Intrinsic neocortical organization: Some comparative aspects

0306-4522/86 $3.00 + 0.00 Pergamon Press Ltd © 1986 IBRO

Neuroscience Vol. 18, No. 1, pp. 1 23, 1986 Printed in Great Britain

COMMENTARY INTRINSIC NEOCORTICAL ORGANIZATION: SOME COMPARATIVE ASPECTS F . VALVERDE

Laboratorio de Neuroanatomia Comparada, Instituto de Neurobiologia, "Santiago Ram6n y Cajal" C.S.I.C., Velfizquez 144, 28006-Madrid, Spain

CONTENTS The anatomy of cortical columns: facts in search of a definition Overview Physiological vs anatomical columns Intrinsic neocortical connectivity The diversity of spiny stellate cells Target non-specificityof corticothalamic fibers Pyramidal cells: the basic unit The exception to the rule: the primate visual cortex Phylogenetic approach Concluding remarks

THE ANATOMY OF CORTICAL COLUMNS: FACTS IN SEARCH OF A DEFINITION

Overview

During the last 20 years, the understanding of the cerebral cortex has been dominated by the concept of columnar organization. The term cortical column was first used to designate the intrinsic neuronal connectivity within a vertical cylinder or column of cortical tissue, which has a central axis formed by a specific thalamocortical afferent fiber. 8° For several years, this elementary unit was envisaged as a functional concept, rather than as an anatomical piece of work, because it explained earlier results obtained around the 1960s by neurophysiology in the somatosensory,97 auditory 162 and visuaP8 primary areas, namely that cells having similar functional properties appear to be arranged along the vertical axis of the cortex from pia to white matter. In the primary somatosensory98 and visual cortices, 5' functional columns are fundamentally defined in terms of receptive field properties, while in the primary auditory cortex they are interpreted in terms of best frequency responses.1 The demonstration with silver impregnation techniques of the existence of two independent and overlapping systems of bands in the striate cortex of

Address all correspondence to: Prof. F. Valverde, Instituto Cajal, C.S.I.C., Velfizquez 144, 28006-Madrid, Spain. Abbreviation: HRP, horseradish peroxidase.

the monkey, coincident with the system of ocular dominance bands,49 was the first anatomical evidence of an organization that could be correlated with physiological columns. The existence of comparable arrangements was subsequently demonstrated in almost every cortical area. Newly developed methods for the tracing of pathways, and the use of enzymatic reactions and radioactive tracers provided the evidence that the cerebral cortex, as far as the thalamic input is concerned, is organized into regularly spaced, periodic subdivisions readily attributable to the spatial distribution of afferent fibers in the somatosensory,69,t6°A6I auditory2'93'1°2and visual cortices 5'24'5° of various animal species, demonstrating that some of these thalamic distributions coincide with visible anatomical entities, such as the barrel field in the somatosensory cortex of rodents, 16"152'164and with the banding pattern of the ocular dominance system of the visual cortex in the monkey. 75 This pattern of orderly partitions is not unique in cortical primary sensory areas. There is now evidence that corticocortical (callosal and association) projections also branch into alternating vertically oriented patches segregated from the thalamocortical terminal r a m i f i c a t i o n s . 37,58,60~62,70,71,152,160,161,166

As it has been demonstrated after appropriate surface reconstructions, the cortical patches in fact represent, two-dimensional slices of larger threedimensional formations, called bands or slabs which, arranged like labyrinthic vertical walls, occupy the entire thickness of the c o r t e x . 39'49'52'54'62'66'72"74These bands are about 500 #m wide, this size being remarkably constant in subjects of different species. 75'16° These figures coincide with those obtained by neurophysiological data. An insight into the columnar organization of the cortex from a functional point of view has to deal with different states of activation and inhibition. Each cortical column or module is heavily connected vertically inside its own perimeter, but it is also connected horizontally with more or less distant columns, so that the input arriving at a column will be able to trigger different columns into a mosaic of excitation and inhibition, which one can imagine like twinkling stars in the dark night sky.

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degeneration, horseradish peroxidase (HRP) and autoradiography. A priori, the size of the anatomical cortical column may be determined by the volume of tissue encompassed by the arborization of one afferent fiber. However, it will soon be realized that this volume of tissue, not only includes a number of cells heavily interconnected vertically, but also in the horizontal direction. The tangential spread seems to have been obscured by highlighting the vertical connectivity of the neocortex, yet it is represented by a very significant number of collaterals of axons of cells located inside the domain of the cortical afferent. These horizontal fibers run mainly in layer I, the lower part of layer III, layer IV, the upper part of layer V, and layer VI, and this has been found to be a constant feature through the mammalian scale. They pass well beyond the limits of the volume of the afferent fiber arborization. The existence of horizontal fibers in the different layers is well known by all students of cortical Physiological vs anatomical columns connectivity. To summarize them briefly, in Golgi preparations, layer I contains the horizontal axons of In spite of such advances in the functional organization of the cerebral cortex, it has not been cells of this layer as well as the horizontal continuation of vertically ascending axons of cells possible to "dissect" a single cortical column, as a separate entity, to analyze its various components. located at different levels (Fig. 5C). An important First, any radial array of cortical neurons, which are contribution to layer I is made up by obliquely supposed to be the skeleton of a cortical column, ascending collaterals of axons of pyramidal cells of always interact with neighbouring columns in the layers II, III and IV turning horizontally after they tangential direction, i.e. perpendicular to the main enter layer I (e.g. Fig. 5A, a; Fig. 6, a, b, c; Fig. 7, input axis. Second, the Golgi method, the most a, 4f). The horizontal plexus of layer IV is clearly seen frequently used tool in the study of the shape and in the visual cortex of the cat and monkey, where it overall morphology of neurons, will never reveal in corresponds to the stria of Gennari (Figs 5B and 7). their proper sequence the pieces of a functional unit, A plexus of horizontal fibers was also found through the lower part of layer III in several of the temporal because it is essentially a random sampling procedure. Third, the cortical volume encompassed by a zones of the monkey (e.g. Fig. 6, 3f) where it may be thalamocortical set of afferent fibers, also contains considered as a homologue of the stria of Gennari. the elements of an output system, so that it would be The upper part of layer V and layer VI, notably in artificial to place any limit between input columns lower mammals (Fig. 4, 2u, 2w), contain many horiand output columns. In most primitive organizations, zontal collaterals of pyramidal cells of these layers the same targets for specific cortical afferents (some (Fig. 5C), as well as the collaterals of descending pyramidal cells in layer III] 17A41)act as likely output intracortical axons, some of which were followed components providing a monosynaptic throughput within this layer for long distances in the visual cortex of the monkey (Fig. 7, lb, lc, li). The horizontal pathway, 9'98 and there is nothing to prevent us from spread of these axons may be one order of magnitude thinking that the same occurs in most elaborate larger that the size of the physiological columns, a types of cortical organization. Fourth, and most fact that is difficult to reconcile with the idea of important, the concept of the cortical column is a functional interpretation derived from a number of isolated cortical units stacked side by side, unless the physiological experiments performed in anesthetized columns are considered pieces of larger processing units with extensive horizontal interactions with more animals and, although it is not clear whether or not anesthesia might alter receptive fields, 15~94it has been or less distant columns. The existence of horizontal inter-relations is now demonstrated that the boundaries of some physiological columns might be positionally dynamic,94 well known after recent studies carried out with intra- and extracellular injections of HRP 33'114'115and which favours the idea that other mechanisms in 2-deoxyglucose autoradiography. 47"76The visual coraddition to fixed wiring patterns, might play an tex of the cat and monkey has been a good model for important role in the delimitation of cortical colunderstanding such horizontal relations and thus, it umns. 97'98 From these considerations it is clear that functional columns, defined in terms of similarity of has been shown that axonal collaterals of pyramidal specific receptive properties of their units, may be cells running for long distances in the horizontal direction, not only may have specific orientation different from anatomical columns, defined by

The present commentary deals with those aspects of intracortical connectivity that traditionally served as the groundwork for understanding neocortical operation from a comparative point of view. It is based on a large number of observations made with the Golgi method in four different mammals: hedgehog, mouse, cat and monkey, with particular interest in the cortical afferent fibers and their presumptive target cells which form the basic structure in cortical columns. The commentary is based on several Golgi drawings selected from our material which we feel can best illustrate some special details. The drawings are self-explanatory, so that the lack of reference to particular cells only means that, in their present context, detailed explanations are unnecessary. Figures 4, 5, 6 and 7 represent general aspects of cortical organization in the hedgehog, cat and monkey. They were made at the same magnification to facilitate comparison.

Comparative neocortical organization patterns, but also their terminal ramifications form distinct clusters which have been related to the thalamocortical columns. 3°'33 In the striate area of the monkey, the pattern of clusters seen after extracellular HRP injections has also been correlated with the pattern of distribution of the enzyme cytochrome oxidase which appears distributed in a series of periodic patches occupying fixed positions, coincident with the patches of geniculocortical terminations in layer I I I . 47'53'76 The intrinsic connections demonstrated by extracellular HRP injections seem to reveal the existence of systems of neurons with horizontal collaterals arborizing at regularly spaced intervals, and although there are similarities of size and distribution, the relationships between both HRP and cytochrome oxidase patches have been controversial.T8'114 The definition that follows is due to Mountcastle:98 "a cortical column is a complex processing and distributing system that links a number of inputs to several outputs". For an anatomist it is not so simple to make a similar definition, for either each column can be considered formed by a single pyramidal cell capable of sampling data over a diversified range of inputs TM containing the attributes mentioned above, or, as defined by Lorente de N6, 8° it consists of all kinds of cells contacted by the cortical afferent fiber capable of carrying out the entire sequence of events from cortical input to cortical output. Using the Golgi method to study the columnar arrangement, the last definition imposes the study of the different neuronal elements and their intrinsic connectivity stained throughout the thickness of the cortex, in a volume of cortical tissue 500/~m wide comprising the terminal arborization of one cortical fiber. This point of view has serious drawbacks because either cortical afferent fibers stain rarely and only in young specimens, or, when they appear stained, they do so frequently in complete isolation. At present, only the barrel field in the somatosensory cortex of rodents presents ideal conditions for this approach because the dendritic morphology is so clear that, even in the case of the staining of a single cortical cell, it can be accurately located in relation to the barrels (Fig. 1A and B). In other brain areas, the staining with Golgi methods does not reveal particular morphological features that can be correlated with any columnar organization. However, recent work on dendritic morphology shows the existence of specific patterns of dendritic orientation in the auditory 34'92 and visuaP 58 cortical areas, suggesting that dendritic branching can actually be correlated with the columnar organization. It is important to mention that dendritic orientation is highly sensitive to a variety of experimental manipulations 6"7,4°'117A36A38so that it can be thought that certain dendritic (and axonal) patterns of orientation can be related to the functional organization of neocortical columns (but see Rakic and Goldman-Rakic, Ref. 112). The

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implementation of computer-aided techniques is essential to unravel such specific patterns. INTRINSIC N E O C O R T I C A L CONNECTIVITY

It is generally accepted that a cortical column can be seen as a radial array of neurons having an entrance gate: the cortical afferent fibers whether thalamic, callosal or associative. In primary sensory areas, the cortical afferent input is represented by a thalamocortical set of fibers ending mainly in the middle of the thickness of the cortex (layers III and IV). Traditionally it has also been accepted that in any cortical area, homo- and contralateral association fibers end in layers II and III, where the neurons giving origin to comparable axons leaving that area a r e located. 17"41'55'56"58'71'8°'99"144'15°A51 Cells in layers II and III project to layer V, which together with layer VI form the main output layers of the cortex projecting to subcortical centers (Fig. 5A, B and C). This schematic sequence of cortical processing has been obtained from the visual cortex of the cat, where the neuronal structure and intracortical connectivity underlying the receptive field organization have been extensively studied. 29"31"32"33'87 Cells in layer IV are considered to be the targets for specific thalamocortical fibers, thus their morphology and functional characterization have attracted considerable interest. Among stellate cells, several types named spiny stellate cells have been found with relative frequency in layer IV in a number of species and in various cortical areas such as the primary visual c o r t e x , l°'ll'23"73'81'96A°lA°8'139 auditory cortex 13t,157 and somatosensory cortex. 59,163'165 Since then, spiny stellate cells have been considered the de facto standard representation of the principal targets for thal a m i c a x o n s 32"83'98'133'134around which several models of cortical organization have been proposed. 18A9'133"135 Such a statement had never appealed to us very much, for the reasons given below. The reader interested in particular details concerning physiological aspects of intracortical connectivity, classes of cells and inhibitory interneurons (which will not be considered here) can refer to recent works (for reviews see Refs 29, 106 and 125).

The diversity of spiny stellate cells It is quite evident that spiny stellate cells do not constitute a uniform population. Not only are there strong differences in their dendritic and axonal morphology in various animal species (even considering the same cortical region) and in different cortical areas, but also their synaptic relations appear different. By a common agreement, spiny stellate cells have dendrites covered by spines at a frequency similar to that of the dendrites of most pyramidal cells. Their presence in the barrel field of rodents and in the visual cortices of the cat and monkey can be considered as three characteristic examples. In the zone of the

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,oo 0oO_oA_oo o o M 5 1 7 BA 7 Fig. 1. Spiny stellate cell in the barrel field of the somatosensory cortex of the mouse. This neuron was drawn from a transverse section and stored in digitized form. (A) is a stereopair of a perspective computer reconstruction after 90 ° rotation, showing the neuron as viewed from the surface of the brain. The Golgi section 200/~m in thickness containing this neuron was demounted, resectioned tangentially (perpendicular to its former transverse plane) and counterstained with neutral red. One section, shown in (B), passes through the body including several dendrites. Counterstained cell bodies delimit two barrels (b, b) showing that the Golgi stained neuron was located in the wall of the right-hand barrel with some of its dendrites penetrating inside the barrel hollow. Golgi-Kopsch method. Adult mouse.

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Fig. 2. Varieties of cells with spinous dendrites in layer IV of various mammals and cortical areas, reproduced at the same magnification. All, except (E), were assembled at the same relative position from the surface. (A) This shows one pyramid-like cell in regio postcentralis of the hedgehog. This cell has a moderately developed apical dendrite and long collateral dendrites richly covered by spines. The axon descends toward the white matter, leaving some horizontal collaterals running in layer V. Golgi method. Hedgehog 20 days old. (B) This illustrates one spiny stellate cell of the barrel field in the somatosensory cortex of the mouse. The cell has relatively short spinous dendrites and one axon descending toward the white matter with numerous obliquely-ascending collaterals. Golgi-Kopsch method. Adult mouse. (C) This depicts one stellate-pyramid or grain-pyramid of the visual cortex of the mouse. The cell has a thin apical dendrite tapering toward layer I, it has a stellate-shaped cell body with dendrites radiating in all directions, profusely covered with spines. The axon descends toward the white matter, leaving some horizontal collaterals through layer V with some ascending branches. Golgi method. Mouse 60 days old. (D) This shows an example of a typical spiny stellate cell found in the temporal cortex of the young kitten. This cell is probably at an immature stage of development, and will probably turn into a cell with sparsely-spinous dendrites in the adult form. The body has some spines, and the axon, originating at the upper pole, ascends to the first layer leaving some very long horizontal collaterals not represented in their full extent. Golgi method. Cat 23 days old. (E) This shows an example of the spiny stellate cell of sublayer IVc in the visual cortex, area 17, of the monkey. The cell has a small, rounded body with few, relatively short dendrites, covered by a moderate number of spines (compare with 2C). The axon, descending initially, turns shortly into three very long ascending collaterals reaching finally layer III. Golgi method. Adult Macaca rhesus.

Fig. 3. Transverse section through the stalk of the olfactory bulb (Bol) showing the anterior olfactory nucleus (Noa) in the hedgehog. This allocortical formation represents the most primitive cortical organization composed almost exclusively of two distinct layers. The superficial layer (Dtp) contains mainly the dendritic arborizations of "primitive" pyramidal cells located in the cellular layer (Lcb). The superficial layer also contains cells with a high degree of dendritic extraversion (f, h) as well as varieties of cells with smooth dendrites and local axons (b, c and g). This "nucleus" receives directly olfactory mitral axons from the olfactory tract (Tol) and sends off, through the lamina medullaris (Lm), close to the olfactory ventricle (Vo), its main efferent system into the anterior commissure and related forebrain structures. The figure is intended to compare the organization at a very simple level of cortical hierarchy with the most elaborate types of neocortical organization in the following figures. It is noteworthy that, intercalated between the afferent system (Tol) and the efferent pathway (Lm), some intrinsic cells begin to appear (e.g. cells b and g). This might represent the origin of the complex intrinsic circuitry found in more elaborate types of neocortical areas. Golgi method. Hedgehog 30 days old. In this and subsequent figures all cells were lettered, and their axons and collaterals were numbered consecutively addressed to the letter of its parent cell.

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Fig. 4. Transverse section through regio postcentralis of the neocortex in the hedgehog. In this animal the basic plan of neocortical organization can hardly be recognized. This type of cortex shows a thick layer I with a densely populated layer II containing large polymorphic cells with extremely spinous dendrites not very different from similar cells found in the paIeocortex. This exuberant number of dendrites penetrate the first layer where they receive an important afferent input. A granular layer (or layer IV), which is typical of most advanced mammals, can not be recognized. Layers V and VI are well developed. Pyramidal cells and varieties of intrinsic neurons with smooth dendrites abound in layer III IV at the level of termination of thalamocortical fibers. Golgi method. Hedgehog 30 days old.

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Fig. 5. Composite drawing made from several adjacent transverse sections through the visual cortex, area 17, of the cat. The overlay A shows four pyramidal cells (a through d) and one specific (presumed geniculocortical) afferent fiber (F). Pyramidal cells b and c might be in relation to thalamic afferents. They, like the pyramidal cell a in layer II, have axons with numerous obliquely-ascending collaterals providing connections, in the tangential direction, with dendrites and cell bodies of the first three cortical layers. The overlay B shows examples of sparsely-spinous (e and f) and spinous (g and h) stellate cells most commonly found in layers III and IV. Notice the varieties of axonal morphologies, all of them having branches entering the white matter. The background C displays the cortical lamination and three examples of cells with completely stained ascending axons (i, j and k). Cell i has smooth dendrites; cell ~ displays sparsely-spinous dendrites, while cell k is one pyramidal cell which does not project to the white matter, instead it has an axon turning into an elaborate system of horizontal and ascending collaterals. Notice that the main level of ramification of these three axonal complexes is in layers III and IV, leaving layer V relatively free from terminal endings. Golgi method. Cat 30 days old.

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Fig. 6. Composite drawing made from several adjacent transverse sections in the region of the superior temporal sulcus of the monkey. This type of cortex displays a dense granular layer IV containing several kinds of cells with smooth dendrites (j and k) and collateral axonal branches running vertically. Small pyramidal cells with strong recurving axons (1, m and n) also abound at this level. There is a broad layer III which can be further subdivided into IIIa and Illb according to the size of pyramidal cells. Larger pyramidal cells were more frequently found in the lower stratum. Chandelier cells (e) appeared frequently stained in this and in all neighbouring temporal areas. This observation may have some significance in the comparison of different areas. Chandelier cells were never observed in our material in blocks of area 17 in the same animal. Notice axonal collaterals running for very long distances in sublayer IIIb. Golgi method. Adult M a c a c a rhesus.

Fig. 7. Composite drawing made from several adjacent transverse sections in the visual cortex, area 17, of the monkey at the level of the superior lip of the internal calcarine sulcus. Layer IV in area 17 is extremely broad, appearing subdivided into three sublayers. In comparison with the neighbouring peristriate and temporal areas, layer III is relatively narrow, containing small to medium-sized pyramidal cells and diverse types of intrinsic cells. Two types of presumed extrinsic (cortical afferent) fibers were observed in this material. The fiber labeled 1 ascends vertically from the white matter and ramifies in sublayer IVc. The fiber labeled 2 is an example of thicker fibers, which follow tortuous, horizontal courses for long distances through sublayer IVc, developing localized plexi of beaded terminal fibers. Spiny stellate cells (j, k and 1) have recurving axons which ascend in small bundles (4) to develop complex terminal ramifications (5) in the lower part of layer III and in sublayer IVa. When viewed at lower magnification, the system of ascending bundles of the spiny stellate cells forms a series of parallel fascicles giving the most striking appearance of a columnar organization. The fiber labeled 3 at the right of the drawing, probably represents an example of another extrinsic axon ramifying in sublayer IVa. Horizontal fibers (2f, 3f) run for long distances through the stria of Gennari or sublayer IVb. Notice at the left of the drawing, giant Meynert cells (p) with relatively smooth dendrites in layer VI and the different levels of ramification of the terminal bouquets of apical dendrites of pyramidal cells of layers V and VI. Golgi method. Adult Macaca irus.

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Comparative neocortical organization somatosensory cortex of the mouse corresponding to the barrel field, several types of cells are present in layer IV. Among these, spiny stellate cells, first described by Lorente de N6 79 as "star cells" or "grains", are particularly abundant. 163 They have dendrites covered by numerous spines, they have no trace of an apical dendrite and their patterns of dendritic orientation depend on whether the cell body is located in the barrel wall (Fig. 1A and B) or in the barrel hollow (Fig. 2B). Recently it has been shown that cells in the barrel field are finely tuned to respond to movements of one single whisker or to the movements of more whiskers according to their position and dendritic orientationJ47,163It has also been demonstrated that degenerating thalamocortical terminals synapse on their dendritic spines, m.~54According to our observations in adult mice (Golgi-Kopsch), the axons of spiny stellate cells in the barrel field have numerous recurrent ascending collaterals distributed within the barrel or entering neighbouring barrels (Fig. 2B), some of which may ascend to layer I. The main axonal trunk always descends vertically to layer V, where it leaves some horizontal collaterals, and to layer VI, where it could not be followed further. In the cat's visual cortex, spiny stellate cells have been a matter of considerable interest since Kelly and Van Essen67 showed that some cells they recovered after identifying simple receptive field types were indeed spiny stellate cells as found in Golgi preparations. ~°'l~'2L73.86~96'~°L~°8 These cells receive direct geniculocortical fibers, 45 and have axons, specially those located at the 17/18 border, projecting to the contralateral hemisphere. 45,46,57,95,~2° That these cells do project to the white matter has been an old claim made by Cajal, H confirmed recently after HRP intracellular injections.31 They are large multipolar cells with several long dendrites richly covered by numerous dendritic spines and morphologically different from the spiny stellate cells of the barrel field. The most distinctive feature corresponds to the axon; it descends toward the white matter, but shortly after its origin at the lower pole of the cell body, it emits very long horizontal collaterals, which might run for distances of up to 1 mm, and several straight ascending collaterals, reaching the upper part of layer III (Fig. 5B, g, h). Intracellular HRP injections reveal that these horizontal collaterals end in a number of terminal arborizations having a patchy distribution87 and, although variations do exist, 86 this type of spiny stellate cell corresponds to the classical description of large stellate cells made by Cajal l°Al who considered them to be unique for the visual cortex. We have identified this type of cell, in addition to the cat's visual cortex, El in the primary auditory cortex of the same animal and in other parts of the temporal cortex (Fig. 2D). In the striate area of the monkey there are several varieties of spiny stellate cells (Figs 2E and 7; g-l). Among these, the spiny stellate cells with recurving axons are the most characteristic element found in

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sublayer IVc. The distribution of their axons varies according to their position in the layer81 but fundamentally they conform to a very specific type. 21,81'82,83,84,t39J42,143It has a small, round cell body with less spine density than pyramidal cell dendrites and has axons which do not leave the cortex but form several loops of ascending fibers ending in layers III and IVa (Fig. 7, 4, j, k, 1). Spiny stellate cells in sublayer IVc of the monkey's area striata are similar to Type 7 cells described by Jones 59 in the somatosensory cortex of the squirrel monkey. Both cells are in a position to receive direct thalamic input fibers 59'81'88'139'143 but should not be confused with the stellate cells of Cajal l°'H nor with the "grainpyramids" or "star-pyramids" of Lorente de No 79 (Fig. 2C). It has been our impression that Cajal included, under the eponym of large stellates, several varieties of stellate cells with spinous, sparsely spinous and smooth dendrites, attending more to the absence or presence of an apical branch, rather than relying on the number of dendritic spines. Large stellate cells with spinous dendrites, some of which may not have direct relation to thalamic afferents, can be identified in all temporo-parieto-occipital cortices of the cat, monkey and man in layers III and IV (IVa and IVb in the visual cortex of the monkey81'139). Cell f in Fig. 6 in the superior temporal sulcus of the macaque monkey is an example of such a type of cell showing a thick descending main axonal trunk (1 f), which most probably enters the white matter, and several horizontal collaterals (2f, 3f) running for very long distances. The "star-pyramids" described by Lorente de N6 79'8°are typical cells of the neocortex of the mouse and rat (Fig. 2C) to be found in layer IV o f the somatosensory and visual cortices. They receive direct thalamic afferents and differ from "star cells", apparently present only in the somatosensory cortex, because they have a thin ascending apical dendrite reaching unbranched layer I. In his study, Jones 59 borrowed the name "star-pyramids" for his Type 7 spiny cells with an ascending apical dendrite and recurving axons. The latter represent a variety of pyramidal cell with an intracortical axon commonly present in the upper part of layer V of the visual cortex of the monkey81'm and man 8 where they have no apparent relation to ttialamic afferents. They abound also in layer IV of the peristriate a r e a 1814° as well as in the temporal cortex of the monkey (Fig. 6, 1,m, n) where, as occurs in the somatosensory cortex of the monkey, 59 they may be related to thalamic afferents.

Target non-specificity of corticothalamic fibers The second point of argument against the exclusiveness of the spiny stellate cells as the principal targets for thalamic fibers comes from data obtained after combined approaches using the electron microscope to localize degenerating axon terminals: the use of the Golgi-electron microscope technique2° and the

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F. VALVERDE

use of retrograde labeling with horseradish peroxidase. After appropriate thalamic lesions, these techniques allow the reconstruction of only a limited part of individual neurons receiving degenerating synaptic contacts. The studies were carried out in various cortical motor and sensory areas and, although it has not been possible to fully categorize the identity of the target neurons, numerical values indicate that four out of every five degenerating terminals in layer IV synapse on dendritic spines 1°4'126of which only some have been positively identified as belonging to spiny stellate cells. 1°9'153'154The rest of the involved dendritic spines belong to collaterals of apical dendrites of pyramidal cells, 1°5'~°9to dendritic spines of apical dendrites, 13,44'1°7'127'156and to dendritic spines of basal dendrites of lower layer III pyramidal cells.131°7 The remaining degenerating axon terminals (about 15-20%) synapse upon dendrites and cell bodies of nonspiny n e u r o n s . 12'13'28'64'65'10a'127'132'155'159 The proportion of spiny stellate cells in any cortical area varies depending on the animal. For instance, in the somatic sensory cortex of the mouse, one half of the cells in layer IV have dendrites covered by spines. 163 As one half of these are "grain-pyramids" according to Lorente de N6, 79 it means that the remaining 25% of the total number of cells may be spiny stellate cells. We also obtain the same impression from our Golgi observations in this cortical area of the mouse. According to Feldman and Peters 23 the frequency of spiny stellate cells in the visual cortex of the rat (Golgi method) is 11% of all impregnated non-pyramidal cells; however, we consider °that most of their examples look more like "grain-pyramids" rather than true spiny stellate cells. We found similar "grain-pyramids" in the visual cortex of the mouse (Fig. 2C). In the visual cortex of the cat it has been mentioned that non-pyramidal cells account for 60-80% of cells in layer IV, 65'159 the spiny stellate cells being as common as the cells with smooth dendritesY However, although the relative frequency of spiny stellate cells in the visual and auditory cortices of the cat is difficult to assess, from the studies of other a u t h o r s 31'32'73'86'96'1°8A57 it is our impression that their number must not be so high, representing only a discrete fraction of the population of non-pyramidal neurons. In our own preparations they appear rarely stained (Fig. 5B, g, h). More frequently present are those stellate cells with smooth or sparsely-spinous dendrites (Fig. 5B, e, f) which probably account for the most significant population of non-pyramidal neurons. Due to their abundance it is probable that cells with smooth and sparsely-spinous dendrites (Fig. 4, g to k; Fig. 5B, e, f; Fig. 6, h to k) represent a significant population of target cells for thalamic axons. Spiny stellate cells have not been found in the visual cortex of the mouse, and, to this respect, an explanatory note must be added here concerning some of our earlier studies. 138In mice, we interpreted

some stellate cells located in the middle of the thickness of the cortex as stellate or granule cells with dendrites covered by numerous spines. When we later compared these cells with the spiny stellate cells of the visual cortex of the cat and monkey, we were convinced that the stellate cells of the mouse ought to be interpreted as cells with sparsely-spinous dendrites, similar to those described in the visual cortex of the rat. 1°3'~°7Spiny stellate cells are virtually absent in the rabbit's neocortexY Very occasionally, non-pyramidal spiny neurons have been observed in layers III and IV of the auditory cortex of the rabbit, 9~ where 87% of all impregnated neurons (Golgi-Cox) are pyramidal cells. 92We were unable to observe them in layer III/IV of the neocortex in the insectivore hedgehog. 141

Pyramidal cells: the basic unit These observations show that in the nonprimate brain the majority of dendritic spines receiving thalamocortical synapses belong to neurons other than spiny stellate cells, and that practically all involved dendritic spines belong to dendrites of pyramidal cells whose bodies lie in layers III, IV and V. 107'129'153'154The results agree with our earlier observations showing the existence of presumed synaptic contacts of cortical afferent fibers on dendritic spines of apical shafts of layer V pyramidal cells 146 and on the basal dendrites of layer III pyramidal cells in the visual cortex of the mouse. H7 At that time it was clear to us that both processes might occur in direct relation to thalamocortical afferents because they were most sensitive to visual sensory deprivation, 117'137 as was later confirmed in other studies. 25'36"H8 As mentioned above, thalamocortical synapses also involved identified non-pyramidal elements. Geniculocortical afferents contact the bodies and dendritic spines of sparsely spinous and smooth dendrites of varieties of intrinsic cells in the visual cortex of the rat 1°4'1°7 and to several types of nonspiny stellate cells in the visual cortex of the cat. 13 Since practically all synapses identified from thalamic terminals are of the symmetric (presumed excitatory) type or Gray Type-I 1°4'1°7'126 it led Peters and his colleagues 1°4'I°7 to arrive at the Solomonic decision that all neurons and dendrites capable of forming asymmetric synapses can receive thalamic input. Clearly an understanding of the precise synaptology of the thalamocortical system is still awaiting more detailed analysis. The cortex appears not to be hardwired for specific elements, but it seems to have retained along evolution the capability to adapt or modify neuronal types in whatever is most convenient for its specific function. In lower mammals, practically all elements in the neocortex are pyramidal cells, so that the number of apical dendrites and their collaterals as well as the basal dendrites of pyramidal cells occupying the neuropil at the level of termination of thalamocortical afferents must be extremely high.

Comparative neocortical organization Figure 4 corresponds to regio postcentralis of the hedgehog, an insectivore considered to be a primitive representative of placental mammals. H6'~22'~4~'145 In this animal, layer Ill/IV is occupied by all ascending apical dendrites of pyramidal cells of layers V and VI (Fig. 4, u,v, w), by pyramidal cells located in the middle thickness of the cortex (a, b, c), and by descending dendrites of polymorphic cells of layer II (1 to t), all of them presumably capable of receiving thalamic input. 38'68 Large multipolar cells with smooth, beaded or finely dentated dendrites (d to k) are not infrequent at this level; they have largely stereotyped, ascending axons (li, l j) with numerous collaterals extending horizontally for long distances, some of them were followed for more than 1 mm horizontally. The exception to the rule: the primate visual cortex

The visual cortex of the monkey, and particularly the striate area or area 17, has been intensively studied during the last 15 years since the demonstration of the systems of ocular dominance and orientation columns. 49'5° More recently, a new dimension has been added with the discovery of a pattern of repeating units in the superficial layers revealed by cytochrome oxidase staining. 42'47'77'78There are hints indicating that the visual cortex of the monkey may be unique in its anatomical and histochemical organization. Some of its cellular components have not been found in the visual cortices of other species and, taking into account that the striate cortex of the monkey occupies about 20% of the total brain surface area ~48~49vs 1.5% in man, 3 this uniqueness seems to be more real than apparent. Evidently, extrastriatal visual and association cortices of the temporal and parietal lobes increased by one order of magnitude in the human brain, but in the monkey the large development of the striate area might reflect its essentially arboreal habitat requiring the most direct performance of highly coordinated movements and good colour vision (but see Polyak, Ref. 110, Chap. XIV). Although in terms of relative proportion, the visual cortex of the hedgehog, too, occupies about 20% of the surface of the neocortex, ~45 it is in the visual cortex of the monkey where an orderly and visible pattern of columnar organization is most evident in Golgi preparations (Fig. 7). In the monkey, geniculostriate fibers have a topographically-organized termination in sublayers IVa and IVc 43'5° with sparse contributions to layers VI and 14,43`50 and recent studies also report the existence of a direct geniculocortical projection to a series of discrete patches in layer III. 26'76Variations in their terminal fields, depending on the particular geniculate laminae from which they originate, are well known. 5'43'5° Extrinsic axons, suggested to be thalamocortical fibers ramifying in layer IV, have been described in Golgi preparations, 21'8~'~39'~42'~43and also after HRP labeling of single afferent fibers. 5 In our material these extrinsic fibers ramify in sub-

17

layer IVc (Fig. 7, fibers 1 and 2) and in IVa (Fig. 7, fiber 3). In the adult monkey, the extrinsic fibers develop in sublayer IVc; one of the densest plexus observed in any cortical area. This sublayer concentrates a population of spiny stellate cells which accounts for nearly 95% of the total population of neurons present in this level.88 From data obtained by O'Kusky and Colonnier 1°° the entire layer IV contains, in Maeaca, almost one-half of the total number of cells of area 17, of which the thalamo-recipient sublayers IVa and IVc represent one-third. The morphology of these cells (Fig. 2E; Fig. 7, j, k, 1) and their synaptic relations have been the subject of several

studies.81,82,83,88,89,90,119,139,143

As mentioned before, spiny stellate cells have strong recurving axons, which grouped in vertical bundles of ascending fibers, end by giving off numerous terminal branches, in the lower part of layer III and in IVa. These terminal fibers form elongated or spherical plexi (Fig. 7, 5) presumably related with the basal dendrites of pyramidal cells like d and e. This pattern of connectivity differs from that found in other mammals. In the monkey, the output of sublayer IVc is almost exclusively made to layer III, bypassing the system of horizontal fibers of IVb and unlike other mammals including the cat, the spiny stellate cells have axons which do not project to the white matter. In the primate brain the ascending bundles of spiny axons emphasize the existence of a visible columnar organization, difficult to recognize in other subjects. The ascending bundles connect with pyramidal cells in layer III in a strictly vertical direction, so that individual areas of thalamic input appear repeated in the supragranular layers in matching overlays. Tangential Golgi sections through layer III reveal the existence of rows of regularly-spaced rounded axonal plexi measuring about 200/~m in diameter, corresponding to the terminal ramifications of these ascending bundles of spiny stellate cells.143 We suggest that they might be related to the particular arrangement of the regularly spaced patches of cytochrome oxidase activity observed in tangential sections through layers II and III, as well as to the pattern of connectivities between areas 17 and 18.42'47'77 We were also interested in the comparison of area 17 with area 18 of the monkey 14° and with other areas of the temporal lobe. Spiny stellate cells are apparently absent from layer IV in area 18, 8~,~4°instead this layer contains small pyramidal cells with recurrent axons similar to those found in the upper part of layer V of the visual cortex. Their axons form strong recurrent arcades ascending to sublayer IIIb in area 18, apparently devoted to contacting large pyramidal cells located there. In the cortex of the superior temporal sulcus (Fig. 6) we found identical small pyramidal cells (1, m and n) with recurving axons (11, lm and In) ascending to layer III. Both layers III and IV also contain small stellate cells with smooth,

F. VALVERDE

18

beaded dendrites (j and k) with ascending axonal branches (lj and lk), as well as varieties of large multipolar and bipolar cells (h and i), particularly abundant in this, and in neighbouring auditory areas. Chandelier cells 14'22'128'13°with either ascending (Fig. 6, e) or descending axons have been found abundantly in layers III and IV, and, in agreement with Lund e t al. 85 their presence may be related to the predominance, in the layers where they occur, of large numbers of pyramidal cells whose initial axon segments are the targets for chandelier axon terminals. The evidence that in certain cortical areas, with well developed granular layer IV, the thalamic afferents are not distributed in this layer, points to a different organization of its intrinsic circuitry. For instance, in several of the temporal and parietal fields, thalamic terminals are reportedly distributed chiefly in layer III. 6~ In this case (e.g. the cortex of the superior temporal sulcus, Fig. 6) it seems that the targets for thalamic fibers are represented by those cells with smooth dendrites mentioned above, and by typical pyramidal cells (e.g. Fig. 6, g) with little participation of the small pyramidal cells, seemingly concentrated below the main level of thalamic termination.

PHYLOGENETIC A P P R O A C H

In the study of the varieties and forms of cells with spinous dendrites (pyramidal and non-pyramidal) one gets the impression that all of them share a common phylogenetic origin, and that a continuum may be traced from lower forms to the primate brain. The idea is not new since it has been put forward several times since the classical comparative neuroanatomy, s° to recent times. 113'122'123A similar but less restricted point of view has been recently expressed in relation to spiny stellate cells.83 We believe that such continuity can be retraced in the mammalian brain from the primitive olfactory cortex. In the hedgehog, layer II of paleocortex (olfactory cortex) contains large ("primitive pyramidal") cells having ovoid or triangular (pyramidal) bodies with two opposite bunches of dendrites, richly endowed with spines. The ascending (pialward) dendritic bunch arborizes profusely in layer I where it receives a strong zonal (olfactory) input. Such a type of dendritic polarization represents a stage of phylogenetic development fully expressed in the amphibian level with the most accentuated dendritic extraversion and the absence of basal dendrites. Cells with these morphological features are still present in the nucleus olfactorius anterior of the hedgehog (Fig. 3, f, h). The descending bunch of basal dendrites of paleocortical cells appear to represent a later acquisition related to increased commissural, associative and localized circuits developed below the first cellular layer or layer II.

The neocortex of the hedgehog contains in layer II similar cells to such paleocortical cells (Fig. 4, 1 to t) which, in Nissl preparations, stand out composing the "accentuated layer II". TM Among them, it is not infrequent to observe the existence of other cells with one or more long dendrites standing out from the remaining dendrites, aimed at the pial surface as an incipient apical dendrite. Several examples of these "quasi-pyramidal" cells have been reproduced in some of our own previous publications, 141,~45so that a gradation, including a complete series of intermediate forms between the most extraverted neurons to fully developed pyramidal cells, can always be found in the neocortex of the hedgehog. At a later stage in phylogenetic development, some pyramidal cells have completely lost their apical terminal bouquets in layer I (which no longer retains its primacy as the source of cortical input), retaining but a thin apical dendrite tapering at some distance from the cell body, while others maintain well developed apical bouquets in different layers below layer I. In the first case the shape of the cell body turns stellate in form. It represents the stellate-pyramids or grain-pyramids, seemingly concentrating its remaining perisomal dendrites to receive localized input within a restricted space or volume (e.g. Figs 1A,B; 2C). This seems to be, in general, the case of the pyramidal cells of the barrel field in the somatosensory cortex of rodents and in the granular layer IV and upper part of layer V in various cortical areas of the primate brain. By removing the remnant of their thin apical dendrite these cells turned into typical spiny stellate cells in sublayer IVc of the visual cortex of the monkey. In the second case, the apical bouquet ramifies in one or in several layers above the cell body as in the visual cortex of the monkey, where various pyramidal cells in layers V and VI develop their terminal bouquets in layers III, IVa and IVb (Fig. 7, n, o) or even in layer V (Fig. 7, q). This pattern of apical terminal bouquets in different layers seems to be most frequent in the primate brain, appearing to serve for collecting information from specific layers. TM These stages of pyramidal cell differentiation also involve variations in their axonal patterns. In the neocortex of the hedgehog, pyramidal cells residing in layers III-IV (presumed recipients of thalamocortical fibers, Fig. 4, a, b, c) have thick descending axons (la, lb, lc) which can be followed to the white matter. They have axonal collaterals predominantly running in a horizontal plane through the middle of the thickness of the cortex. Rarely do they emit obliquely ascending collaterals, and if they do so, the recurrence is not very pronounced. In this type of pyramidal cell the degree of collateral axonal recurrence appears more accentuated in rodents (Fig. 2C) and it seems to have attained its extreme degree in the primate brain up to the point that the main axonal trunk no longer descends to the white matter (Figs 2E; 7, j, k, 1).

Comparative neocortical organization CONCLUDING REMARKS

The existence of a basic plan of neocortical organization is demonstrable throughout the mammalian scale: layers III and IV appear to be the major recipients of cortical afferents, from here impulses are relayed mainly to layers II and III, layer III is the source of long and short association fibers and intrinsic descending connections with layers V and VI which contain a majority of cells projecting subcortically and a number of intrinsic cells with ascending axons. This suggests that the neocortex is functionally uniform at a rather fundamental level of organization. However, the study of the varieties of cells and the mode they intervene in intrinsic wiring patterns in different animals, clearly shows the existence of important variations, some of which may be unique for a given species. We have commented on the differences existing in certain varieties of cells with recurving axons seemingly unique for the primate brain, the existence of stellate pyramids peculiar of the neocortex of the rodent, varieties of spiny stellate cells with axons projecting to the white matter in the visual cortex of the cat, and certain pyramidal cells in the neocortex of the hedgehog which have no counterpart in other subjects. With the exception of the visual cortex of the monkey we also have suggested that spiny stellate cells are by no means a

19

c o m m o n target for the thalamocortical fibers, nor do they form a single class of neurons. The comparison in different species points out that certain pyramidal cells and portions of their dendrites, may be more directly related to cortical afferents. It is also concluded that, even though modern tracing techniques have emphasized that the major cortical afferent systems appear broken up in multiple column-like patches with remarkable constancy through the mammalian scale, the intrinsic circuitry of cortical columns may be quite different. This suggests that the stage of neocortical organization attained in higher mammals might have been accomplished not by replication of a basic module already present in lower mammals, as it has been sustained elsewhere, 98'11~ but by reshaping the dendritic and axonal arbors of various categories of cortical cells, resulting in different patterns of intracortical connectivity. The differences can be minimal in closely related species, but they are substantial when the comparison is made between distant subjects such as the insectivore and the primate. Acknowledgements--This investigation has been supported

by research grant 1329/82 from Comisi6n Asesora de Investigacibn Cientifica y T&nica (CAICYT) and project no. 177 from Consejo Superior de Investigaciones Cientificas (CSIC).

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