Download a review with emphasis on the projections of specific thalamic nuclei

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.<layers of
the monkey lateral geniculate nucleus receives input from only one eye, a lesion in a
single geniculate layer would cause the degeneration
of thalamocortical
afferents carrying information
from a single eye. Thus they lesioned single layers of the monkey
lateral geniculate nucleus, and using the Fink-Heimer
method, subsequently
stained
the degeneration
products of this ‘monocular’ thalamocortical
projection. As predicted, the appropriate
ocular dominance columns appeared, in layer IV, as discrete 250500 /cm wide patches of terminal degeneration.
More recently, LeVay et aLLo used a
reduced silver stain for normal fibers to demonstrate the pattern of ocular dominance
columns in monkey visual cortex. Their results indicate that, in general, the pattern of
* 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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APPENDIX
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4
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in the rabbit. II. Cytoarchitectoni: structure
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I6 Walker, A. E. The thalamic projection to the central gyri in Macaclrs rlpesrrs, 1. corny, Nerrrol., 60
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17 Walker, A. E., An experimental study of the thalamocortical projection of the macaque monkey.
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APPENDIX
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Casseday, J. H., Diamond, I. T. and Harting, J. K., Auditory pathways to the cortex in Tupaiaglis,
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Ebner, F. F., AtTerent connections to neocortex in the opossum (Didelphis virginiana), J. camp.
Neural., 129 (1967) 241-268.
Glendenning, K. K., Kofron, E. A. and Diamond, I. T., Laminar organization of projections of
the lateral geniculate nucleus to the striate cortex in Galago, Brain Research, 105 (1976) 538-546.
Glickstein, M., King, R. A., Miller, J. and Berkley, M., Cortical projections from the dorsal
lateral geniculate nucleus of cats, J. romp. Neural., 130 (1967) 55-76.
Gould, H. J., 111. Hall, W. C. and Ebner, F. F., Connections of the visual cortex in hedgehog
(f~rruechinu.r hypomelus). I. Thalamocortical projections, J. conlp. Neural., 177 11978) 445-472.
Hall, W. C., Visual pathways from the thalamus to the telencephalon in the turle (fse&er,7J,s
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Anat. Rec., 166 (1970)3 13.
Harting, J. K., Diamond, I. T. and Hall, W. C., Anterograde degeneration study of the projections of the lateral geniculate and pulvinar nuclei in the tree shrew (Tupaia g/is), J. con7p. Neural.,
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