

of the cerebral

ment exemplified

by the specific thalamic

of the neocortex.

The purpose of this review is to critically

cortical

conducted

relations

projections

since the technological

as to provide the necessary historical framework of thalamocortical connectivity. An evaluation for neurobiology

has recently

entered

rela-

discrete groups of nerve cells cortex,

to the primary** evaluate

revolution

an arrange-

receptive

areas

studies ofthalamo-

of the 19th century

so

to better understand current concepts of past work at this time is desirable.

a second period of technological

revolution

--

one which has in large part focused on thalamocortical connections. Whereas the 19th century revolution was marked by the rapid development of various light microscopic techniques, the essence of this second technological revolution rized as a blending of light and electron microscopic methods.

may best be characteFor instance. it is now

possible to use the light microscope to determine the specific cell type of a neuron in the cerebral cortex, and to then examine the same neuron with the electron nncroscope to identify those regions of its cell membrane which are involved in thalamocortical synapseslsa. In this way the specific cortical targets of thalamic projection systems can now be elucidated.

Consequently,

we have entered an age where we can expect to learn

the intimacies of thalamocortical relations, and as the details of thalamocortical microcircuitry become known we shall be compelled to refine and redefine current concepts of thalamocortical organization. This review is being written on the premise that an examination

of previous

cal synaptic

relations.

work will facilitate

and guide future studies of thalamocorti-

* Excellent accounts of developments in nemoanatomical techniques during the 1800s may be found in Polyak138 and WaIkertg5. * * The following definitions of the word ‘primary’ are offered in the hope that they will alleviate some of the confusion which has resulted from the various ways in which the word ‘primary’ has been applied to describe specific regions of the cerebral cortex. In the context of studies of cortical evoked potentials, primary was used to denote short latency responses of the cortex whose characteristic waveforms were reproducible with successive peripheral stimulation. These ‘primary’ cortical responses’ were highly localized to regions of cortex which were then referred to as primary response areas. Primary cortical responses were followed by secondary cortical responses which were more varied in shape, phase, latency and in incidence of occurence i14. Secondary responses were not related to specific regions of the cortex. In time, the primary response areas as determined by studies of cortical evoked potentials, came to be equated with the ‘primary projection areas’ which had been defined by anatomical methodst5t*ts2. These latter regions were defined as those regions of the cortex which receive input from ‘extrinsic’ thalamic nuclei, i.e. those thalamic nuclei which receive substantial portions of their input from sources outside the thalamus. Included in this classification would be the sensory nuclei which lie along the main ascending sensory pathways from the periphery to the cortex. Studies of cortical evoked potentials confirmed anatomical findings that the primary auditoryzZs, areas contain topographically organized representations of the visuaPs5 and somatosensorysJe7 appropriate peripheral receptive fields. In 1941, Adriana reported the digits of the cat to be represented in a ‘second’ sensory area of the cortex. Soon, a number of studies reported second areas of cortical representation for the peripheral receptive fields of the somatosensory222-226~Z2g, auditoryZzs and visuaItsssis4 systems in a variety of mammalian species. The important point is that secondary areas are secondary simply because they were described after the primary cortical areas. It is only because much less is known of the projections and synaptic organization of the secondary than of the primarv cortical regions that the latter are the main focus of this review.

277 3. RETROGRADE

Guddencjs. functional

CELL DEGENERATION

in 1870, provided

link between the thalamus

the first experimental and cerebral

evidence

of an intimate

cortex by showing that ablation

the cortex in young rabbits led in time to the death and disappearance the

thalamus*‘.

retrograde relations

Gudden’s

method,

cell degeneration,

which

came

was soon widely

in many species. One approach

to be known applied

employed

of

of cell bodies in

as the method

of

to study thalamocortical

in these studies was to ablate an

entire cerebra1 hemisphere, allow the animal to survive for periods ranging from several weeks to nearly a year, and then examine the thalamus for signs of cellular degeneration. The rationale for this approach was to obtain a comprehensive of the origin of the entire thalamic radiation. Thus, Wallerlg7 examined thalamus

following

hemidecortication

and

noted

a full spectrum

picture the cat

of degenerative

effects associated with various thalamic nuclei. Whereas the ventral nuclei sustained a total cell loss, little or no effect was seen in the mid-line and intralaminar nuclei. Most other thalamic nuclei showed varying degrees of cell loss. Similar- results were reported following hemidecortications in the ratzg, rabbitlso, dog9fi,133, rhesus monchimpanzee193 and human139~l~3, leading to the conclusion key 12-1,193,macaquelgj, that whereas most of the thalamus projects directlu to the cerebral cortex, the mid-line and intralaminar nuclei do not. A persistent problem facing investigators

who employed

the method

of retro-

grade cell degeneration was that some neurons in severely affected thalamic showed no ill effects even after total cortical ablation’~“9,1g4.1g5. Although

nuclei it was

generally accepted in the early part of this century that these surviving neurons simply did not project to the cortexlg”, this reasoning was insufficient to explain the occurrence of surviving cells whose appearance was only slightly altered by the cortical lesion. For this reason, Rose and Woolseyl52 proposed that surviving neurons might well project to the cortex, but that they are sustained

to a greater

or lesser degree after cortical

damage by having intact collateral axonal projections to other regions of the brain. Alternatively, Powell and Cowan140 concluded that surviving thalamic neurons showed minor degenerative of corticothalamic the cellular

effects following

cortical ablations

afferents to them. An implication

degeneration

observed

might result from the deafferentation

in the thalamus of thalamic

because of the removal

of this conclusion following

neurons

lesions

is that some of of the cortex

rather than from damage to

their axons, a conclusion reached many years earlier by Waller and Barrislg*. This suggests that retrograde cell degeneration is unreliable for elucidating thalamocortical projections. but as Walker1g5 observed, a variety of experimental evidence indicates that areas of the cerebral cortex project to thalamic nuclei having thalamofugal pro.iections to the same cortical area. More recent studies have confirmed this finding for many areas of the cerebral cortex (see discussions in Colwell’*, and White and

* An extensive description of the effects of axonal transection on neuronal perikarya may be found in Lieberman’“‘. Briefly, before disappearing, affected neurons undergo chromatolysis, decrease in size and show a diminished afinity for cell stains,

278 DeAmicisZo”), and thus deafferentation might not significantly influence the interpretation of studies using the method of retrograde cell degeneration. There are, however, a number of difficulties which should be kept in mind when considering the results of retrograde degeneration studies. One of these concerns the true extent of the cortical lesion; nearly every hemidecortication referred to above was accompanied by damage to subcortical structures and it is conceivable that subcortical strvctures might be comprised even with less extensive lesions of the cortex. Walker’“” noted that, even when the lesions are clearly restricted to the cerebral cortex, the interpretation of retrograde studies using large cortical lesions is complicated by the fact that the resultant thalarnic degeneration may be so extensive as to distort the cytoarchitecture of the thalamus, rendering thalamic nuclei no longer recognizable. In addition, a number of factors independent of the character of the lesion have been shown to influence the severity of the effects of retrograde cell degeneration. For instance, several studies report more severe degenerative effects in young animals than in adults with similar Iesionslz,102~lJ7,although sometimes the reverse is true’“l. Rose and WooIseyl”g noted the effects of retrograde cell degeneration in the thalamus grew more severe with increasing postoperative survival time. This was recently confirmed by Chow and Dewson17 who also reported retrograde cell degeneration to be faster and more complete in rabbit than in cat thalamus. Finally, it has recently been shownl-” that the severity of retrograde cell effects depends to some extent on the particular thalamocortical projection system under investigation. Thus the size and extent of the lesion, the age and species of the animal, the length of postoperative survival time, and even the particular projection system involved, are all factors which might complicate the interpretation of retrograde cell degeneration studies. The many disadvantages of the method of retrograde cell degeneration might tempt one to think this technique played a minor role in the elucidation of thalamocortical relations. In fact, just the opposite is true, for it was through the judicious use of this method that a number of investigators provided the first evidence that certain of the thalamic nuclei project in a topographic fashion to the cerebral cortex. Shortly after Gudden’s discovery that rather extensive lesions of the cerebral cortex caused a marked atrophy of thalamic nuclei, von Monakow116 reported very small lesions of the cerebral cortex in newborn rabbits produced localized areas of cellular degeneration in the thalamus. Using similar methods, Minkowski115 noted that lesions as small as 0.5 mm of cat striate cortex produced sharply delineated areas of retrograde cell degeneration in the ipsilateral lateral geniculate nucleus. Further. Minkowski realized that the locus of degeneration in the thalamus depended on the exact placement of the lesion in the cortex. Similarly, Putnam and PutnamlJ2 showed that discrete lesions of varied size in the striate cortex of rabbits produced, in the lateral geniculate nucleus, sharply delineated areas of retrograde cell degeneration which were consistently related in size and location to the cortical lesions. Extensive analyses of the cortical projection of the lateral geniculate nucleus in the rag8 and in monkey137,138 were soon to follow, and in these species, the projection of the lateral geniculate nucleus to the cortex was also shown to be topographically organized. Information on the topographic nature of the geniculocortical projection came

279 at a time when other studiesll.97 were elucidating the strict topography of the retinogeniculate projection. As a result of these studies, it became possible on anatomical bases alone to specify the areas of the visual cortex which subserved particular regions of the visual fieldr4s. Henceforth, the cortical representation of the retina was to be thought of as very detailed, and the concept (see discussions in Polyaklss and LashleylO’J) that the retina projected in a more or less diffuse and unstable way to the cortex became untenable. Other studies used retrograde cell degeneration to elucidate the thalamocortical relations of the somatosensoryss,gg~t95 and auditory195 systems*, and here again, thalamic nuclei were shown to project in a topographically organized fashion to their respective regions of cortex. The phrase ‘respective regions of cortex’, implies a concept which, although taken for granted nowadays, was not universally accepted in the early 1900s namely particular regions of the cerebral cortex receive input from particular nuclei of the thalamus. In fact, there existed a school of thought which held that the thalamic nuclei projected diffusely over wide areas of the cerebral cortex, a notion

which implied that each

area of the cortex was the functional equivalent of any other area of cortex (see discussions in Polyak137Jss). Convincing evidence against this concept of cortical organization was contributed

by the results of numerous

studies using retrograde

cell degeneration,

for the results of these studies strongly indicated that certain of the thalamic nuclei project only to particular areas of the neocortex. This finding provided firm support

Fig. 1. Illustration of the intensity of the thalamic projection to the cerebral cortex of the monkey (macaque?) as determined by the methods of retrograde cell degeneration and Marchi. The most intense thalamic projections are to the primary areas of the neocortex (see Fig. 2). Reproduced from Walke+ with permission of the Univ. of Chicago Press. * The reader is referred to Appendix A and to the books by Walkerta6 andPolyak’38 for additional references to studies of thalamocortical relations using the method of retrograde cell degeneration.

280

02 Fig. 2. Illustration of the macaque cerebral cortex showing the primary and secondary areas as determined by studies of cortical evoked potentials. Comparison with Fig. 1 shows that it is the primary cortical areas which receive the most intense thalamocortical projections. Reprinted from Rose and Woolseyrsl with permission of Elsevier Publishing Co.

for the currently accepted notion of specific functions being localized to specific regions of the cerebral cortex. The foregoing discussion well illustrates how knowledge of the details of thalamocortical projections can contribute significantly to our understanding of the organization of the cerebral cortex. An early proponent of this philosophy was A. E. Walker, whose own extensive studies of the primate thalamus and its projections provided a wealth of important information suggesting the cytoarchitecture of the cerebral cortex is intimately related to its thalamic projections. Helsfi, and later ClarkeI, conceived of the cortex as composed of cytoarchitecturally distinct zones involved in different functional activities, each zone related to a particular region of the thalamus”. This relationship is perhaps best illustrated by the thalamic projection to the primary sensory areas of the neocortex; the cytoarchitectural organization of the primary sensory areas is remarkably similar from one area to the nextloJg9 and each primary sensory area receives a particularly intense projection from a specific** thalamic * This should not be taken to imply that a region of cortex receives input from only a single thalamic nucleus, for as Killackey and Ebnerg’** suggested, each area of mammalian neocortex likely receives input from 2 or more separate thalamic nuclei. * * ‘Specific’ in this context was first applied by Lorente de NO‘110 to denote the thalamocortical projections of the main relay nuclei of the thalamus which lie directly along the ascending sensory pathways from the periphery to the cortex. The thalamocorticai projections from these nuclei are specific in the sense that they terminate mainly within layer IV of the primary sensory regions of the neOCOrteX. In contrast, the thalamocortical projections from the non-specific nuclei terminate in ail layers Of more extensive regions of the cortex. The reader is referred to the discussion by Ebnel”Ll for additional information on non-specific thalamocortical projections.

281 nucleus.

A comparison

be distinguished

of Figs. 1 and 2 shows how, partly on this basis, primary

from secondary

Thus, although

the method

standards,

we must

elucidation

of several important

these is the concept ordered,

credit

fashion

may

of the cortex.

of retrograde

cell degeneration

is crude by today’s

investigators

who

technique

used

aspects of thalamocortical

this

relations.

of the main sensory nuclei of the thalamus

topographic

3. MARCH1

the

regions

to the primary

with

Foremost

projecting

the

among

in a highly

sensory areas of the neocortex.

METHOD

Additional support for the concept that thalamocortical projections are topographically organized was provided by studies using the Marchi method. This that technique, developed in 1886 by Marchi3g,19j was based on the observation degenerating myelinated fiber tracts could be labeled by a deposit of black granules by treating the tissue first with potassium dichromate and then with osmic acid. Although the Marchi method often stained normal as well as degenerating fiber tracts, careful application of the technique confirmed the concept of the main sensory relay nuclei of the thalamus projecting topographically onto the cerebral cortex~~~,2”~g4~137,1s*,~5*,2~*. An important disadvantage myelinated or unmyelinated

of the Marchi method is an absence of staining of thinly fibers and consequently the technique has proved of little

use in specifying the layers of cortex which receive the axon terminations of thalamocortical projections (see ref. 64). Some insight into this question was provided by analyses of Golgi impregnated brains which indicated that the specific thalamic nuclei project mainly to the fourth layer of sensory cortex1~,10g,110,1P%,13*and to the third layer of motor cortex5. However, the difficulty of tracing identified fiber tracts over long distances rendered the Golgi method nearly as unsuitable as the method of Marchi for elucidating the details of the terminal arborizations of thalamocortical projection systems. More exact information on the patterns of termination of thalamocortical projections had to await the development of reduced silver impregnation methods which stain degenerating axoplasm rather than myelin sheaths. 4. REDUCED

SILVER IMPREGNATION

Significant

METHODS

advances in the study of the terminal

distribution

patterns

of thalamo-

cortical projections were made possible with the introduction by Nauta1t8 in 1950 of a reduced silver stain for degenerating axon terminals. The original Nauta method enabled, for the first time, the visualization of the precise layers of cortex which contained degenerating axon terminals and preterminals of identified thalamocortical projections. Theusefulness of theNautamethod was, however, limited by theconcomitant staining of normal axons and their terminals. Recognizing this deficiency. Nauta and Gygaxltg modified the original Nauta technique to suppress the staining of normal fibers. Although this new method facilitated the identification and tracing of degenerating thalamocortical projections, it soon became clear 63 that suppressing the staining of normal axons often also resulted in the failure to demonstrate the full extent of the distribution

282 of degenerating

axon terminals.

in 1967 of the Fink-Heimer48 impregnation terminals.

of degenerating

The literature

cortical connections

This problem modifications axons

was greatly alleviated

which combined

with a more successful

since that time is replete with references

using the Fink-Heimer

by the introduction

the selective reduced silver staining

of their axon

to studies ofthalamo-

and other (e.g. ref. 211) modifications

of the

original Nauta technique. These studies, which confirmed the topography of the specific thalamocortical projections to the primary visua1~,1~.50.74,~5,9~~1*1,135~~~~. somatosenSOry3~.F1.;9.83,R9.91 , auditoryl~l~“l” and motor 178,179cortices, also demonstrated the intense projection of the specific thalamic nuclei to the fourth layer of primary sensory cortex and to the third layer of primary motor cortex *. A smaller, but consistent projection to the first layer of these regions of cortex was also demonstrated by reduced silver staining of degenerating specific thalamocortical projections (e.g. refs. 50 and 83). A variety of mammals, including the monkey, cat, rat, opposum and hedgehog were examined in these studies, and thus a principal contribution of the reduced silver methods has been to show the remarkable similarity in widely divergent mammalian species of the laminar distribution of specific thalamocortical afferents. A second contribution of the reduced silver methods concerns their application to demonstrate functional columns in monkey primary visual cortex’*q7”. Functional columns were first elucidated by Mountcastle 117who showed that all neurons encountered in vertical microelectrode penetrations of cat primary somatosensory cortex were related to the same sensory modality and responded with similar response latencies to stimulation of nearly identical peripheral receptive fields. The diameter of one functional column was estimated to be about 500 ,um. The existence of similar columns has since been confirmed in each of the primary sensory areas of the cerebral cortex in several species: for example, in SI of mouselfi5, rat”,lfiJ and monkey’“, in VI of cat7” and rnonkey73,““”

and in Al of cat’. The anatomical

demonstration

of functional

columns was first provided by Hubel and Wiesel74375 using the Fink-Heimer method. Previously, Hubel and Wiese172p73 had shown cells in cat and monkey primary visual cortex to be arranged

in alternating

columns

according

to eye dominance,

the cells of

one set of columns responding preferentially to the left eye, those of the alternate columns to the right eye. Hubel and Wiesel reasoned that since each of the si.
* See Appendix B for additional references to studies using reduced silver methods to study thalamocortical relations.

2x3 ocular dominance ferent members Further distribution

columns

-

evidence

that the organization

of thalamocortical

and mouse primary that neurons

and thus of geniculocortical

afferents -

is similar in dif-

columns

is related to the

of the same species. afferents

somatosensory

of functional

has been adduced

by studies of barrels in rat

cortex. Woolsey and Van der Loos”~~‘~,~“~observed

in layer IV of mouse somatosensory

lular units, which because of their three-dimensional

cortex are organized

rels have since been shown to occur in layer IV of the somatosensory species of rodent comprise arrangement

into multicel-

shape, were termed ‘barrels’. Barcortex of several

and in rabbit3aj202,2”3, and in each species, the large barrels

the posteromedial

barrel

to the large mystacial

subfield

vibrissae

(PMBSF)

correspond

on the animal’s

which

in number

and

snout. It is interesting

that

Fig. 3. Light micrograph of a 40 pm thick section stained with cresyl violet showing barrels in the posterior region of the posteromedial barrel subfield (PMBSF) of the mouse. Barrel sides, composed of densely packed cell bodies, are more intensely stained than barrel hollows where cell bodies are less densely packed. Compare with Fig. 2. Magnification, 150 X, scale 100 /rm. Fig. 4. Light micrograph of a 30 /tm thick Fink-Heimer stained section, through the posterior region of the PMBSF in a mouse whose ventrobasal thalamus had been lesioned. In this preparation, barrel hollows are filled with darkly stained, degenerating thalamocortical axon terminals. Magnification, 150 X , scale, 100 /cm.

2X4 barrel-like

aggregations

thalamus

of neurons

have also been demonstrated

by Woolsey and Van der Loos that each barrel in mouse PMBSF

suggestion

the morphological

manifestation

throughout

the full thickness

al columns

to the distribution

by Killackey*”

in layer JV of a functional of specific thalamocortical

and Killackey

and Leshinas

show that lesions of the ventral

posterior

and 4 which allow for the comparison

afferents

nucleus produced

which extends

was demonstrated method

distribution

to the PMBSF barrels in for the mouse by Figs. 3

of degenerating

afferents

of the specific distribution

within layer IV which is closely related

pre-

thalamocortical

to our knowledge is the elucidation

of thalamocortical

species, and second is the demonstration

to

discrete clusters of termin-

of PMBSF barrels as seen in a Njssl-stained

The reduced silver methods have thus contributed mocortical connections in two important ways. First

aRerents

the

cortex is

of these function-

who used the Fink-Heimer

paration with the distribution, in the PMBSF, ents stained by the Fink-Heimer method.

of the laminar

column

of the cortex~0~r’j.1,t65. Th e relationship

al degeneration which corresponded in both size and location rat somatosensory cortex. This correspondence is illustrated

methods

in the region of the

which projects to the mouse PMBSF r9r. Recent studies have confirmed

to the columnar

afferof thalaby these

in a number

of

of thalamocortical organization

of the

cortex. However, there are several disadvantages of using reduced silver methods to study thalamocortical connections. For instance, the methods are often not sufficiently sensitive to stain minor thalamocortical projections. Thus, using the Fink-Heimer method, Peters and Feldmanlz8 observed degenerating thalamocortical afferents in Iayers IV and 111 of rat visual cortex, whereas with the electron microscope they observed degenerating thalamocortical axon terminals in layers 1 and VI as well. In contrast, it is likely that some of the silver reaction product does not represent degenerating axons or their terminals, and further, the methods do not allow for the accurate differentiation of true axon terminals from preterminal fiber fragment&. Additional disadvantages of the reduced silver methods derive from the fact that they are typically

used following

the placement

of lesions

in the brain parenchyma.

The

problem is that lesions might injure fiber tracts which pass through but do not originate, in the lesion site, and thus a proportion of the degeneration illuminated by the reduced

silver methods

might

consist

of degenerating

axons

and terminals

of

unknown origin. Further, lesions placed in one region of the brain might cause unforeseen damage to other regions by compromising the circulation of blood or of cerebrospinal tluidasl. For these reasons it would be desirable to examine the terminal distribution of thalamocortical projections using a method which does not require making lesions. Just such a method became available in 1972 with the introduction of an anterograde tracing technique which enabled the autoradiographic demonstration of thalamocortical projections in non-lesioned brain@. 5. AUTORADZOGRAPHfC

TRACING

METHODS

The autoradiographic method for tracing axonal projections is based on the uptake of radioactively labeled amino acids by neuronal cell bodies at an injection site,

285 and the subsequent materials

anterograde

in other regions

axon terminals and development

axonal

of the brain.

are then coated will contain

transport Sections

of radioactive

containing

with a photographic reduced

silver grains

material

to axon

the radioactively

labeled

emulsion localized

which upon exposure over the labeled

axon

terminals30. A distinct sensitivity

advantage

of the autoradiographic

for demonstrating

thalamocortical

tracing

method

axon projections.

is its increased

For example,

studies

with reduced silver methods

had shown the cat lateral geniculate nucleus to project to of this projection using layers IV and I of primary visual cortex ~O,~ta.A reinvestigation the autoradiographic tracing method showed the lateral geniculate nucleus also cortex tj3, Subsequent autoradiographic projects to layer VI of cat primary visual investigations

have shown a specific thalamic projection to layer VI in VI of ratl-l”, squirrelI”* and cat103, in SI of raPs and in SI and AI of monkeyal. In fact, a main contribution of the autoradiographic tracing method has been to confirm and extend previous findings with regard to the laminar and area1 distribution of thalamocortical confirmed earlier reports that the afferents. Thus, JonesT and Jones and Burtor+ most intense thalamic projection is to the primary sensory and motor areas of the primate cortex and that the boundaries of the different thalamocortical projection fields are distinct and invariably with zones of cytoarchitectonic

coincide change.

with sharp cytoarchitectonic

boundaries

or

The geniculocortical projection to monkey striate cortex is arranged in two distinct bands within layer IV, one band of terminals is contributed by cells in the dorsal layers of the lateral geniculate nucleus, the other band of terminals arises from cells located in the ventral layers of the lateral geniculate injections of radioactive amino acids into single laminae

nucleus75v1t1,r45. Following of the cat lateral geniculate

nucleus,

tracing method

LeVay and Gilbertlo

used the autoradiographic

to show that

the geniculocortical projection in this species is also characterized by a laminar segregation in cortex of afferents from the dorsal and ventral sets of geniculate laminae. LeVay and Gilbert also observed a segregation of geniculocortical input in cat, as in monkey, on the basis of eye preference into patches about 500 pm wide. Additional cortical

afferents

active substances

information

on the laminar

has been provided injected

visual cortex. For instance,

and columnar

distribution

of geniculo-

by studies based on the findings6.17” that radio-

into the eye are carried this method

by transneuronal

was employed

by Drage?

transport

to the

to show that the

lateral geniculate nucleus in mouse projects, as in other species, to layers I, IV and VI of the primary visual cortex. In addition, injections of radioactive materials into one eye have been used to demonstrate ocular dominance columns in VI of cat’62 and macaque monkey”tO and in VII of cat162 and squirrel monkeysZ, but have failed to demonstrate ocular dominance columns in VI of New World monkeyssG*ls”, gray squirrellgg, tree shrew16370 and mouse37,j7. The transneuronal transport method has also been used to study the development of ocular dominance columns in both the cat106 and monkey76 in which it has been shown that the segregation of geniculocortical afferents by eye into discrete patches is preceded by a stage in which the geniculocortical afferents from both eyes are completely intermingled. Thus, during

286 development, columnar

the thalamic

distribution

physiological

afferents concerned

in layer

IV. This

with either eye present a uniform:

finding

is consistent

non-

with the results

of

investigations’

J(J,lO~which show layer IV cells in immature animals to be both more equally driven by both eyes than in the adult, and not clustered into groups

according

to eye preference.

The autoradiographic regarding

the terminal

tracing

distribution

method patterns

has thus provided of thalamocortical

this technique nor the anterograde tracing methods to identify the cells of origin of the thalamocortical these cells had to await the development horseradish peroxidase (HRP). 6. THE HRP RETROGRADE

The HRP method

TRANSPORT

precise

information

afferents,

but neither

which preceded it have been able projection. The identification of

of the retrograde

transport

method

using

METHOD

for the retrograde

labeling

of neuronal

cell bodies is based on

the uptake of HRP by axons and their terminals at an injection site and its subsequent intraneuronal transport to cell bodies in other regions of the braintot. Although several factors may adversely affect the retrograde transport of HRP (see refs. 80, 120 and 167) application of the method has confirmed the topographic nature of the thalamocortical projection to the primary sensory and motor regions of the neocortex in several species (e.g. in Al of catta3,ZtH, SI of cat*a,t‘tl, rata5JsO and monkey*o*p ia5,ao8. VI of rat77, opossum24, rabbits7, minkljg and rnonkey”l7>“20, and MI of monkeyu9, both

and has provided

non-specific

additional

and specific thalamic

evidence ls that layer I receives input from These and other studies using the

nuclei.

retrograde transport of HRP have provided new insight into the organization of thalamocortical projections by giving information on the number, size and threedimensional arrangements of thalamocortically projecting neurons. For example, Saporta and Krugert@J counted 3000-5000 HRP-filled neurons arranged in distinct curvilinear arrays in the rat ventrobasal (VB) complex for every square millimeter of SI cortex neurons

involved

with an HRP injection.

have also been observed

Clusters

of thalamocortically

in the cat VBsa, and columns

projecting

of retrogradeIy

cells extending through all layers of the lateral geniculate nucleus following injection of HRP into the striate cortex of this speciesli2.

labeled

have been noted Somogyi et a1.171

compared the shapes and sizes of HRP-filled thalamic neurons with those of neurons impregnated by the Golgi method and concluded that three different types of thalamocortical relay cells can be identified in the cat anteroventral thalamic nucleus. Hollander and Vanegas”” observed geniculate cells of all sizes projecting to cat area 17, but found mainly the larger cells projecting to area 18. This finding is consistent with the suggestionl7” that both fast and slow conducting geniculate cells project to area 17, whereas area 18 receives input from only fast conducting geniculate cells. More direct evidence on the collateral projections of single thalamic neurons has been obtained by a method using radioactively labeled HRP. In this method, HRP is injected into one area of the cortex and tritiated, but enzymatically inactive, HRP into another area of the cortex. Sections of the thalamus are first reacted for HRP, and then autoradio-

287 graphed to demonstrate the presence of tritiated HRP; thalamic neurons containing both labels are presumed to project to each of the cortical injection sites. Thus Geisert5” identified cells in the cat lateral geniculate nucleus which project to both areas 17 and 18, and Hayes and Rustiom ‘Q demonstrated cells in the cat VB which project to both SI and SII. These findings are consistent with the results of electrophysiological studies (e.g. ref. 113) which show single cells in cat thalamus to be antidromically invaded by stimulation of SI or SII. Recently, the retrograde HRP method has been combined with the anterograde autoradiographic tracing method to provide information on the reciprocity of thalamocortical and corticothalamic projections. This technique was introduced in 1975 by Colwel12a, who injected a mixture of tritiated amino acids and HRP into small regions of rabbit striate cortex. Colwell observed that regions of the lateral geniculate nucleus containing HRP-filled cells also contained high concentrations of radioactively labeled corticothalamic axon terminals. The combined anterograde-retrograde tracing technique has since been applied to study thalamocortical relations in the primate visuall*23186and somatosensory1°8 systems and in the mouse somatosensory systemzo5. In each instance, the strict topography of the thalamocortical projection has been correlated with the presence of an equally precise corticothalamic projection. Thus the long-held concept 195 that discrete regions of the thalamus are reciprocally connected with corresponding regions of the cortex has been confirmed. Finally, Ferster and LeVay45 took advantage of the anterograde transport of HRP to study the distribution of thalamocortical afferents to primary visual cortex. They injected HRP into the optic radiation of the cat, and related the laminar distribution of labeled axons in visual cortex with the distribution of geniculocortical afferents as shown by the autoradiographic method 104.They concluded that thalamocortical afferents which arborize in different layers of the visual cortex have different branching patterns and diameters. 7. THE 1DENTITY OF NEURONS

WHICH RECElVE INPUT FROM THE THALAMUS

The studies thus far discussed have provided basic information on the kinds and arrangements of thalamic neurons which project to the cortex, and on the area1 and laminar distribution in cortex of thalamocortical axon terminals. An important question left unanswered by these studies is the identity of those neurons in cortex which receive input directly from the thalamus. Since most sensory information ascending from the periphery enters the cerebral cortex only after having passed through the thalamus, the identity of the neurons which directly receive this input is crucial for understanding how the cortex receives and processes information from the periphery. Some clues to the identity of neurons which receive thalamocortical input have been obtained by light microscopic analyses of Golgi impregnated neurons from the cortices of sensory deprived animals or from animals which had sustained damage at some point along an ascending sensory pathway *. For example, layer IV stellate * In general, the eI%cts of deaflerentation(e.g. thalamic lesions, eye enucleations, etc. ; see refs. 189 and 190) are different and usually more severe than those caused by sensory deprivation (e.g. lidsuturing, dark-rearing, etc.; see refs. 18,31 and 60), and the effects of either on cortical physiology and anatomy are greater the younger the animal (e.g. refs. 33 and 59).

288 cells in the striate cortex than

do layer

rabbits,

of cats reared

IV stellate

animals’j.

Furthermore.

layer 1V stellate cells show a greater than usual variation

whereas the dendrites

of layer IV stellate cells in mice enucleated

away from layer IV to adjacent afferent axonal relations that

in the dark exhibit fewer and shorter dendrites

cells of control

layer

IV stellate

evidence to support

layers as if, as Valverdel”o

in dark-reared

in dendritrc

at birth are directed

suggested,

they are seeking

outside layer IV. These results may be interpreted cells receive

this hypothesis

input

directly

from

lengths”,

the thalamus.

as evidence Additional

is the finding that, in mice, the aggregation

of layer

IV stellate cells to form barrels does not occur when the related mystacial vibrissae and their follicles are removed prior to five days of age 192,203 . Related to this result is the finding

that damage

to a row of vibrissae

thalamic projection to the corresponding form of a relatively narrow, continuous

in newborn

rats and mice results in a

region of the barrel field which takes the strip filling the space occupied in normal

animals by discrete clusters of thalamic terminals associated with single barrelsgo. The concomitant disorganization of barrels, whose walls consist mainly of layer IL stellate cells, and of the thalamocortical projection to barrels, tends to support the conclusion that layer IV stellate cells are a major target of thalamocortical aRerents. Other reported effects of sensory deprivation and deafferentation on cortical neurons include alterations of the shapes and sizes of spines on the apical dendrites of layer V pyramidal

cellsL”,j5, apparent reductions in the numbers of these spinesd6,‘7y in the numbers and lengths of the basal dendrites of layer III

15J,15fi,157,and decreases pyramids’““.

In contrast, increases in the numbers and lengths of the terminal dendritic branches of layer II and III pyramidal cells have been correlated with ‘enriched’ environmental conditions 188. These results suggest that pyramidal cells of layers III and V directly receive thalamocortical input, but the interpretation of the results of sensory deprivation studies is complicated because the methods employed lacked the resolution to visualize synaptic contacts. Thus it cannot be excluded that transneuronal effects, rather than direct deafferentation observed changes in the morphology of cortical neurons.

were the Certainly,

bases for the transneuronal

effects seem to be involved in the observation 5~1that subsequent to eye enucleation in newborn rabbits, the numbers or spines along the middle portions of the apical dendrites of layer III pyramidal cells in striate cortex is reduced, for these dendrites occur in laminae

known to receive little or no direct thalamic

input. Clearly, to identify

the cortical neuronal types which receive input directly from the thalamus, it is necessary to use the resolving power of the electron microscope, for at present, only this instrument provides the opportunity to directly visualize synaptic connections. 8. ELECTRON

MICROSCOPIC

ELUCIDATION

OF THALAMOCORTKAL

SYNAPSES

In 1964, Colonnier”6 observed that lesioning axonal pathways afferent to the cerebral cortex induces characteristic degenerative changes in the fine structure of their axon terminals. These changes include the disruption of mitochondria and synaptic vesicles and a marked increase in the electron density of the affected terminals. The method of lesion-induced degeneration was subsequently employed by Jones78 who

289 examined lesions involving

thin

sections

of the thalamus. identified

of the somatosensory This study,

thalamocortical

which a similar approach

cortex

of cats which had undergone

which was the first demonstration axon terminals,

of synapses

was soon followed

was used to study thalamocortical

synapses.

by others in A significant

result of these studies is the observation that the dendrites and somata of non-spiny cells in the visual cortex of the rat’s”, cat27,50Jt~~ls and monkey51, in the somatosensory

cortex of the cats4985 and in the motor

synapse directly with thalamic axon terminals. these studies did not allow the three-dimensional and so the specific identity

of these non-spiny

cortex of the catlal

and monkey16g

However, the methods employed in forms of neurons to be determined, neurons

could

not be ascertained.

Moreover, in each region of the neocortex for which figures are available (see Table 3 in Peters and Feldmanles), between 70 and 91 7: of thalamocortical axon terminals synapse with dendritic spines, and for the most part it has not been possible to identify the cell type of origin of these spines. A notable exception to this is the description by Strick and Sterling1*L of thalamic synapses with two spines of a Betz cell in cat motor c cortex. One reason for the failure to determine the origin of dendritic spines is that the diameter of spine stems is often as small as 0.1 pm and thus, even with the use of serial thin sections, it is exceedingly difficult to connect most spines back to their parent dendrites. Further, even when these connections can be established, few criteria exist to identify the majority of dendritic profiles encountered in thin sections of the cortical neuropil. Peters and Feldman129 attempted to overcome this difficulty by comparing the shapes of spiny dendrites reconstructed from serial thin sections with the shapes of dendrites identified by light miscroscopic examination of Golgi impregnated neurons. Their observations suggested that some of the spines which synapse with thalamocortical axon terminals arise from spiny stellate cells, whereas others might arise from pyramidal cells. SloperLGg found degenerating thalamocortical axon terminals in monkey motor cortex to occur in clusters associated with pyramidal cell apical dendrites

and concluded

from this that pyramidal

cells are a principal

recipient

of thal-

amocortical synapses. However, no synapses were observed between thalamocortical axon terminals and spines of unequivocally identified pyramidal cell dendrites, and so in this instance also, it could not be determined with certainty if spines which synapsed with thalamocortical

axon terminals

arose from pyramidal

or spiny stellate cells or

from other neuronal types. The problem of identifying the cell type of origin of spines which are involved in thalamocortical synapses could be solved by the application of methods to This intracellular horseradish stimulation.

selectively label neurons in cortex which receive input from the thalamus. approach was taken by Christensen and Ebnerlg ‘who recorded the activity of single cells in opossum sensorimotor cortex and then injected peroxidase into those cells which responded at short latency to peripheral Their observations indicated that both pyramidal and non-pyramidal

cells of layer III receive input directly from the thalamus. There are, however, several problems which would preclude the wide application of this method to study thalamocortical synaptic connections. One of these is the difficulty with which small diameter neuronal bodies can be successfully impaled for recording and staining. Although, in time, technological developments might alleviate this difficulty, there

290 exists a more serious problem with the method which is unlikely to be solved by advances in technology. This problem is that every cortical neuron which might be involved in thalamocortical synapses most likely receives other input from many nonthalamic sources. Some of these non-thalamic inputs are undoubtedly inhibitory and so there is no guarantee that under all stimulus conditions thalamic input would be sufficient to cause detectable changes in the activity of the neurons which receive it. For example, Hellweg et al.65 recorded simultaneously from thalamic fibers and from their postsynaptic cells in the cortex, and found that the fiber discharge might precede the firing of the postsynaptic cell by as much as 5 msec. Another problem is to distinguish, on the basis of electrophysiological recordings alone, cells which are monosynaptically activated by thalamocortical afferents from those which are di- or polysynaptically activated. Still, the technique of intracellular recording and staining provides the unique opportunity to correlate the morphology of neurons (e.g. Kelly and Van Essenas) with their electrophysiological responses to specific stimuli. Further, it now seems feasible to combine the recording/staining method with techniques to label thalamocortical axon terminals and thus obtain valuable information on the distribution of thalamocortical synapses with neurons whose electrophysiology has been studied. The notion was expressed at the beginning of this review that neurobiological investigation had recently entered a new phase characterized by the blending of light and electron microscopic techniques. The necessity for combining light and electron microscopic methods grew out of the realization that neither method alone is sufficient to study the synaptic organization of complex neuronal systems. For exampie, although electron microscopy is capable of elucidating the fine details of the cytology of neurons and their synaptic relations, the technique is limited because only very thin sections can be examined with the electron microscope. Thus, the usual electron microscopic picture of the cortex (see Peters et al. tat) is one of large numbers of separate neuronal profiles which for the most part cannot be related to their cells of origin even by extensive reconstructions from serial thin sections. In contrast, much thicker sections of tissue can be examined with the light microscope and so by using appropriate staining procedures, such as the Golgi method, it is possible to view entire neurons and to distinguish neuronal types on the basis of their characteristic shapes. Combining the Golgi method with electron microscopy would enable individual neurons to be identified by light microscopy and to then be examined by electron

Fig. 5-7. The triptych composed of Figs. 5-7 shows in Fig. 5, a Golgi impregnated layer ill pyramidal cell from mouse SmI cortex. The same neuron, following katment with the gold-toning method of Fairen et al.d3, is shown in Fig. 6. Arrow in Fig. 6 indicates spine shown in inset between Figs. 5 and 6. Magnification of Figs. 5 and 6,850 x , scale, 10 pm. Fig. 7 is anelectron micrograph of a thin section through part of the cell body and apical dendrite (AD) of the layer III pyramidal cell shown in Figs. 5 and 6. Note the fine deposit of gold particles which labels the cell body and apical dendrite of this gold-toned neuron. x 6.500. Inset between Figs. 5 and 6 is a montage of electron micrographs of two adjacent thin sections showing the synapse of a degenerating thalamocortical axon terminal (TA) with the spine (S) indicated by the arrow in Fig. 6. x 50,000. Fig. 7 reprinted from Whites04 with permission of Wistar Press.

292 microscopy to assess their cytology and synaptic connections. This combined approach has been fohowed by a number of investigators since Stellr7a and Blacks&d* first introduced methods whereby Golgi impregnated neurons could be prepared for electron microscopy. The principal disadvantage of these early methods was that the Golgi deposit obscured the cytology of the impregnated neurons making it di%cult to assess their synaptic relations. Subsequent attempts” to overcome this difficulty by reducing the amount of the deposit within Golgi impregnated cells culminated in the

Fig. 8. Electron micrograph showing a synapse between a degenerating thalamocortical axon terminal (TA) and the spine (S) of a spiny stellate cell in layer IV of mouse SmI cortex. The parent dendrite (D) of this spine is also shown. x 60,000. Figure reproduced from Whiteao4 with permission of Wistar Press. Figs. 9 and 10. Electron micrographs of serial thin sections showing the synapse, in layer IV of mouse SmI cortex, of a degenerating thalamocortical axon terminal (TA) with a spine (S) of the apical dendrite of a layer VI pyramid. x 60,000. Figures provided by Steven M. Hersch.

* For a discussion of these methods, see ref. 43.

293 work of Fairen et al.j3. These investigators devised a technique whereby Golgi impregnated neurons in sections up to 200 pm thick are first examined by light microscopy, and then chemicaily treated to replace the dense Golgi precipitate with a deposit of fine gold particles. The neurons are still visible with the light microscope because of their content of gold (Figs. 5 and 6); in the electron microscope, the gold particles clearly label the cell body and processes of the ‘gold-toned’ neuron (Fig. 7). Furthermore, the gold particles are usually so distributed within the labeled neurons that their cytological details are not obscured and consequently, their synaptic relationships can be determined (Figs. 8-10). Combined with methods to label thalamocortical projections, the gold-toning technique has provided an excellent means to identify and to study the cytology of neurons in the cerebral cortex which are postsynaptic to thalaInocortica1 axon terminals. Indeed, soon after the development of the gold-toning method, Peters et al.134 combined it with lesion-induced degeneration and established without doubt

-I II

1

cl

-III /I IV V

VI -

Eff.

Th. Aff

Eff.

1

Fig. Il. Diagram showing the various cell types (P, pyramidal; NSS, non-spiny stellate; SS, spiny stellate; NSB, non-spiny bipolar cells) in mouse primary somatosensory204,20fis207 and in rat primary visuall3” cortex which are postsynaptic, in layer IV, to thalamocortical afferents (Th. Aff.). Pyramidal cells in layers V and V1 are represented by the single pyramid at the right of the diagram. Also included are the synaptic connections of non-spiny stellate cells as observed in rat visual cortex127JY2. Synaptic junction types are indicated as ‘a’, asymmeteri~l and ‘s’, symmetrical. Roman numerals at left indicate layers of cortex. Eff, efferent. Reprinted with slight modifications from Whitez~4 with permission of W&tar Press.

294 that spines involved stellate

in thalamocortical

cells. Subsequently,

thalamocortical

synapses

primary

visual

White”?

to study

somatosensory

cortex,

perikarya

and by White”“*,

White

synaptic

cortex. Their findings,

Thalamocortical spines of pyramidal

arise from both pyramidal and dendrites and

relations

Rockz””

directly

in layer IV of rat and by Hersch

in layer IV of mouse

and

primary

in Fig. I I ~ demonstrate

which are summarized

types synapse

and spiny

was used by Peters et al.i”‘;s to examine

with neuronal

thalamocortical

that a variety of neuronal

synapses

this approach

with thalamocortical

aRerents.

axon terminals in both mouse SmI and rat VI synapse with the cells whose somata occur in layers III and Vr”as”o1. layer VI

pyramids in mouse Sm167 are also involved in thalamocortical synapses; this cell type was not examined in rat VI. In agreement with earlier resultslzg, Peters et al. ~xJ report that some apical dendrites of layer V pyramidal cells in rat VI are not involved thalamocortical synapses, whereas in mouse SmI cortex”7,anl all apical dendrites

in of

layer V pyramidal cells possess some spines which receive thalamocortical synapses. These findings might signify a real difference in the organization of thalamocortical input to neurons in SmI or in VI. but more likely, the negative finding in rat VI ii; related to the fact that geniculocortical

afferents

to VI degenerate

course. Thus, at any time following lesions of the lateral ratt2s. cat or monkev”’ only 5 IO”;, of the axon terminals

over a v;iried time

geniculate nucleus in the in layer IV show signs of

degeneration, although it has been established by the autoradiographic tracing techniquetO that somewhat more than 20 ‘/,, of the axon terminals in layer IV of cat VI are derived from the thalamus. Tn contrast, thalamocortical axon terminals in mouse SmI degenerate nearly simultaneouslyAfl4, and so at any one postoperative :nterval, more than 20”,, of the axon terminals in layer IV are labeled by degeneration. The chances

of observing

thalamocortical

synapses

with particular

postsynaptic

elements,

e.g. the apical dendrites of layer V pyramids, would thus be much greater in mouse SmI than in rat VI. Further, for approximately equal lengths of dendrite, the apical dendrites of superficial layer V pyramidal cells in mouse SmI cortex make far fewer thalamocortical

synapses than do other dendrites

which receive thalamic

input”“.

existence of a similar situation in rat VI would further decrease the likelihood observing synapses between degenerating thalamocortical axon terminais and

The of the

apical dendrites of layer V pyramidal cells. Somogyilio, using the traditional Golgi-EM approach of Stelli73 and Blackstads, described thalamocortical synapses with the spines of two layer IV cells in rat primary visual cortex: one was a small pyramidal cell, the other either a pyramidal cell or a spiny stellate cell. In mouse Sml cortex, the spines of layer TV stellate 41s are also postsynaptic to thalamocortical axon terminals”“‘. Peters et a1.i”” observed thalamocortical synapses with the perikarya and dendrites of two sparsely spined stellate cells in rat VI; one was identified as a bitufted cell and the other as a multipolar stelllate cell. Similarly, in mouse SmI cortex, White204 observed thalamocortical synapses with the dendrites and perikarya of a bipolar cell of layer IVjV and with a multipolar stellate cell of layer IV. Both cells lacked spines; however, these cells were identified from serial thin sections of unimpregnated neurons, so it cannot be excluded that these ‘non-spiny’ stellate cells possessed a few spines which escaped detection.

295 The combination Golgi

impregnated

of lesion-induced

neurons

degeneration

which receive thalamocortical

input.

microscopy

to identify

Thus it has been shown

axons synapse in layer IV with pyramidal inclusive,

with electron

has been used to great advantage

of

neurons

that thalamocortical

cells whose somata occur in layers III to VI

with layer 1V spiny stellate cells and with several types of layer IV non-spiny

sparsely spined stellate cells. At this point, it seems worthwhile limitations

of the techniques

Golgi-EM

method

physiology conceivable

as applied

which

have

provided

to consider

this data.

in these studies can provide

input.

Furthermore,

although

example,

no information

of the impregnated neurons and, disconcerting that the Golgi method has selectively impregnated

thalamocortical

For

or

some of the about

the the

as it may be, it is neurons which receive

layer IV receives a massive projection

from the specific thalamic nuclei, some proportion of the degenerating synapses observed in this layer may be derived from non-specific thalamic nuclei whose projections

were damaged

by the lesion.

9. THEORETICAL IMPLlCATlONS OF WIDESPREAD SELECTION OF CORTICAL FUNCTIONAL UNITS

In view of the results presented conclude

that every cortical

of its input directly

neuron

THALAMIC

in the preceding with a dendrite

from the thalamus.

section,

INPUT:

THALAMIC

it seems reasonable

to

in layer IV receives some portion

We might then suppose

that thalamocortical

projections to layers I and VI also terminate on dendrites irrespective of their cell type of origin. If so, then neurons throughout the full thickness of the neocortex receive input directly from the thalamus. Presumably, a change in the rate of firing of a thalamic projection could then be detected by, and to some degree directly alter the activity of, every neuron in a specified region of cortex. Perhaps this widespread thalamic

input

might serve to facilitate

input by neurons common thalamic considered proposed

the principal

selection

and processing

of thalamic

which might not always act in concert, but which by virtue of input are selected out to form a functional unit. Whether this unit is

to be a local neuronal

not matter;

the transmission

processing

of selection

mechanism

sequence or a functional

by afferent

input

would allow each cortical

column1r7

does

would

apply to either. The

neuron,

which must receive

many different kinds of input and projects to various targets, to participate simultaneously or sequentially in more than one kind of functional unit. The relationship of a neuron

at any particular

time to a specific processing

would depend on such factors as the numbers and on the timing of synaptic events. 10. HIERARCHICAL

VS PARALLEL

sequence or functional

and locations

column

of the synapses it receives

PROCESSING

Hubel and Wiese171,7a proposed that the responses of different electrophysiologically defined cell types in cat and monkey visual cortex could best be explained by a hierarchical neuronal sequence whereby cells with simple receptive fields directly receive thalamic input and then project to cortical neurons which possess more complex receptive field properties. ‘Complex’ cells, which would represent a later stage

296 in the cortical

processing

of thalamic

with even more complex, this hierarchical cortical

input,

input,

i.e. hypercomplex,

model would predict but in view of recent appears

evidence

mentary

aspects

cortex.

Consistent

of visual

suggesting

activated

too simplistic.

classes of simple and complex

to cortical

cells of

Furthermore, in paraM

information

that complex

and hyper-

by the lateral geniculatej”.fis,‘6*,1s7.

cells which he believes

with this finding

to project

fields. A strict interpretation

that only simple cells directly receive thalamo-

complex cells are also monosynaptically this interpretation

are presumed receptive

Dow36 has described process different

within

is the conclusion

the separate

of Ferster

several

but complelayers of the

and LeVayls,

that

geniculocortical afferents carrying information along the ascending pathways from X and Y retinal ganglion cells” arborize in different sublaminae of layer IV in the cat visual cortex. Evidence

for the anatomical

and physiological

Y pathways at the level of the lateral geniculate nucleus catl”a and monkeyas~r”t. A third retino-geniculo-cortical a14,a15, has also been identified

and so it appears

segregation

of the X and

has been adduced for the pathway, termed Wr7”,

that there are at least three separate

pathways which convey different but presumably complementary aspects of information from the retina through the thalamus to the cortex. This implies that thalamocortical input is processed in parallel by different neurons in visual cortex a notion fully consistent with the revelation that many different kinds of cortical neurons receive input directly from the thalamus. But, as StoneIT” and later WhiteaO* observed, hierarchical conceivably

and parallel processing mechanisms are not mutually exclusive and the cortex uses both parallel and serial mechanisms to process input from

the thalamus. Consequently, cells in striate cortex which are known to receive either X or Y input16*, but not both, might be at the beginning of hierarchical processing sequences for their respective inputs. The degree to which these sequences interact in striate cortex or elsewhere has yet to be determined, but we must suppose that someplace the separate aspects of visual information are combined complete picture of visual space. Although parallel processing pathways

to produce a have not been

identified by electrophysiological studies of non-visual cortical areas, the anatomy of thalamocortical connections in somatosensory cortex suggests parallel processing mechanisms

might also occur in this region. The reader is referred to the discussion

Whiteaa” and to the excellent review by Henry66 for additional on parallel

vs hierarchical

1 I. A CONCEPT

processing

OF THALAMOCORTICAL

of thalamocortical

references

in

and thoughts

input.

RELATIONS

Thalamocortical relations have been the object of intense investigation for about a century, but it is only within the past few years that technological advances have enabled the identification of those cortical neurons which are directly involved in thalamocortical synapses. The realization that thalamic input is distributed to many different kinds of neurons compels us to consider the possibility that other pathways

* For descriptions and 177.

of the X and Y retino-geniculo-cortical

pathways, see especially refs. 23, 42, 175

297 afferent to the cortex also terminate notion

are the findings by Cipolloni

afferents

to rat auditory

whose somata

cortex synapse

types. In support

communication)

in layer III with spines

occur in layers II, III, IV and V. Furthermore,

the axons of non-spiny neuronal

on a variety of neuronal and Peters (personal

stellate cells in rat visual cortexla7

of pyramidal

been observed

to form symmetrical

synapses

cells

it has been shown that synapse

types and in one instance 132 the axon of a single non-spiny

with other non-spiny

of this

that callosal

with a variety

not only with a layer III pyramid

stellate cells, but with one of its own dendrites

of

stellate cell has and

as well. We might

thus consider the broader implication of Peters and Feldman’s128 prophetic suggestion that thalamocortical axons synapse with any element in layer IV capable of forming asymmetrical synapses, and surmise that other afferent and even intrinsic axons also synapse with any neuronal type within their terminal projection field (see ref. 126). While this apparent non-specificity of cortical wiring might be more explicable in developmental terms than would a system of rigidly specified interneuronal connections, the formation of synaptic connections in a non-specific fashion appears inconsistent function. At non-specific projections, Obviously

with our concept of the cerebral cortex as the seat of higher brain this point, it is useful to remember that cortical synaptic organization is only with respect to the identity of neurons postsynaptic to axonal but that these projections terminate within specific layers of the cortex.

then, the degree to which a neuron

is directly

influenced

by a particular

axonal projection would partly depend on the extent to which its dendrites occur within the terminal projection field, i.e. the specific layer(s) in which the projection terminates. Consequently, a neuron with its entire dendritic tree in layer IV would presumably be more greatly influenced by thalamic input to this layer than would a neuron which sends only a small proportion of its dendrites into layer IV. Additional factors capable of specifying synaptic connections are the type of synaptic junction formed by the axon and the types of synaptic junctions the postsynaptic element can form. Thus, for example, the cell bodies of pyramidal cells are apparently specified to form only symmetrical synapses and so they do not synapse with thalamocortical axons which form asymmetrical synapses. Finally, the density of synapses possible along prospective postsynaptic elements would limit the numbers of synapses formed. The following concept, which Alan Peters and 1 have developed, is an attempt to define thalamocortical relations in the context of what is known about the specificity and non-specificity of thalamocortical synaptic connections. A striking feature of the mammalian brain is the strict topographic organization of the so-called specific thalamocortical projections. The exact disposition of these thalamocortical axons must be rigidly specified during development to provide the precise topography found in the adult. We presume that ‘mechanical’ factors, such as the glial tubes described by Singer et al.lfifi, direct thalamocortical axons to their cortical destinations. Having reached their sites of termination, thalamocortical axons synapse with every available neuronal element capable of forming asymmetrical synapses, the numbers and locations of synapses being partly constrained by the density of synapses possible along postsynaptic elements and by the numbers of pre-existing synapses. We propose that the formation of synapses by other axonal projections to the cortex occurs in a similar fashion.

298

Fig. 12. A montage of light micrographs taken at 20 planes of focus through a gold-toned layer IV spiny stellate cell from mouse Sml cortex. This neuron was serial thin sectioned and reconstructed (SW Fig. 13). Magnification, 1000 x, scale, 10 /Lrn. Fig. 13. Reconstruction from serial thin sections (see ref. 206) of the layer IV spiny spellate ceil shown in Fig. 12. Arrow indicates spine shown in inset. Scale, IO/cm. Inset is an electron micrograph showing a degenerating thalamocortical axon terminal (TA) synapsing with the spine (S) indicated by the arrow. x 80,000.

300 12. QUESTIONS

TO BE ANSWERED

One of the largest gaps in our present knowledge of thalamocortical synaptic relations concerns the spatial arrangement of thalamocortical synapses on their postsynaptic elements. In an attempt to provide this information, Michael P. Rock and IeOs,rO7have reconstructed a Golgi impregnated/deimpregnated spiny stellate cell from layer IV of mouse SmI cortex in a preparation containing degenerating thalamocortical axon terminals (Figs. 12 and 13). Lesion-induced degeneration is generally considered unreliable for the quantification of thalamocortical axon terminals because in most systems (e.g. refs. 84, 8.5 and 128) these axon terminals degenerate over a varied time course such that some have been phagocytosed before others have begun to degenerate. This is not true of thalamic terminal degeneration in mouse SmI cortex where all affected terminals -- about 207; of the terminals in layer IV - degenerate simultaneouslys04. Consequently, lesion-induced degeneration may reliably indicate the numbers of thalamocortical synapses on the reconstructed spiny stellate cell. Results indicate thalamocortical synapses form about 10% of the synapses onto the spines of the reconstructed dendrites; no thalamic synapses are observed with the cell body or dendritic shafts. To assess the distribution patterns of thalamocortical synapses, measurements were made along dendrite shafts from the somatic origin of

*t D4-,

f i

,I+

l

tt

l

i

*

:

+

t

Fig. 14. Graphs showing the locations of thalamocortical synapses onto four reconstructed dendrites of a layer IV spiny stellate cell. The far left of each of the four lines labeled Dl through D4 represents the origin of each dendrite from the cell body. A 20,um segment of D2 is missing: the dendrite distal to this hiatus is represented beneath the right hand portion of the main part of D2. To conserve space, some dendritic branches are connected to their parent shafts by dashed lines. The intersection of the dashed line with the parent shaft marks the point of origin of the daughter branch. Thalamocortical synapses are indicated by stars, spine stems by dotted lines. Scale at the bottom right is 5 /km. Reprinted from White and Rock2Os with permission of Elsevier Publishing Co.

301

the dendrites

to the points

where the stems of spines involved

synapses join the dendritic

shaft. The assumption

are the sites where thalamocortical on straight

reconstructed

segment

dendritic

which are distributed

lines, each line representing

(Fig.

14). This analysis

revealed

over most regions of the dendritic

fashion along portions

thalamocortical

tree, to be arranged

in a regular,

periodic

of Dl and the distal part of D2 in Fig. 14. In these regions, thalamic

input

These

the total length of a

mid-portion

spines receiving

junctions

input to spines enters their parent dendrites.

points were then plotted synapses,

in thalamocortical

is that the stem-dendrite

of two of the reconstructed

dendrites:

the

the necks of

attach

to the dendritic shaft at regular intervals of between 4.5 and 5.5 pm. The suggestion was made 20s that this periodicity reflects the spacing of thalamocortical synapses which might form with the dendritic shafts prior to the time of spine formation. The rationale for this suggestion is the observation that only the loci where these spines whereas the spine heads are not of the dendritic tree depicted separated by intervals of about

connect to their parent dendrites are regularly spaced, separated by regular intervals. In several other regions in Fig. 14, two spines receiving thalamic input are 5 ,um. The 5 ,um intervals might result from the spacing

of thalamocortical receptor sites along postsynaptic membranes. An alternative explanation, consistent with the concept of thalamocortical relations described above, is that the formation of a thalamocortical synapse at one site might inhibit the formation

of thalamocortical

synapses

along the dendritic shaft. A further observationaOsJ07

by other axon terminals

within

is that spiny stellate cell spines involved

about

5 pm

in thalamo-

cortical synapses are not clustered in particular regions of the dendrites, but are interspersed with spines receiving synapses from other sources. It is not yet known whether non-thalamic inputs are regularly distributed along spiny stellate cell dendrites, nor whether thalamic inputs are regularly distributed along the dendrites of other types of cortical neurons which receive input from the thalamus. Moreover, the extent to which a single thalamic

fiber synapses with individual

dendrites

or single cells

has yet to be determined. Future reconstructions of neurons using similar techniques are expected to answer these questions, but as this account has shown, only the application of a wide variety of approaches can provide the information necessary to understand

how the cortex receives and processes its thalamic

input.

ACKNOWLEDGEMENTS

The author acknowledges with gratitude the patience and assistance of Rosalyn M. White during the preparation of this manuscript; I’am particularly grateful to Mrs. Mary D. Alba for her flawless typing and Mr. Rubin Appel for the cloth.

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