The Pyramidal Cell and Its Local-Circuit Internemom: a Hypothetical Unit of the Mammalian Cerebral Cortex

The Pyramidal Cell and its Local-Circuit Internemom: A Hypothetical Unit of the Mammalian Cerebral Cortex

Miguel Marin-Padilla Department of Pathology Dartmouth Medical School Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021

Abstract A pyramidal cell with five of its local-circuit interneurons model infers that the number of pyramidal cells contacted by (Cajal-Retzius, Martinotti, Cajal double-bouquet, basket, and each Idcircuit interneuron as well as the nunzk of synaptic chandelier cells), constitutes a distinct structural/functional as- contacts established with each one are elements acquired post- semblage of the mammalian neocortex. This pyramiWld- natally in response to individual needs. Thereby, the overall circuit neuronal assemblage is proposed herein as a basic three-dimensional distribution and extent of these pyramidal/ neocortical unit. This unit is shared by all mammals, embodies local-circuit neuronal assemblages should be species-specific, both specific structural as well as functional elements, and variable among individual of the same species, and able to constitutes an essential developmental building block of the adapt in response to environmental needs. The model intro- neocortex. In the model, the pyramidal cell represents a dis- duces a different approach, perhaps a new vantage point, for tinct, stable, projective, excitatory neuron that has remained the study of the basic structural organization of the mammalian essentially unchanged in the course of mammalian phylogeny. cerebral cortex. Relationships of the proposed model to cortical On the other hand, its localcircuit interneurons are more likely function in general and to learning behavior in particular are to be inhibitory and less stable, designed perhaps to adapt, and discussed. modify in response to environmental needs. The proposed

INTRODUCTION comprehending the common basic cytoarchitecture of There are fundamental similarities as well as dissimilar- the mammalian neocortex. ities in the structural organization of the cerebral cortex The pyramidal cell represents the projective neuron (neocortex) among mammals. The establishment of a of the unit and the local-circuit interneurons are the common structural/functional unit may facilitate a com- intracortical modulators of its functional activity. Each parative study of the basic neocortical cytoarchitecture. interneuron establishes a specific type of synaptic con- Hypothetically, a pyramidal cell together with five of its tacts with a different compartment of the pyramidal cell. local-circuit interneurons (Cajal-Retzius, Martinotti, Cajal The pyramidal cell represents a relatively stable neuron double-bouquet, basket, and chandelier cells) is pro- that has remained essentially unchanged in the course posed as a fundamental building block of the mammalian of mammalian phylogeny. On the other hand, the inter- neocortex. This pyramidaVlocal-circuit neuronal assem- neurons are less stable cells that change or adapt in blage is shared by all mammals, and embodies specific response to environmental demands. structural as well as functional elements. Hence it con- The structural and functional interrelationships among stitutes a structuralhnctional neocortical unit. It is fur- the various components of this hypothetical neocortical ther proposed that the cytoarchitectural plan of the unit will be analyzed and described in this article. The mammalian neocortex is based on the sequential devel- development of some of its components (e.g., the pyra- opment of these units at various cortical levels. Cortical midal cell) will also be analyzed. The relevance of this units of this type may be found at layers V, IV, 111, and I1 unit to neocortical structural organization in general, and throughout the entire neocortex. It must be emphasized to neuronal plasticity and learning in particular, will be that the proposed unit is but a hypothetical one out of discussed. Statements such as “We have no explanation many other possible units. It has been selected because why the histology of the cerebral cortex is what it is” it is structurally simple, universal, and may be useful in (Braitenberg 1978), and “we have yet to achieve a uni-

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MATEIUb.L AND METHOD To describe and define this pyramidalllocal-circuit neuronal unit, Golgi preparations of the human cerebral cortex from the author’s collection have been used (see Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021 Journal‘s cover page). The collection has been gathered over many years and is comprised of autopsy material from the cerebral cortex of premature fetuses (26, 28, 30, 32, 36, and 38 weeks old), newborns, and young children (2, 4, and 8 months old). Prematurity, respira- tory distress syndrome, bronchopulmonary dysplasia, cerebral hemorrhages, and congenital malformations were among the causes of these infants demise. The collection is made up of thousands of 100- to 150-~m- thick rapid Golgi preparations ranging in staining quality Erom excellent to poor. The Golgi method permits limited but accurate glimpses of the nervous structure. It is possible, with time and perseverance, to study within such preparations the location, morphology, composition, and spatial interrelationships of entire neuronal assemblages. Neurons, as well as fibers, from many well-stained areas can be extracted from these preparations and reproduced in camera lucida drawings. Drawings from many such views can then be assembled into large mosaics that are useful for the study and reproduction of the basic cytoarchitecture of any CNS region (Fig. 1). This unique feature has not been surpassed and is undoubtedly the main reason for the uninterrupted use of this old, classic method (Golgi 1873). Figure 1. Mosaic reconstruction of camera lucida drawings, from rapid Golgi preparations (see Journal‘s cover), illustrating the struc- ~ralorganization of the motor cortex of a newborn child and its fundamental neuronal types. The pial surface is at the top of the figure, and at the bottom there are few polymorphous neurons of layer Wb. The various sizes and locations of pyramidal cells and of THE PYRAMIDA.L/LOCAL-CIRCIJIT localcircuit interneurons (Cajal-Retzius, Martinotti, double-tufted, NEURONAL UNIT basket cells) of the motor cortex as well as their spatial interrelation- Although the model of hypothetical neocortical unit ships (neuronal assemblages) are illustrated at the Same magnilica- this tion to facilitate tkir comparative analysis. Layers I, 11 (a,b), III utilizes neurons of the human cerebral cortex, its basic (a,b,c), N,V, and VI as well as remnants of the still undifferentiated structural and functional features should be applicable cortical plate (CP) are also illustrated. Scale=100 pm. to all mammals. The structure, intracortical distribution, and organization of each of its neuronal components will Mammalian Pyramidal Neuron be described separately. Particular attention will be paid The to the special type of synaptic contacts established be- The pyramidal cell, the most distinctive neuron of the tween each local-circuit interneuron and a different com- mammalian neocortex, is.characterized by unique department of the pyramidal cell as well as to their spatial velopmental, structural, and functional features (Cajal interrelationships. The role of this unit as a develop- 1911; Lorente de N6 1949; Marin-Padilla 1970a, 1971, mental building block of the basic cytoarchitecture of 1972, 1978, 1988; Marin-Padilla and Marin-Padilla 1982; the mammalian neocortex will be emphasized. A three- Feldman 1984). Pyramidal cells are distributed through- dimensional reconstruction of the proposed neocortical out the entire neocortex and represent -70-80% of all unit illustrating its overall structural organization and the its neurons. According to their size and cortical depth, intracortical interrelationships among its various com- four types of pyramidal cells are generally recognized: ponents is reproduced in Figure 2. giant cells of layer V, large cells of layers V and lower

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Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1990.2.3.180 by guest on 25 September 2021 Figure 2. Stereo pair of camera lucida drawings illustrating the structural organization and the various components and their interrelationships of the pyramidaVlocal-circuit neocortical unit proposed herein. Each pair illustrates the stable giant motor pyramidal cell (layer V) of the unit and five of its associated local-circuit interneu-

Tons, including a Cajal-Retzius Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021 cell (C-R) of layer I, a Cajal double-bouquet cell (D) of layer 111, a Martinotti cell (M) of layer V, a basket cell (B) of layer V, and a chandelier cell (C) of layer V. The entire unit represents a basic neuronal assemblage characteristic of the mammalian neocortex. For the purpose of improving its stereoscopic view, the following pyramidal neurons (stable cells of other units) have been added to the mosaic: another giant pyramidal cell of layer V, a large one of layer 1111, a medium one of layer 1113, and a small one of layer III. In addi- tion, the bodies of pyramidal cells from layers 111 (1, 2, 3) and I1 (1, 2) are reproduced MOTOR CORTEX ‘NEWBORN ~NFANT schematically.

111, medium cells of upper layer 111, and small cells of mordial plexiform layer (PPL). Its appearance separates layer 11. Regardless of size, location, or cortical depth, the neuronal and fibrillar elements of the PPL into su- mammalianpyramidal cells are distinguished by an ap- perficial (future layer I) and deep (future layer VII or ical Mrite (occasionally CWO) that invariably is per- subplate zone) components. The functional activity of pendicular to the pial su#zce and terminates within these two primitive layers (I and VII) starts early in layer I,forming a dxaracterktic Mritic bouquet (Figs. development and precedes the functional maturation of 1, 2, and 3). The intrinsic cortical milieu of each type of the CP (Marin-Padilla 1971, 1972,1978, 1988; MCCOMell pyramidal cell is unique and is essentially similar in all et al. 1989). Although the development of the PPL follows mammals. It should be emphasized that any neocortical an “outside-in”gradient, the mammalian CP follows an neuron that does not share these features is neither “inside-out’’one (Bayer and Altman 1990). structurally nor functionally a pyramidal cell. The so- The “inside-out” developmental gradient of the CP is called “inverted pyramidal neuron” (frequently en- an evolutionary innovation that explains the unique counted in the 1iteratu;e) may indeed be a type of cortical structural and functional features of the mammalian py- neuron, but neither developmentally, structurally, posi- ramidal cell. Embryonic neuroblasts (future pyramidal tionally, nor functionally could it represent a pyramidal neurons) migrate from the ependymal surface toward cell in the strict sense. Hence the use of such terms is the PPL. They are attracted to the PPL and, guided by the misleading. radial glia, start to accumulate within it (Marin-Padilla The pyramidal cell represents‘a mammalian innovation 1971, 1978, 1988; Rakic 1982; Luskin and Shatz 1985; in cortical evolution and its unique development is es- Bayer and Alunan 1990). The subsequent establishment sential to an understanding of the basic cytoarchitecture of layer I progressively transforms most migratory neu- of the neocortex (Marin-Padilla 197Oa, b, 1971, 1972, roblasts into pyramidal cells. Migratory neuroblasts that 1978; Bayer and Altman 1990). During development, the reach layer I grow a terminal dendritic bouquet that pyramidal cell is the essential component of the cortical branches within it as well as an apical dendrite (Berry plate (CP). The CP is formed within a more primitive, and Rogers 1965; Morest 1970; Marin-Padilla 1972, 1984, premammalian-like,cortical organization named the pri- 1988; Marin-Padilla and Marin-Padilla 1982; Feldman and

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Figure 3. Schematic representation of the prenatal development (from week 11 to 40 of gestation) of a layer V giant pyramidal cell of the human motor cortex illustrating the persistence of its original connection with layer I, the progressive upward elongation of its apical dendrite, and hence its obligatory perpendicular orientation to the pial surface of the cerebral cortex. The bodies of developing pyramidal neurons of the cortical plate are schematically reproduced. The pyramidal cells functional maturation follows an “inside-out”progression. Both the phyloge- netic and ontogenetic evolutions of this stable mammalian neocortical neuron are comparable.

Peters 1974; Konig et al. 1975; Raedler et al. 1980; Lar- rather never loses its original connection with it (Marin- roche 1981). These young pyramidal neurons are forced Padilla and Marin-Padilla 1982; Marin-Padilla 1988). This to progressively elongate their apical dendrite upward unique developmental strategy explains why the apical as new migrating neuroblasts bypass them in order to dendrite of all pyramidal cells, regardless of cortical lo- reach layer I and to become, themselves, pyramidal neu- cation or depth, is always perpendicular to the pial sur- rons (Fig. 3). This process is repeated throughout the face, a fact never before explained satisfactorily (Figs. 1, formation of the cortical plate so that the pyramidal 2, and 3). Furthermore, if a cortical neuron loses its neurons formed earliest have the longest apical dendrites connection with layer I, it can no longer be considered and occupy the lowest cortical regions (Figs. 2 and 3). to represent a pyramidal cell or to function like one. The The mammalian pyramidal cells, early in their devel- prenatal development of neither the nonpyramidal cells opment, become anchored to layer I by their apical (neurons without a characteristic dendritic termination dendrite and remain attached to it throughout its sub- in layer I) nor the localcircuit interneurons has been sequent development and functional maturation (Fig. 3). studied adequately. Therefore, a pyramidal cell does not grow an apical By this evolutionary strategy, pyramidal cells are com- dendrite toward layer I as is generally assumed, but parable and essentially identical type of neurons in the

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Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1990.2.3.180 by guest on 25 September 2021 neocortex of all mammals. Their body and basal den- cently, it has been postulated that a common basal tone drites may be located at different cortical depths (layers is transmitted by the Cajal-Retzius (C-R) cell to the den- VI, V, 111, or 11), but their apical dendrite should always dritic bouquet of all pyramidal cells regardless of their be anchored to layer I and oriented perpendicular to the size, location, or functional role (Marin-Padilla and pial surface. The only difference among them is in the Marin-Padilla 1982, Marin-Padilla 1984, 1988). The C-R length of their apical dendrites, a fact that reflects their cell is the only recognizable neuron in layer I at the time. functional competence and proficiency. In mammalian Primitive corticipetal fibers from mesencephalic centers phylogeny, each group (layers V, IV, 111, and 11) of pyra- (possibly from the reticular activating system) are the midal cells has progressively elongated the apical den- first to reach the embryonic cerebral cortex. Their arrival drites to accommodate an increasing number of inputs initiates the development of the neocortex, establishes Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021 (Cajal 1911). Although the apical dendrite of a hamster’s the PPL, and induces the d8erentiation of C-R cells that layer V pyramidal neuron measures -700 p+m and has represent their main target (Marin-Padilla 1988; Muller between 400 and 500 postsynaptic spines, that of a com- and O’Rahilly 1988, 1989). parable human cell measures -2500 p+m in length and On the other hand, the pyramidal cell’s apical dendritic has between 2000 and 2200 spines (Marin-Padilla, 1967; trunk will eventually receive inputs from all subsequent Marin-Padilla et al. 1969; Marin-Padilla and Stibitz 1968, afferent fibers reaching the neocortex. A layer V human 1974; Feldman 1984). Consequently, the number of axo- pyramidal cell, without losing its attachment to layer I, spinodendritic inputs received by the apical dendrite of elongates its apical dendrite, progressively and upwardly, a layer V human pyramidal cell may be up to five times from about the eighth week of gestation to the time of larger than that of a comparable hamster cell. birth and postnatally for several years (Fig. 3). At first, One could speculate that as the muscular, skeletal, and the upward elongation is passive and caused by the ar- articular components of a mammalian front paw or a rival of new migrating neuroblasts during the formation primate arm have remained essentially unchanged in the of the CP. Later in development, the apical dendrites course of phylogeny, the neurons controlling their func- continue to elongate upwardly as part of this cell’s function (e.g., layer V motor pyramidal cell) should have also tional maturation, which starts around the fifteenth week remained essentially unchanged. Increasing motor dex- of gestation with the appearance of postsynaptic apical terity reflects the capability of pyramidal neurons to pro- dendritic spines (Marin-Padilla 197Oa, 1988). Thereafter, gressively increase their main receptive surface (e.g., the formation of new postsynaptic spines follows an “in- length of their apical dendrite) to accommodate an inside-out’’ gradient as different systems of corticipetal fi- creasing number of inputs. A mammalian pyramidal cell, bers progressively invade higher levels within the by elongating its apical dendrite without changing its developing cortical plate. essential structure and cortical milieu (e.g., cortical depth Eventually, the spines (postsynaptic structures) dong and anchorage to layer I), may be capable of responding the apical dendrite of layer V pyramidal cells are distrib- to environmental pressures for the development of new uted in a characteristic‘manner, which is similar in all motor skills and/or specializations. Between two cortical mammals (Fig. 4), a feature that further supports the levels (layer I and either layer V, IV, 111, or 11) a motor structural and functional similarities among all mammal- pyramidal cell receives, in all mammals, essentially the ian pyramidal cells. The universal type of spine distri- same kind of inputs. In my opinion, this unique capability bution curve has been interpreted in various ways. One best defines the nature of the mammalian pyramidal cell hypothesis is that it reflects the superposition of at least and characterizes its essential structure. This unique py- five different populations of axospinodendritic synapses ramidal cell capability (enlargement of receptive surface (Marin-Padilla and Stibitz 1968; Marh-Padilla et al. 1969; without changing cortical milieu) represents a significant Feldman 1984). As different systems of afferent fibers mammalian innovation in cortical evolution. enter into the developing CP following an “inside-out” The pyramidal cell’s apical dendrite has two distinct gradient, they will target the pyramidal cell’s apical den- compartments: the terminal dendritic bouquet that in- drite at different levels. Afferent fibers (e.g., nonspecific variably branches within layer I, and the dendritic trunk thalamic) reaching layer V will primarily aim at estab- that crosses various cortical levels perpendicularly. Dis- lishing synaptic contacts with the apical dendritic seg- tinct developmental, structural, and functional features ment crossing that cortical level. Subsequently, afferent characterize these two compartments. The first inputs fibers reaching layers lV (specific thalamic), I11 (inter- reaching a pyramidal cell are those it receives through hemispheric or callosal), and I1 (corticocortical) will tar- its terminal dendritic bouquet at the start of its devel- get their corresponding apical dendritic segment (Fig. opment when the apical dendrite is still immature and 4). Consequently, in all mammals, layer V pyramidal cells quite short (Fig. 3). ’The same kind of primitive input receive inputs from subcortical, interhemispheric, and reaches all pyramidal cells of the neocortex. This input other intrahemispheric cortical sources that reach their is retained throughout the entire development of the particular cortical region. This extrinsic information (as neocortex and persists throughout the animal life. Re- well as the essential sensory inputs reaching the CNS)

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Figure 4. Schematic representation of the spines distribution curve (post synaptic structures) along the apical dendrite of the giant pyramidal cell (layer V) of the human cerebral cortex. The curve (microscopic counts) tabulates the number of spines in consecutive segments, 50 pm in length, of the apical dendrite from its origin at the cell body to its end within layer I. The curve also reflects the number of spines in the apical dendrite as it crosses through layers V, lV, III,II, and I. It has been proposed that this type of spine curve could represent the summation of five Merent and overlapping populations of spines, each one representing synaptic contacts made with a difFerent system of afferent fibers. Merent fibers reaching different cortical levels (e.g., layers V, N,111, 11, or I) will preferentially establish synaptic contacts with the apical dendritic segment crossing that particular level. A computer model using five different populations reproduces a nearly identical type of spine curve (computer calculation curve) as well as the appropriate location for each of the proposed populations (V, lV, 111, I1 and I), which coincide with their corresponding cortical levels. Similar types of spine distribution curves have been reported along the apical dendrite of large pyramidal neurons in many mammalian species studied. (From Marin-F’adilla et al. 1969.) has remained essentially unchanged in the course of neocortex (Figs. 2C-R and 5C-R). It plays an essential role mammalian phylogeny, and constitutes the basic inputs in the development of the pyramidal cell and conse- for the pyramidal cell’s functional activity. quently in the architectural organization of the mam- Later on, as the cortex matures and becomes more malian neocortex. By the time of birth, the C-R cell of differentiated, pyramidal cells also receive inputs from the human cerebral cortex is a large solitary multipolar many intrinsic intracortical sources. Important sources neuron with dendrites, axonic collaterals, and a terminal of intrinsic inputs are the local-circuit interneurons as- axon distributed within separate planes parallel (hori- sociated with the pyramidal cell. In general terms, these zontal) to the pial surface (Marin-Padilla and Marin-Pad- interneurons act as modulators of the basic extrinsic illa 1982; Marin-Padilla, 1970a, 1972, 1978, 1984, 1988, information received by the pyramidal cell. Five local- 1990). The actual number of C-R cells is established very circuit interneurons, structurally and functionally asso- early in neocortical development and prior to the ap- ciated with pyramidal cells, have been selected as essen- pearance of the CP. In the human brain the number of tial components of the proposed neocortical unit. They C-R cells is established at stage 18, -l&day-old embryos are the Cajal-Retzius, the Martinotti, the Cajal double- (Marin-Padilla 1983). Hence, these neurons undergo a bouquet, the basket, and the chandelier cells. considerable developmental dilution and it may be quite difficult to locate them in the adult brain. That difficulty has prompted some investigators to postulate their post- Cajal-Retzius Local-Ckuit Interneuron The natal disappearance. However, C-R cells are invariably The Cajal-Retzius (C-R) cell is the fundamental neuron found throughout the cerebral cortex if a sufficient num- of layer I, and the first neuron to differentiate in the ber of sections is studied (Marin-Padilla 1984, 1990).

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Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1990.2.3.180 by guest on 25 September 2021 The functional target of C-R cells is the dendritic bou- This primitive input is crucial for both the structural quet of all pyramidal cells regardless of their location, development and the functional maturation of the mam- depth, or functional role (Figs. 2C-R and 5C-R). By the malian pyramidal cell (Marin-Padilla and Marin-Padilla time of birth, a C-R cell of the human cerebral cortex 1982). This universal kind of input may provide a com- has both proximal and distal functional territories. The mon basal tone that transforms neuroblasts into neurons proximal territory is established by its axonic collaterals and eventually prepares them equally throughout the and the distal one by its terminal axon. The dendritic neocortex to perform any of their many different func- bouquet of all pyramidal cells within an area of -500,000 tional tasks. p,mz may be contacted by the radiating axonic collaterals Concerning our hypothetical unit, pyramidal cells

of a single C-R cell. Pyramidal cells located within a throughout the neocortex are spatially segregated into Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021 narrow and long (up to several mm) area may be con- specific functional territories, each one determined by tacted by the terminal axon of the C-R cell (Marin-Padilla the axonal arborization of a single C-R cell. The activity 1990). Both proximal and distal functional territories of of each pyramidaVloca1-circuitunit must be conceived as different C-R cells overlap. The functional significance of part of a much larger functional organization represented the spatial orientation and distribution of the C-R cell’s by the many interrelated units contacted by the same C- functional territories remains unexplained. R cell. A C-R cell might be conceived as the functional The type of synaptic contacts between the C-R cell’s activator of the pyramidal/local-circuit units throughout axonic terminals and the dendritic bouquets of pyramidal the neocortex. The C-R cell, by estabIishing specific con- cells remain unknown. The numerous ascending and tacts with a compartment (terminal dendritic bouquet) descending terminals that characterize this cell’s axon of the pyramidal cell, modulates its functional activity, and its collaterals must be involved in these contacts. and hence it constitutes an essential component of the Axospinodendritic and axodendritic contacts between proposed neocortical unit (Fig. 2). the ascending and descending axonic terminals of C-R cells and the dendritic bouquets of pyramidal cells are The Martinoffl Local-Circuit Interneuron often observed in good rapid Golgi preparations (Fig. 5). Further investigations will be needed before this im- The Martinotti local-circuit interneuron is distinguished portant functional problem is resolved. by its long ascending axon and by its distinctive termi- The nature of the primitive input transmitted by the nation within layer I (Martinotti 1889; Koelliker 1896; C-R cell to the dendritic bouquet of pyramidal cells also Cajal 1911; Marin-Padilla 1970a, 1971, 1984; SzentAgothai remains unknown. This primitive input is spread 1975, 1978; Peters and Saint-Marie 1984; Fairkn et al. throughout the entire surface of the cerebral cortex by 1984). It is one of the earlier interneurons to differentiate the C-R cells reaching all pyramidal cells regardless of in cortical development. According to their size and cort- their location, cortical depth, or eventual functional role. ical depth, various types of Martinotti cells are recog-

Figure 5. Camera lucida drawing of a Cajal-Retzius (C- R) interneuron illustrating its large body, the proximal segments of its long horizontal dendrites, the descending segment of its axon (a) with several fine horizontal collaterals and its terminal horizontal axon. The drawing represents a vertical parasagittal view of a segment layer I of the motor Cortex of a newborn child. In Golgi preparations, the characteristic ascending and descending fibrils of this cell’s axonic collaterals and terminal axon seem to make contact with spines of the terminal dendritic bouquet of pyramidal cells (P). The pial surface (pial) of the cerebral cortex is at the top of the figure.

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Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1990.2.3.180 by guest on 25 September 2021 nized, including large cells of layer V, medium cells of 15 for larger ones. The entire axonal distribution of a layer 111, and small cells of layer I1 (Figs. 1 and 2M). single double-bouquet interneuron covers a relatively Developmentally and structurally, they are closely asso- narrow vertical columnal territory (Cajal 1911; Fair& et ciated with the pyramidal cells of their cortical level. al. 1984). Golgi impregnation of isolated double-bouquet They are double-tufted cells with ascending and descend- interneuron often demonstrates the presence of vertical ing dendrites and a long ascending axon. Its ascending apparently empty spaces between contiguous axonal axon has short, spine-like projections and ends within branches. These spaces are occupied by the apical den- layer I in a characteristic manner (Figs. 1 and 2M). As it drites of unstained pyramidal cells. The number of these approaches layer I, the axon divides into several fanlike spaces ranges from 6 to 10 depending of the cell’s size. branches that enter obliquely into this layer paralleling The functional targets of the double-bouquet interneu- Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021 the arborizations of the pyramidal cell’s dendritic bou- ron are the apical dendritic trunks of a group of 6 to 9 quet (Fig. 2M). In Golgi preparations, the axonic termi- contiguous pyramidal cells. In this respect, it should be nals of Martinotti cells follow quite closely the dendritic pointed out that layer V pyramidal cells are often seg- bouquet of pyramidal cells mimicking each other’s ter- regated into distinct clusters composed of 3 to 9 neurons minal arbors (Figs. 1 and 2M). The striking structuril (Feldman 1975, 1984). This feature is common to many similarities between these two elements strongly suggest mammals including primates, and has been considered functional interrelationships between the two neurons to represent specific finctional territories (Feldman (Cajal 1911; Marin-Padilla 1970a, 1988). 1975,1984;Feldman and Peters 1974). Each one of these The Martinotti cell’s axonic terminals have short spine- pyramidal cell’s clusters may be determined by a single like projections that are considered to represent this double-bouquet local-circuit interneuron. Each interneu- neuron’s presynaptic elements. They establish axoden- ron will establish synaptic contacts preferentially with dritic symmetrical contacts with the dendritic shaft. A the pyramidal cells of a different cluster. Hence, from possible inhibitory role has been suggested for this local- the point of view of a Cajal double-bouquet interneuron circuit interneuron‘(Somogyi et al. 1981, 1982; Fairen et the pyramidal cells throughout the neocortex will appear al. 1984; Marin-Padilla 1984). From the point of view of to be spatially segregated or clustered into small groups a single Martinotti cell the pyramidal cells throughout composed of 3 to 9 cells. From the perspective of this the neocortex will appear to be spatially segregated or interneuron the functional activity of each pyramidall clustered into small groups, each one determined by a local-circuit unit will be correlated with that of the other different interneuron. A Martinotti local-circuit interneu- units of the same cluster. ron acts as a modulator, possibly through inhibition, of Double-bouquet interneurons have been shown to es- only those inputs reaching the terminal dendritic bou- tablish both asymmetric and symmetric synaptic contacts quet of its associated pyramidal cells. As a modulator of with the apical dendrite of a group of contiguous pyra- a specific functional compartment of the pyramidal cell, midal cells. Recent investigations have suggested that the Martinotti interneuron also constitutes an essential, these interneurons may also be inhibitory in nature possibly inhibitory, component of the proposed neo- (Somogyi et al. 1981, 1982; Somogyi and Cowey 1984; cortical unit. Fairen et al. 1984). Accordingly, the double-bouquet interneuron modulates only those inputs reaching the apical dendritic trunk of a group of contiguous pyramidal The Cajal Double-Bouquet Local-Circuit cells. a modulator of a specific functional compart- Interneuron As ment of the pyramidal cell, this interneuron also consti- The Cajal double-bouquet interneuron is also distin- tutes an essential, possibly inhibitory, component of the guished by the special distribution of its axon (Cajall911; proposed cortical unit. Lorente de N6 1949; Marin-Padilla 1970a, 1971, 1984, 1988; Fairen et al. 1984; Peters and Saint-Marie 1984). The Basket Local-Circuit Interneuron These local-circuit interneurons are also recognized very early in neocortical development and are numerous The association of the pericellular nest formed around throughout the neocortex. They are found at all cortical the pyramidal cell’s body, originally described by Cajal levels and various types are recognized by their size and (1911), to a distinct local-circuit interneuron was not cortical depth. They include large cells of layers V-IV, established until 1969 by Marin-Padilla (Figs. 1, 2B, and medium cells of layer 111, and small cells of layer I1 (Figs. 6A). This type of local-circuit interneuron originally de- 1 and 2D). They are double-tufted cells with long as- scribed in the human cerebral cortex has been subse- cending and descending dendrites that have short spine-’ quently demonstrated in the cerebral cortex of many like projections and a distinctive axonal arborization. mammals including primates (Jones and Hendry 1984). The axon of these interneurons divides profusely into Basket interneurons are also found at all coitical levels. a cascade of long vertical ascending and descending ter- According to size and cortical depth, various types are minals (Fig. 2M). The number of these vertical axonal also recognized, including giant cells of layers VI-V, large terminals ranges from 6 to 8 for smaller cells to 12 to cells of layers IV-111, medium cells of layer 111, and small

Marin-Padilka 187

Figure 6. Photomicrographs (A,B) of rapid Golgi preparations of the motor cortex of a newborn chdd. (A) The spatial interrelationships of a pyramidal cell (p), a basket cell (b), and a chandelier cell (c). Their cortical location is between layers IV and V. The relative sizes of the Merent rectangular functional territories of the basket (b) and the chandelier (c) interneurons are outlined. Stable pyramidal cells within each of these functional territories may be contacted either by axosomatic (basket cell) or by axoaxonic (chandelier cell) inhibitory synapses. (B) A chandelier local-circuit interneuron of the human motor cortex is reproduced herein at a higher magnification illustrating its characteristic structural features. The short recurving dendrites, the axonic terminals or “candles,”and the relatively small size of this type of specialid local- circuit interneuron are illustrated. Scale = 50 pm.

cells of layer I1 (Marln-Padilla 1969, 1970b, 1974, 1975; with the pyramidal cell’s body. A single basket cell’s axon Marin-Padilla and Stibitz 1974; Szenthgothai 1975, 1978; establishes axosomatic contacts with pyramidal cells Jones and Hendry 1984). They are multipolar stellate within a narrow vertical territory which could range from interneurons,with ascending, descending, and transverse 500,000 pm2 for the small cells of layer 11 to ~,OOO,OOO dendrites, distinguished by their axonal arborization. pm2 for the giant cells of layer V. Their ascending or descending axon branches into sev- The most important functional aspect of this local- eral long horizontal collaterals from which the terminal circuit interneuron is its spatial intracortical distribution fibrils forming the pericellular basket originate. Each (Fig. 7). The cell’s dendritic and axonal arborizations are basket cell participates in the formation of many baskets distributed within a narrow rectangular space that is at various levels, and each pericellular basket is formed vertical to the pial surface and perpendicular to the long by the axonic terminals of several basket cells. Basket axis of the cortical gyrus. From the persp6ctive of basket cells are spatially oriented inhibitory interneurons that interneurons, the pyramidal cells throughout the neo- establish (GABAergic) axosomatic symmetrical synapses cortex will appear to be spatially segregated or clustered

188 Jownul of CognWi? N- Volume 2, Number 3

Figure 7. Mosaic reconstruction of camera lucida drawings illustrating the structure, spatial orientation, intracortical distribution, and cortical location of giant, large, medium, and small basket local circuit interneurons of the human motor cortex. The left-hand figure illustrates these interneurons as viewed from a vertical plane transverse to the precentral gyrus, and the right-hand figure reproduces the same group of cells viewed from a 45" angle. The mammalian cerebral cortex appears to be subdivided into a series of rectangular, parasagittal, narrow, parallel, and vertical functional territories of basket/pyramidal inhibitory systems. (From Marin-Padilla 1975.) into a series of parasagittal, narrow, parallel, vertical, and pyramidal cell, namely its body. Hence, this interneuron rectangular territories (Fig. 7). Each one of these terri- also constitutes an essential inhibitory component of the tories is represented by a different baskevpyramidal sys- proposed pyramidal/local-circuit newortical unit. tem (Marin-Padilla 1970b, 1975). The dimension and spatial orientations these rectangular basket/pyramidal of The Chandelier Local-Circuit Interneuron territories are not unlike the narrow and vertical receptive fields established by the distribution of many specific Since its recent discovery (SzentAgothai and Arbid 1974), corticipetal fiber systems (Blakemore and Tobin 1972; this localcircuit interneuron has received considerable Hubel and Wiesel 1977, Jones 1984; Jones and Hendry attention (Somogyi et al. 1983; Valverde 1983; Fairen et 19841.- al. 1984; Peters 1984; De Car10 et al. 1985; Marin-Padilla A basket local-circuit interneuron modulates inputs 1987). This interneuron is characterized by distinct den- passing through a distinct functional compartment of the dritic and axonal arborizations. It is a small, round, stel-

Madn-Padilka 189

Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1990.2.3.180 by guest on 25 September 2021 late cell with several short ascending and descending ebral cortex (Figs. 6B and 8). The human chandelier cell dendrites with several “wavy” and “recurving” branches may be the smallest of any mammalian cell so far de- (Figs. 2C, 6B, and 8). Its axonal arbor is its most distin- scribed (Valverde 1983; Marin-Padilla 1987). A human guishing feature. The ascending or descending axon chandelier interneuron establishes axoaxonic contacts branches profusely within a small territory and gives off with only about 60 to 80 pyramidal cells located within many specialized candle-like terminals from which the a small, rectangular space that measures 300 X 200 X cell receives its colorful name. These specialized termi- 100 pm. A reduction of the neuronal size and the num- nals consist of short vertical arrays of presynaptic boutons ber of axoaxonic “candles” per cell seems to have oc- varying in length from 2 to 10 pm. These vertical axonal curred in the course of mammalian phylogeny (Somogyi terminals or “candles” embrace the first portion of the et al. 1982; Muller-Paschinger et al. 1983; Valverde 1983; Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021 pyramidal cell’s axon establishing with it axoaxonic syn- Marin-Padilla 1987). The chandelier interneuron is a aptic contacts (Figs. 6B and 8). The chandelier local- powerful inhibitory cell that modulates inputs passing circuit interneuron is also a GAI3Aergic inhibitory cell. through a distinct functional compartment of the pyra- Chandelier cells are found in many areas (motor, sen- midal cell, namely the first portion of its axon. Therefore, sory, parietal, and visual regions) of the mammalian cer- this local-circuit interneuron also represents an essential inhibitory component of the proposed neocortical unit.

DISCUSSION The structural complexity of the mammalian cerebral cortex is indeed incomprehensible, and so far we have been unable to develop a reasonable theory to explain its basic organization. Even more incomprehensible are the bases for its functional activity. It will be fruitless and utterly unsuccessful to deal or study structural and functional aspects separately. Attempts must be made to com- bine, and recombine, both aspects whenever possible. The purpose of this communication is to simplify an extraordinarily complex problem and to visualize neocortical organization from a new vantage point, which may be applicable to all mammals. Hence, a hypothetical structural/functional neocortical unit is proposed that may prove to be useful in unraveling some aspects of this complex organization. This paper represents an at- tempt to offer some thoughts about a new perspective on the organization of the mammalian neocortex for the purpose of stimulating an open dialogue. The central nervous system has evolved two basic components necessary for the animal’s survival. The major component deals with the animal‘s motor activities such as locomotion and the search for food and mates. A more minor but crucial component deals primarily with the animal’s ability to adapt to modifications in its environment. Consequently, the nervous system must have essentially evolved two fundamental groups of neurons: a more-stable group for its motor needs and less-stable one Figure 8. Mosaic reconstruction of camera lucida drawings illustrat- able to react, to adapt, and possibly, to change in re- ing the characteristic dendritic (1VI1) and axonal(2111) arborizations sponse to environmental needs and/or pressures. The of a local-circuit chandelier interneuron of the human visual cortex. Also schematically illustrated are the small rectangular functional ter- less stable group of neurons will act as functional mod- ritories that characterize these interneurons. The lower drawing rep- ulators of the more stable ones and hence will participate resents the view of the visual cortex illustrating the predominant in the development and acquisition of new patterns of location of these local-circuitinterneurons at the 17/18 border and behavior. Although the development of some of the an- throughout layer 111 of area 17. A local-circuit chandelier cell of the essential motor tools (e.g., arms and legs and their human visual cortex establishes axoaxonic inhibitory synaptic con- imal‘s tacts with 60 to 80 stable pyramidal cells. It appears that the human controlling motor neurons) has required millions of chandelier local circuit interneuron may be the smaller tell of this years to evolve, the animal‘s adaptations to environrhen- type so far described. (From Marin-hdilla 1987.) tal needs and/or pressures are mostly learned during the

190 Journal of Cognitive NeumcienCe Volume 2, Number 3

Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1990.2.3.180 by guest on 25 September 2021 animal’s own life. The proposed pyramidalllocal-circuit The structural organization of pyramidal cells is uniform neuronal unit is composed of both types of cells: a more and nearly identical throughout the entire neocortex, and stable pyramidal neuron and five less stable local-circuit remains indistinguishable viewed from either sagittal, interneurons. transverse, or diagonal perspectives. Hence, the struc- To define our conception of the nature of the pro- tural organization of the mammalian neocortex, from the posed nwcorrical unit, two fundamental ideas concern- perspective of its pyramidal cells, is universally uniform ing animal learning behavior should be briefly outlined. (excepting the primate visual cortex). Furthermore, this Cajal (1923), discussing adaptation and motor enhance- uniform structural organization has remained essentially ment (speaking, writing, piano playing, fencing, etc.) unchanged throughout millions of years, in the course through exercises, expressed the following thoughts: of mammalian phylogeny, in spite of its increasing role Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021 they may be achieved “through either a progressive in the animal’s overall motor activity. This uniformity has thickening of fiber pathways stimulated by a persistent always puzzled investigators because it has been impos- passing of inputs (conjecture suggested by Tanzi and sible to conceive or elaborate different functional roles Lugaro) or by the creation of new neuronal appendices for such a monotonous and uniform structure and, as (growth of new dendritic branches and extension and Braitenberg has pointed out, we have no clear ideas growth of axonic collaterals, not congenital) capable of about it. improving the fine adjustment and extent of interneu- Large pyramidal cells from the motor or Broca’s areas ronal contacts, and even by establishing totally new con- of a newborn child are structurally indistinguishable. The nections bemen neurons originally unconnected’’ distribution of their apical dendrite postsynaptic spines (English translation and italics mine). On the other hand, is identical, and, in all probability, they already possess manipulations of the environment have been shown to all the necessary extrinsic inputs as well as synaptic sites cause neuronal biochemical modifications that through to eventually participate in piano playing or in the usage functional rearrangements of preexisting (genetic and/ of an idiom. The different function of either of these two or developmental) ‘maptic pathways (improving their more stable motor neurons surely could reflect the se- fine adjustment, in Cajal’s words) new patterns of behav- lection of effective rearrangements among their numer- ior may evolve (Kandel 1985; Kandel et al. 1987). Is ous synaptic sites. However, the degree of proficiency learning based on the establishment of new synaptic achieved in either piano playing or in the‘number of contacts between previously unconnected neurons as languages mastered by an individual (or in the creation Cajal proposes, or is it the result of a varied and more of music or poetry) cannot be simply explained by syn- effective usage of preexisting synaptic connections as aptic rearrangements. These activities will require the proposed by Kandel, or is it the result of both me&- establishment of complex neuronal interrelationships nismc? Needless to say, this is an oversimplification of an between the more-stable motor neurons and the less- important and complex problem well covered elsewhere stable local-circuit interneurons. The number of synaptic (Edelman 1978; Smith-Churchland 1986; Changeux and contacts established between these two types of neurons, Konishi 1987; Gazzaniga 1988; Menenich et al. 1988; particularly their intracortical extent and spatial distri- Rakic and Singer 1988; Von der Malsburg and Singer bution, will determine the particular cortical organiza- 1988). tion that distinguishes each individual, as well as his or I propose the following: first, the nervous system is her overall motor proficiency. Undoubtedly, both func- capable of both structural (morphological) as well as tional (synaptic rearrangements) as well as structural functional adjustments and/or alterations in the course (new synaptic connections) modifications among more- of the animal’s lifetiqe; and, second, Kandel’s advanta- stabldess-stable neuronal assemblages occur through- geous functional rearrangements are particularly appli- out the life span of each individual in response to envi- able to the group of more-stable neurons, while Cajal’s ronmental demands. structural modifications are applicable to the lessstable Although the biochemical nature of pre- and post- group of local-circuit interneurons. synaptic structures of these two types of neurons is pre- Pyramidal cells represent the most important group of determined and hence will remain unchanged, the actual more-stable neurons (-80%) of the mammalian neocor- number of more smble neurons contacted by each one tex. Most of them are projective, excitatory, and either of its associated less-stable local-circuit interneuron is sensory or motor neurons. They are uniformly distrib- not predetermined but acquired postnatally. Similarly, uted throughout the entire neocortex in distinct groups the actual number, the intracortical extent, and the three- of giant (layer V), large (layers V and 111), medium (layer dimensional distribution of the specialized synaptic con- 111), and small pyramidal cells (layer II), and all of them tacts between less-stable interneurons and more-stable are distinguished by a vertical apical dendrite and a pyramidal cells are also acquired throughout the life span terminal dendritic bouquet within layer I. Neurmzs with of each individual in response to each one’s particular out these m& features are notpyramidal cells in the environmental needs. Therefore, the organization of the szrict sense, and are not elements of the proposed unit. mammalian neocortex viewed from the perspective of

Marin-Padilka 191

Downloaded from http://www.mitpressjournals.org/doi/pdf/10.1162/jocn.1990.2.3.180 by guest on 25 September 2021 its less stable local-circuit interneurons should be quite damentally different, but concomitant and interrelated different from that of pyramidal cells. It will be species- paths. One path has established many, more-stable, pro- specific, variable among individuals of the same species, jective, and essentially excitatory components, while the and capable of changing in response to the animal's other path has established fewer, smaller, less-stable, lo- particular needs and/or environmental pressures. cal-circuit and essentially inhibitory components. Al- The model of a neocortical unit proposed herein con- though the larger component serves the animal's motor sists of a mre-sf&le pyramidal cell and five of its asso- needs, the smaller inhibitory component acts as a mod- ciated les(i-stable interneurons (the Cajal-Retzius, ulator of the animal's behavior being able to adapt and/ Martinotti, double-bouquet, basket, and chandelier cells). or to change in response to environmental modifications

The spatial intracortical distribution of each one of these and/or pressures. Although in the course of mammalian Downloaded from http://mitprc.silverchair.com/jocn/article-pdf/2/3/180/1755663/jocn.1990.2.3.180.pdf by guest on 18 May 2021 interneurons is distinctive. The apparently monotonous phylogeny, the evolution of either component has pro- and uniform structural organization of the mammalian gressively increased in complexity, the developmental nmortex will be quite different, both structurally and augmentation of the inhibitory local-circuit component functionally, when viewed from the perspective of any of has been noticeable in primate evolution and particularly its less-stable local-circuit interneurons. From a basket in man (Cajal 1923). The variety, structural complexity, interneuron perspective (Fig. 7), the more-stable pyra- and relatively large size, of the local-circuit interneurons midal cells will appear segregated or clustered into a that characterized the primate and the human cerebral series of parasagittal, narrow, parallel, and vertical cortex could reflect that fact. The extraordinary, and so- groups. Undoubtedly, the capacity of basket interneurons far unexplained, enlargement (in both weight and vol- to establish GABAergic axosomatic synapses with the ume) of the human brain achieved during the relatively body of more-stable pyramidal cells (and with other short biological time of its evolution could reflect the cells) is genetically determined. However, the number growth and expansion of its less-stable, local-circuit of pyramidal cells contacted by each basket cell or the group of interneurons. number of axosomatic contacts established with the body of each one is not predetermined but acquired postnatally. Consequently, the number of pyramidal cells con- Acknowledgment tacted by each basket interneuron, the number of This work has been supported by the National Institute of axosomatic synaptic contacts established on each one, Neurological and Communicative Disorders and Stroke, Grant and, hence their overall intracortical extent and three- NS22897, NIH, USA dimensional distribution will either increase or decrease in response to each individual's environmental needs REFERENCES and/or pressures. Accordingly, the structural organization of the cerebral cortex viewed from the perspective of its Bayer, S. A, & Altman, J. (1990). 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Volume 2, Number 3

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