3.08 the evolution of neuron classes in the neocortex of

3.08 The Evolution of Neuron Classes inthe Neocortex of Mammals

P R Hof, Mount Sinai School of Medicine, New York,NY, USAC C Sherwood, The George Washington University,Washington, DC, USA

ª 2007 Elsevier Inc. All rights reserved.

3.08.1 Introduction 1143.08.2 Neuronal Typology and Chemical Specialization 114

3.08.2.1 Pyramidal Neurons 1143.08.2.2 Spiny Stellate Cells 1163.08.2.3 Inhibitory Interneurons: Basket, Chandelier, and Double Bouquet Cells 116

3.08.3 Relationships of Neurochemical Phenotype and Phylogenetic Affinities 1173.08.3.1 General Phylogenetic Patterns 1173.08.3.2 The Distribution of Some Neuron Classes Closely Matches Phylogenetic Affinities 1183.08.3.3 Other Phylogenetic Distributions of Cortical Neuron Classes Indicate Convergent Evolution 120

3.08.4 Functional Considerations 121

Glossary

Afrotheria A clade of placental mammals that isthought to have originated in Africa ata time when it was isolated from othercontinents. This clade containsPaenungulata (elephants, hyraxes, andsirenians), Afrosoricida (tenrecs andgolden moles), Tubulidentata (aard-varks), and Macroscelidea (elephantshrews). Molecular data indicate thatthe Afrotheria diverged from other pla-cental mammals 110–100 Mya.

Anthropoidea A primate clade that includes NewWorld monkeys, Old World mon-keys, apes, and humans. Tarsiers arethe sister group to the Anthropoidea.

Boreoeutheria A clade of placental mammals thatencompasses Euarchontoglires andLaurasiatheria. This taxonomic divi-sion within the Boreoeutheriaoccurred 95–85 Mya in the Cretaceous.

Cetartiodactyla A clade of placental mammals thatincludes cetaceans (whales, dolphins,and porpoises) and artiodactyls(even-toed ungulates). This phyloge-netic grouping is based on molecularevidence indicating that cetaceansevolved from within the artiodactylsand have their closest relationshipwith the hippopotamus and thenruminants (cattle and deer).

Euarchontoglires A supraordinal clade of boreoeuther-ian placental mammals that includesRodentia, Lagomorpha, Dermoptera,Scandentia, and Primates.

Hominidae A primate clade that includes greatapes (orangutans, gorillas, chimpan-zees, and bonobos) and humans. Thehylobatids (gibbons and siamangs)are the sister taxon to the Hominidae.

homoplasy A structure that is the result of con-vergent evolution, where organismsthat are not closely related indepen-dently acquire similar characteristics.Homoplasy is contrasted withhomology, which means that struc-tures have a common origin derivedfrom a shared ancestor.

Laurasiatheria A supraordinal clade of boreo-eutherian placental mammals thatincludes Cetartiodactyla, Perisso-dactyla, Carnivora, Pholidota, andEulipotyphla.

marsupials A clade of mammals in which thefemale has a pouch where the young isnurtured through early infancy. Thereare approximately 280 species of livingmarsupials, with the majority beingnative to Australia and the remainderliving in South America (however, thereis a single North American native mar-supial species, the Virginia opossum).

monotremes A clade of mammals that lay eggs,rather than giving birth to live younglike marsupials and placental mam-mals. The extant representatives ofthis group, the platypus and the echid-nas, are indigenous to Australia, NewGuinea, and Tasmania. Fossil evidence,however, suggests that monotremeswere once more widespread.

114 The Evolution of Neuron Classes in the Neocortex of Mammals

placentalmammals

A clade of mammals in which thefetus is nourished during gestationby a placenta. This group encom-passes the majority of livingmammals.

Xenarthra A clade of placental mammals pre-sent today only in the Americas.This group includes sloths, anteaters,and armadillos. Molecular data indi-cate that the Xenarthra divergedfrom boreoeutherian mammals100–95 Mya.

3.08.1 Introduction

A diverse array of neuron types populates themammalian neocortex. Physiological activitywithin a cortical area, in turn, is largely deter-mined by interactions among these different celltypes and incoming afferents. Neurons in the cer-ebral cortex of mammals can be divided into twomajor classes on the basis of morphology andfunction, pyramidal excitatory cells, and inhibi-tory interneurons. Each class includes manysubtypes that can be identified by their size,shape, dendritic and axonal morphology, and con-nectivity. These neuronal subtypes exhibit avariable distribution among cortical layers andregions, and some are differentially representedamong species (see Hof et al., 1999, 2000; Hofand Sherwood, 2005). Neurons can be furtherclassified based on their expression of variousproteins, such as neurofilament proteins (NFPs),calcium-binding proteins, and neuropeptides.

The morphology of a given neuron, particularlyof its dendritic arborizations, reflects the size of itsreceptive field and the specificity of its synapticcontacts. Thus, the structure of the dendriticarbor as well as the distribution of axonal terminalramifications confer a high level of subcellular spe-cificity in the localization of particular synapticcontacts on a given neuron. The three-dimensionaldistribution of the dendritic tree is also a key factorwith respect to the type of information transferredto the neuron. A neuron with a dendritic treerestricted to a particular cortical layer may bereceptive to a very limited pool of afferents,whereas widely expanding dendritic branches typi-cal of large pyramidal neurons will receive highlydiversified inputs in the cortical layers throughwhich the dendrites course. Considering the varia-bility in cortical morphology, size, and cellularorganization in mammals, it is important to inves-tigate how specific characteristics of corticalmicrocircuitry differ among species, and how

these cellular phenotypes could be used to assesstaxonomic affinities and functional differencesamong species.

3.08.2 Neuronal Typology and ChemicalSpecialization

3.08.2.1 Pyramidal Neurons

Pyramidal neurons are the principal excitatoryneuronal class in the cerebral cortex. They arehighly polarized neurons, with a major orientationaxis orthogonal to the pial surface of the cerebralcortex. Their cell body is roughly triangular oncross section, although a large variety of morpho-logic types exist with elongate, horizontal orvertical fusiform, or inverted perikaryal shapes.They typically have a large number of dendritesthat emanate from the apex and from the base ofthe cell body. The span of their dendrites maycover several millimeters and their somata arefound in all cortical layers except layer I, withpredominance in layers II, III, and V. Small pyr-amidal neurons in layers II and III of theneocortex have a restricted dendritic tree andform vast arrays of axonal collaterals with neigh-boring cortical domains, whereas medium to largepyramidal cells in deep layer III and layer V havea much more extensive dendritic tree and furnishlong corticocortical connections. Layer V alsocontains very large pyramidal neurons disposedin clusters or as isolated, somewhat regularlyspaced elements. These neurons are known toproject to subcortical centers such as the basalganglia, brainstem, and spinal cord. Finally, layerVI pyramidal cells exhibit a greater morphologicvariability than those in other layers, and areinvolved in certain corticocortical as well as corti-cothalamic projections. The dendrites ofpyramidal cells show large numbers of dendriticspines that receive most of the excitatory synapticinputs. As many as 40 000 spines can be encoun-tered on a large pyramidal neuron.

The major excitatory output of the neocortex isfurnished by pyramidal cells. Their axon extends inmost cases from the base of the perikaryon andcourses toward the subcortical white matter andgives off several collateral branches that are direc-ted to cortical domains generally located within thevicinity of the cell of origin. While many of thesebranches ascend in a radial, vertical pattern ofarborization, a separate set of projections also tra-vels horizontally over long distances. One functionof the vertically oriented component of the recur-rent collaterals may be to interconnect layers III

The Evolution of Neuron Classes in the Neocortex of Mammals 115

and V, the two major output layers of the neocor-tex. Horizontal intrinsic connections are positionedto recruit and coordinate the activity of modules ofsimilar functional properties while inhibiting otherdomains. Together these recurrent projectionsfunction to set up local excitatory patterns andcoordinate the output of neuronal ensembles.NFP immunoreactivity, chiefly recognized by theexpression of dephosphorylated epitopes of NFPmedium and heavy molecular weight subunits,characterizes a subpopulation of pyramidal neu-rons in the neocortex of mammals that exhibitsclear regional and species differences in their dis-tribution and densities (Hof et al., 1992, 1996; vander Gucht et al., 2001, 2005; Kirkcaldie et al.,2002; Boire et al., 2005; Figure 1). The expressionof NFP has been studied most comprehensively inprimates, where it has been shown that this proteinis enriched in a subset of large pyramidal neuronsthat have an extensive dendritic arborization, aredistributed in well-defined laminar positions, form

(a)

(d) (e)

(b)

Figure 1 Examples of cytoarchitecture and cellular typology usi

cortex in a long-tailed macaque monkey (Macaca fascicularis). NF

V. b and c, Distribution of NFP-immunoreactive neurons in the pri

and the California sea lion (c, Zalophus californianus). Note the p

layer III, whereas layer IV in the middle is devoid of labeled neuron

neurons is obvious. d, NFP-immunoreactive cells in the visual are

relatively small and predominate in the deep layers. e and f, NFP

Kogia breviceps), and of the beluga whale (f, Delphinapterus leuca

layer IIIc/V only. Scale bar (on f): 300 mm. Reproduced from Ho

phenotypes in the neocortex reflect phylogenetic relationships amo

permission from John Wiley & Sons, Inc.

highly specific long corticocortical projections, andshow regional specificity in their distribution pat-terns (Campbell and Morrison, 1989; Campbellet al., 1991; Hof and Nimchinsky, 1992;Carmichael and Price, 1994; Hof and Morrison,1995; Hof et al., 1995b; Nimchinsky et al., 1995,1996, 1997; Preuss et al., 1997, 1999; Sherwoodet al., 2003a; Vogt et al., 2001, 2005). Althoughthe precise function of NFP is not completelyunderstood, its restricted distribution among cer-tain subsets of corticocortical circuits in primatessuggests that it confers unique neurochemical andmorphologic properties subserving a range ofhighly specialized functions in neocortical connec-tivity, as well as selective vulnerability toneurodegenerative diseases unique to humans(Hof et al., 1995a, 1995b; Nimchinsky et al.,1996; Bussieere et al., 2003; Hof and Morrison,2004). NFP may be present, to some degree, infunctionally homologous subsets of cortical outputneurons in many species.

(f)

(c)

ng an antibody against NFP. a, Organization of the primary visual

P-immunoreactive neurons are predominant in layers III, IVB, and

mary visual cortex of two carnivores, the dog (b, Canis familiaris),

rominent labeling of very large cells in layer V and smaller cells in

s. The large size and extensive dendrites of NFP-immunoreactive

a of the camel (Camelus dromedarius). The labeled neurons are

immunolabeling in the visual cortex of the pigmy sperm whale (e,

s). Note the prominent clusters of large immunoreactive neurons in

f, P. R. and Sherwood, C. C. 2005. Morphomolecular neuronal

ng certain mammalian orders. Anat. Rec. A 287, 1153–1163, with


3.08.2.2 Spiny Stellate Cells

Spiny stellate cells are the other class of corticalexcitatory neurons and are found in highest numbersin neocortical layer IV. The spiny stellate cell is asmall multipolar neuron with local dendritic andaxonal arborizations. These neurons resemble pyra-midal cells in that they are the only other corticalneurons with large numbers of dendritic spines, butdiffer from them in lacking most of an apical dendriteand having a restricted dendritic arbor that generallydoes not extend beyond the layer in which the cellbody resides. The axons of spiny stellate neurons areprimarily intrinsic and form links between layer IV,that receives a major input from the thalamus, andlayers III, V, and VI. In some respects, the axonalarbor of spiny stellate cells mirrors the verticalplexuses of recurrent collaterals, albeit in a morerestricted manner. Given its axonal distribution,spiny stellate neurons appear to function as ahigh-fidelity translator of thalamic inputs, maintainingstrict topographic organization and setting up initiallinks of information transfer within a cortical area.

3.08.2.3 Inhibitory Interneurons: Basket,Chandelier, and Double Bouquet Cells

There is a large variety of interneuron types in thecerebral cortex. These neurons contain the neuro-transmitter �-aminobutyric acid (GABA), and exertstrong local inhibitory influences on postsynapticneurons. The dendritic and axonal arborizations ofinterneurons offer important clues as to their role inthe regulation of pyramidal cell function. In addition,many morphologic classes of GABAergic interneur-ons can be further defined by a particular set ofneurochemical characteristics. Three major subtypesof cortical interneurons are classically described,principally based on rodent and primate studies,namely basket, chandelier, and double bouquetcells. It must be noted, however, that interneuronsexhibit a rich variety of size and morphologies, suchas clutch cells, neurogliaform cells, Martinotti-typeand Cajal–Retzius cells, bipolar cells and other stel-late cells, and multipolar neurons, which all havediverse representations depending on the brain regionas well as on the species studied.

Basket cells are characterized by axonal endingsthat form a basket of terminals surrounding a pyr-amidal cell soma and provide most of the inhibitoryGABAergic synapses to the soma and proximal den-drites of pyramidal cells. One basket cell maycontact numerous pyramidal cells, and in turn sev-eral basket cells can contribute to the pericellularbasket of one pyramidal cell. The basket cells have arelatively large soma and multipolar morphology

with dendrites extending in all directions for severalhundred micrometers such that the verticallyoriented dendrites cross several layers. Their axonarises vertically, quickly bifurcates and travels longdistances, forming multiple pericellular arrays as itspreads horizontally. The basket cells predominatein layers III and V in the neocortex and are numer-ous amid hippocampal pyramidal neurons.

Chandelier cells generally have a variably bituftedor multipolar dendritic tree. The defining character-istic of this cell class is the very striking appearanceof its axonal endings. In Golgi or immunohistoche-mical preparations, the axon terminals appear asvertically oriented cartridges, each consisting of aseries of axonal swellings linked together by thinconnecting pieces making them look like old-style chandeliers. These neurons synapse exclu-sively on the axon initial segment of pyramidalcells. Most of the chandelier cells are located inlayer III and their primary target appears to bepyramidal cells in layer III, and to a lesser extentlayer V. One pyramidal cell may receive inputsfrom multiple chandelier cells, and one chandeliercell may innervate more than one pyramidal cell.This cell exerts powerful inhibition on postsynap-tic pyramidal cell firing.

Double bouquet cells are mostly prevalent inlayers II and III, and are also present in layer V ofthe neocortex. These interneurons are characterizedby a vertical bitufted dendritic tree and a tight bun-dle of vertically oriented varicose axon collateralsthat traverse layers II through V. Many double bou-quet cells synapse on spines of pyramidal cells andmost of their remaining synapses are on fine dendri-tic shafts, in striking contrast to the basket andchandelier cells. Another subclass of double bou-quet cell has similar synaptic targets but primarilyin layer V, thus influencing the activity of differentpopulations of pyramidal cells.

GABAergic interneurons can also be classified innonoverlapping subtypes based on their content inthe calcium-binding proteins parvalbumin (PV), cal-bindin (CB), and calretinin (CR), as well as severalneuropeptides (Hendry et al., 1989; Andressenet al., 1993; Conde et al., 1994; DeFelipe, 1997;Gonchar and Burkhalter, 1997; Glezer et al., 1998;Morrison et al., 1998; Hof et al., 1999; Markramet al., 2004). CB- and CR-expressing interneuronsshare many morphologic similarities, and aremainly bitufted, bipolar, and double bouquet neu-rons, as well as a few pyramidal neurons, withminimal overlap among these subpopulations inthe rodent and primate neocortex (Rogers, 1992;DeFelipe, 1997; Morrison et al., 1998). PV-immu-noreactive neurons are mainly observed in layers II


to V, and are principally basket and chandelier cells(Blumcke et al., 1990; Van Brederode et al., 1990;Hof and Nimchinsky, 1992; Conde et al., 1994;Nimchinsky et al., 1997). PV has also been reportedto occur in certain pyramidal neurons in primatesomatosensory and motor cortex (Preuss and Kaas,1996; Sherwood et al., 2004).

3.08.3 Relationships of NeurochemicalPhenotype and Phylogenetic Affinities

3.08.3.1 General Phylogenetic Patterns

Phylogenetic patterns in the distribution of NFP andthe three calcium-binding proteins appear to be asso-ciated with interspecific variation in other aspects ofthe cytoarchitecture of mammalian neocortex.Monotremes (i.e., echidnas and the platypus) arethe sister taxon to all therian mammals. In thesespecies, neurons containing CB, CR, and PV arefound throughout the cortex, although CR-immu-noreactive neurons are most dense in the piriformcortex where they predominate as a polymorphicphenotype. In monotremes (Hof et al., 1999), CBand PV comprise morphologic types that resemblethose found in placental mammals, including largePV-immunoreactive multipolar neurons that aresimilar to basket cells. In echidnas, however, PVis present in a unique cell type characterized by alarge pyramidal-like or multipolar morphology thatis common in layers V and VI. Such PV-labeledneurons have not been observed in any other mam-malian species. It is also worth noting that theAustralian echidna (Tachyglossus aculeatus) pre-sents NFP-expressing cells in layer V of itsneocortex (Hassiotis et al., 2004). Although thereare no studies of NFP staining in the most closelyrelated taxon, the platypus, NFP is enriched inlayer V neurons in the marsupial tammar wallaby(Macropus eugenii) throughout its cortex, as wellas occasionally in layer III neurons of select sensoryand association regions (Ashwell et al., 2005). Inplacental mammals, NFP-containing pyramidalneurons are found frequently in layers III, V, andVI. Thus, NFP-rich cells in layer V may be inter-preted as a conservative trait among mammals,with variable patterns of NFP expression in otherlayers having arisen in different lineages in subse-quent evolution (Figure 1).

All species of marsupials examined to date displaycomparable staining patterns in the neocortex forPV, CB, and CR (Hof et al., 1999). The most pre-valent calcium-binding protein in marsupialsappears to be CR, which is present in numeroussmall bipolar neurons located in layers II and III,

as well as small pyramidal-like neurons in layers Vand VI in the lateral cortex. Compared to CR-immunoreactive neurons, CB is more sparsely pre-sent in bipolar and bitufted neurons in thesupragranular layers throughout the cortex, and insome larger multipolar neurons in the deep layers.A major difference between marsupials and othermammalian taxa is the remarkable paucity of PV-immunoreactive neurons and fibers. PV isobserved only in a few small interneurons,whereas it is much more prevalent in othersmall-bodied mammals as well as in primatesand carnivores. Surprisingly, PV-containing neu-rons in layer II have a morphology resemblingdouble bouquet cells that are usually labeled byCB in rodents and primates. This may represent aneuronal specialization in certain marsupials thatis not found in placental mammals.

A current limitation to interpreting regional pat-terns of distributions of neuron classes is thepaucity of data from the phylogenetic groupsthat diverged close to the base of the adaptiveradiation of placental mammals, the Xenarthra(i.e., sloths, anteaters, and armadillos) andAfrotheria (i.e., tenrecs, golden moles, elephantshrews, aardvarks, manatees, hyraxes, and ele-phants). Substantially more is known regardingvariation in cortical architecture of the other pla-cental mammals, the Boreoeutheria. Amongboreoeutherian mammals, species showing a highdegree of morphologic differentiation of neocorti-cal areas, a variable development of layer IV, andsubstantial variation in neuronal size and packingdensities across the cortical plate are also generallycharacterized by a balanced representation of thethree calcium-binding proteins and morphologicaldiversity of NFP-immunoreactive pyramidal neu-rons across cortical regions (Hof et al., 2000). Incontrast, species characterized by greater cytoarch-itectural monotony throughout the cortical mantle,a poorly defined or lack of layer IV in most regions,and the presence of very large pyramidal cells in allneocortical areas, display a predominance of CB-and CR-containing populations in comparison toPV-immunoreactive neurons, and rather uniformNFP-containing pyramidal cell morphology. Thefirst type occurs in primates, rodents, carnivores,and to some extent megachiropterans, as well as intree shrews and lagomorphs. Most of the taxa thatare characterized by this cortical organization aremembers of the supraordinal groupEuarchontoglires, with the exception of carnivoresand bats. In contrast, the second type of corticalorganizational pattern is present in cetaceans,artiodactyls, and perissodactyls, which are all


members of the Laurasiatheria. Thus, the distribu-tion of these particular aspects of the corticalphenotype follows a major taxonomic division thatoccurred about 80–90 Mya at the base of the radia-tion of boreoeutherian mammals (Murphy et al.,2001a, 2001b). While these general patterns appearto differentiate cortical organization in major bor-eoeutherian clades, the lack of data fromxenarthrans and afrotherians makes it difficult toclearly establish which character states are conserva-tive and which are derived for placental mammals.This is a particular challenge because cortical celltypes in monotremes and marsupials often differ sig-nificantly from placental mammals and from eachother. Our examination of calcium-binding proteinimmunoreactivity in the xenarthran giant anteater(Myrmecophaga tridactyla), however, shows simila-rities with marsupials and cetartiodactyls in thatPV-immunoreactive neurons are very sparse, whereasCB- and CR-immunoreactive neurons are expressedin a morphologically diverse population of cells thatincludes a high frequency of pyramidal neurons (Hofand Sherwood, 2005; Figures 2 and 3).

3.08.3.2 The Distribution of Some NeuronClasses Closely Matches Phylogenetic Affinities

Reports of the cyto- and chemoarchitecture of odon-tocete cetaceans, particularly of visual and auditoryregions, and analysis of neocortical neurons in a fewlarge artiodactyls have revealed commonalities incortical organization between these sister taxa(Morgane et al., 1988, 1990; Glezer et al., 1992,1993, 1998; Hof et al., 1992; 1999). In both groups,PV is present only in sparsely distributed large stellateneurons located in layer IIIc/V. A few small pyrami-dal neurons in layer III also exhibit PVimmunoreactivity in dolphins. In cetaceans and artio-dactyls, CB- and CR-immunoreactive cells are farmore numerous than PV-immunoreactive cells,occurring in large fusiform, bipolar, or multipolarneurons in layers I, II, and superficial layer III. CB-containing neurons are much less numerous and lessintensely stained than CR-immunoreactive neurons.The CR-containing neurons located in layer I have amorphology quite comparable to that of the bipolar/bitufted CB- or CR-expressing neurons typically seenin layer II of other mammals such as rats, carnivores,and primates (Ballesteros Yanez et al., 2005),whereas the CR-containing neurons in layers IIand III are much larger and more variable inshape than in other species, with a predominanceof multipolar and fusiform types. These neuronshave long dendrites that extend into layers I andIII. Very large CR-immunoreactive neurons are also

encountered in layers V and VI, especially in theneocortex of large artiodactyls, such as the giraffe(Giraffa camelopardalis), llama (Lama glama), andcamel (Camelus dromedarius), whereas they are lessnumerous in the pig (Sus scrofa), and in smallerruminants. A few pyramidal-like neurons in layer IIIare also faintly CR-containing in dolphins, and thelarge pyramidal neurons in layer IIIc/V contain lowlevels of CB. The distribution and morphology ofNFP-immunoreactive neurons are also comparablein cetaceans and artiodactyls, but differ considerablyfrom those in primates, carnivores, and rodents. Incetartiodactyls, NFP is expressed in very large pyra-midal neurons located in the deep portion of layer IIIand in upper layer V (Hof et al., 1992). These neu-rons are present as clusters of three to six neurons,regularly spaced throughout the cortical mantle andintensely labeled with prominent apical dendritesextending well into layer I, with no major regionalvariability in their densities.

Another cell class that shows a restricted phylo-genetic distribution is the spindle-shaped neuron,which is found exclusively in the cerebral cortex ofhominids (i.e., great apes and humans). Spindle-shaped cells are characterized by a vertical, fusiformmorphology, very large size, and high levels of NFPimmunoreactivity (Nimchinsky et al., 1995, 1999).They are prevalent in a restricted sector of the ante-rior cingulate cortex (areas 25, 24a, and 24b; Vogtet al., 1995) and are also numerous in the antero-ventral agranular insular cortex (see The Evolutionof Neuron Types and Cortical Histology in Apesand Humans, Role of Spindle Cells in the SocialCognition of Apes and Humans). These neuronsare found exclusively in hominids and have notbeen reported in any other mammalian speciesinvestigated thus far (including other primate spe-cies; Nimchinsky et al., 1999; Hof et al., 2000). Thevolume of spindle-shaped cells is strongly correlatedwith encephalization, which is not the case for theother neuron types (Nimchinsky et al., 1999).These spindle-shaped cells are a particular typeof projection neuron, as they send an axon inthe subcortical white matter, although their exactdomain(s) of projection cannot be ascertained inthe species in which they are present. They may,however, provide well-defined projections, similarto Meynert cells or Betz cells (Sherwood et al.,2003b). Furthermore, although CR-immuno-reactive pyramidal neurons have been reported inthe entorhinal cortex of several mammalian spe-cies, CR-containing small pyramidal neurons inlayer Va of anterior cingulate cortex (area 24)appear to be present exclusively in hominids, pos-sibly indicating a recent evolutionary character in

(a)

(c)

(f)(e)

(b)

(h) (i)

(l)

(o)(n)(m)

(k)

(g)

(d)

(j)

Figure 2 Immunoreactivity patterns of calcium-binding proteins in the neocortex of various mammals. a and b, CB (a) and PV (b)

immunoreactivity in the primary somatosensory cortex of the echidna (Tachyglossus aculeatus). There is a large population of small

neurons that express CB, whereas PV is contained in a heterogeneous collection of neurons, some very large and multipolar. This

differs radically from other members of the Australian fauna (Hof et al., 1999), such as the koala (Phascolarctos cinereus, c), which

displays a rather sparse population of CB-containing cells. d and e, The giant anteater (Myrmecophaga tridactyla) is also characterized

by a sparse population of relatively large CB-immunoreactive multipolar neurons (d) and PV-expressing neurons (e). These patterns are

fully distinct from that in rodents (f, CR immunoreactivity in the somatosensory cortex of the chinchilla, Chinchilla laniger), carnivores (g,

CR immunoreactivity in a dog motor cortex displaying bipolar neurons as well as pyramidal-like neurons), and a cetacean visual cortex

(h, the bottlenose dolphin, Tursiops truncatus). Layers I and II are particularly enriched in the cetacean (layer II is located about one-third

down from the top of the photomicrograph). Panels (i–l) show details of the chemoarchitecture of the frontal cortex of a Siberian tiger

(Panthera tigris). CR-immunoreactive neurons exhibit a typical distribution predominating in the superficial layers (i, k), and large

multipolar CB-immunoreactive (j) and PV-immunoreactive (l) neurons are encountered in deep layer III. Large multipolar CR-containing

neurons are found in layer III of a dog (Canis familiaris) primary motor area (m). Note the large size of this neuron and compare it to the

CR-immunoreactive giant neuron located in layer VI of a giraffe (n, Giraffa camelopardalis), and to a typical bipolar neuron in layer III of

the mouse visual cortex (o, Mus musculus). Scale bar (on n): 300 mm (a, b); 400 mm (f–i); 50 mm (c–e, j–o). Reproduced from Hof, P. R.

and Sherwood, C. C. 2005. Morphomolecular neuronal phenotypes in the neocortex reflect phylogenetic relationships among certain

mammalian orders. Anat. Rec. A 287, 1153–1163, with permission from John Wiley & Sons, Inc.


this primate clade (Hof et al., 2001). These obser-vations of multiple novel cellular specializationssuggest the occurrence of functional modificationsalong the hominid lineage during the last 15–20

My in cortical regions that play major roles inthe regulation of autonomic function, cognition,self-awareness, emotionality, and vocalization(Figures 2 and 3).

PV

CB

CR

Echidna Quoll Flying fox Macaquemonkey

Rat Dolphin GiraffeDogHedgehog

Figure 3 Schematic representation of the major calcium-binding protein-immunoreactive neuronal types in the mammalian

neocortex. A few representative species of monotremes, marsupials, and placentals are shown. Many species have comparable

neuronal types, especially with respect to small CR-immunoreactive bipolar neurons and CB-containing bitufted and double-bouquet

cells. Primates, rodents, and carnivores, with the exception of CR, tend to show comparable patterns. The shading of the neurons

indicates the relative intensity of the staining. Faintly labeled neurons are shown as empty symbols, moderately labeled neurons as

gray symbols, and intensely labeled neurons as black symbols. Dotted triangles indicate the presence of PV-immunoreactive basket

terminals on pyramidal neurons. Triangles represent pyramidal and pyramid-like neurons; black dots represent small multipolar or

round neurons; diamonds represent large multipolar neurons and basket cells. Other symbols identify CB- and CR-immunoreactive

bipolar, bitufted, and double bouquet cells, as well as neurons with atypical morphology. Note the presence in the monkey and the rat

of CB-immunoreactive neurogliaform (represented as small star-shaped elements), and Martinotti cells (shown as large, ovoid

horizontally oriented elements), in layers V and VI, that have not been reported in other species. On each panel, the dashed lines

identify layers I and IV. Note the thick layer I and the absence of layer IV in cetaceans and ungulates. Layer IV is also not clearly

defined in the hedgehog. Adapted from Hof, P. R., Glezer, I. I., Conde, F., et al. 1999. Cellular distribution of the calcium-binding

proteins parvalbumin, calbindin, and calretinin in the neocortex of mammals: Phylogenetic and developmental patterns. J. Chem.

Neuroanat. 16, 77–116, Elsevier.


3.08.3.3 Other Phylogenetic Distributions ofCortical Neuron Classes Indicate ConvergentEvolution

Although many aspects of cortical architecturereflect phylogenetic affinities, it is likely that manycortical phenotypes present examples of homoplasy,where certain characters have evolved indepen-dently in nonrelated groups of mammals. In thisregard, it is noteworthy that there are several traitsshared by Carnivora and Euarchontoglires, such asthe distribution and typology of calcium-bindingprotein-containing neurons (Glezer et al., 1993,1998; Hof et al., 1999; Ballesteros Yanez et al.,2005). For example, in the dog neocortex, PV ispresent in a large population of morphologicallydiverse interneurons with a typology generally

comparable to that observed in anthropoid pri-mates. Some of these large multipolar neurons maybe basket cells, due to the presence of PV-immuno-reactive basket terminals around unstainedpyramidal perikarya. Furthermore, CR is presentin a very dense population of bipolar and doublebouquet cells in layer II and the upper portion oflayer III, as observed in primates and rodents. Theseaspects of chemoarchitecture in carnivores that aresimilar to primates, rodents, and otherEuarchontoglires are not derived from a commonancestral state and hence have arisen due to conver-gent evolution. Other features of carnivore corticalorganization resemble traits observed in their closerelatives in the Laurasiatheria, the perissodactylsand cetartiodactyls, and so were probably inherited


from the last common ancestor of these taxa. Forexample, in canids, felids, and pinnipeds, giganticintensely labeled CR-immunoreactive, multipolarneurons occur in layer III of agranular motor cor-tices. These neurons are morphologicallycomparable to the very large CR-containing neu-rons found in layers III, V, and VI throughout theneocortex of large artiodactyls and cetaceans (Hofet al., 1996, 1999), which shows a poorly differen-tiated layer IV only in certain regions (Morganeet al., 1990; Glezer et al., 1993, 1998; Hof et al.,1999). It is interesting that in spite of many simila-rities in cortical organization and connectivitybetween carnivores and primates, the dog neocortexdisplays several differences in neurochemical orga-nization compared to anthropoids (Hof et al., 1996,1999). Canids have a high degree of cellular specia-lization in primary motor and sensory cortices,contrasting with fairly homogeneous patterns inassociation cortices. Large PV- and CB-containingpyramidal cells are present only in primary motorand visual regions, and high numbers of large PV-immunoreactive basket cells and multipolar CR-containing interneurons occur only in primarymotor, somatosensory, and visual areas (Hof et al.,1996).

Besides these observations in carnivores, otherexamples show that the distribution of cortical neu-ron classes exhibit a mosaic pattern of evolution,with some unique specializations, in particularlineages and other examples of homoplasy (forinstance, a paucity of PV expression is observed inthe neocortex of cetartiodactyls and marsupials).The predominance of CB and CR in the neocortexand subcortical systems of cetartiodactyls is similarto the calcium-binding protein distributionsobserved in microchiropterans and hedgehogs butdiffers from that in rodents and primates (Glezeret al., 1993, 1998; Hof et al., 1999). In addition,large multipolar PV-containing neurons are foundin the deep layers of the neocortex of hedgehogs anddolphins, unlike in rodents, carnivores, and pri-mates, where PV-expressing cells are morecommon in layers III and IV. It is also notable thatmegachiropterans are characterized by the absenceof neocortical expression of CR, whereas their tha-lamic neurons do express it.

3.08.4 Functional Considerations

Calcium-binding protein-containing interneuronsare known to influence the activity of pyramidalneurons in a manner specific to each cell class(Conde et al., 1994; DeFelipe, 1997; Hof et al.,1999; Ballesteros Yanez et al., 2005), and as such

the role of calcium-binding protein in cortical inte-gration is likely to be similar to a large degreeamong rodents, carnivores, and primates, suggest-ing that similar mechanisms exist acrossboreoeutherian mammals at least. However, differ-ences are present at the level of particular neuronalsubclasses, as recently revealed in a study of CB-expressing interneurons in primates compared torodents, lagomorphs, carnivores, and artiodactyls(Ballesteros Yanez et al., 2005). These authorsreported that, in the nonprimate species, axon bun-dles of CB-immunoreactive double bouquet cells arenot observed except for some in the visual cortex ofcarnivores, indicating that although somata thatresemble typical CB-expressing cell types from pri-mates can be found in these species, their axonalprojections are likely to differ from primates.Whether such differences in axonal organizationcan be extended to PV- and CR-immunoreactiveneurons remains to be demonstrated.

The degree to which functional interpretations ofbiochemical neuron types can be applied to allmammalian orders is difficult to determine owingto large differences in morphological phenotypesand distributions for any given cell type across spe-cies. The relative rarity of PV-immunoreactiveneurons in cetaceans and artiodactyls could beinterpreted as an ancestral retention for theLaurasiatheria because it also occurs in other laur-asiatherians such as echolocating bats andhedgehogs, which may show many plesiomorphicfeatures (Glezer et al., 1988). The neocortex ofcetaceans and large artiodactyls appears to containan inordinate number of cortical modules revealedby clusters of large NFP-containing pyramidal cellsin layer IIIc/V (Glezer et al., 1988; Morgane et al.,1988; Hof et al., 1992). Much cortical integrationin cetaceans may take place in the cellular, thicklayer I that contains 70% of the neocorticalsynapses in these species (Glezer and Morgane,1990). Consistent with this observation, most CB-and CR-containing interneurons are located inlayers I and II in cetaceans, and the few PV-immu-noreactive cells lie in nearby layers IIIc/V and VIpyramidal cells. The PV-immunoreactive neuronsmay represent basket cells, and axons of CB- andCR-immunoreactive interneurons may be located ina position to interact with inputs to the neocortexand connect the apical dendrites of the deep layersof pyramidal neurons (Glezer et al., 1988; Morganeet al., 1988). It is possible that in cetartiodactylscalcium-binding protein-immunoreactive neuronsplay a comparable role in neocortical microcircuitsas in primates and rodents. The similarities in neu-rochemical specialization of the cetartiodactyl


neocortex parallel the paleontological and molecu-lar evidence, indicating that these species share arelatively recent common ancestor, and that muchlike primates, the evolution of the species with thelargest brains (the delphinids) is a recent event(Marino et al., 2005).

Although there are major gaps in our knowledge ofthe evolutionary history of neocortical organization inmammals and of the chemical organization of thecerebral cortex in most species, collectively theseobservations indicate that brain organization and neu-rochemical cellular specialization reflect evolutionaryrelationships among many mammalian species.

Acknowledgments

This work was supported by the National ScienceFoundation (BCS-0515484 and BCS-0549117), theWenner-Gren Foundation for AnthropologicalResearch, and the James S. McDonnell Foundation(grant 220020078). Brain materials were madeavailable from the Great Ape Aging Project, theFoundation for Comparative and ConservationBiology, and the Cleveland Metroparks Zoo.

References

Andressen, C. I., Blumcke, I., and Celio, M. R. 1993. Calcium-

binding proteins: Selective markers of nerve cells. Cell TissueRes. 271, 181–208.

Ashwell, K. W., Zhang, L. L., and Marotte, L. R. 2005. Cyto- and

chemoarchitecture of the cortex of the tammar wallaby

(Macropus eugenii): Areal organization. Brain Behav. Evol.66, 114–136.

Ballesteros Yanez, I., Munoz, A., Contreras, J., Gonzalez, J.,Rodriguez-Veiga, E., and DeFelipe, J. 2005. Double bouquet

cell in the human cerebral cortex and a comparison with other

mammals. J. Comp. Neurol. 486, 344–360.Blumcke, I., Hof, P. R., Morrison, J. H., and Celio, M. R. 1990.

Distribution of parvalbumin immunoreactivity in the visual

cortex of Old World monkeys and humans. J. Comp. Neurol.301, 417–432.

Boire, D., Desgent, S., Matteau, I., and Ptito, M. 2005. Regionalanalysis of neurofilament protein immunoreactivity in the

hamster’s cortex. J. Chem. Neuroanat. 29, 193–208.Bussieere, T., Giannakopoulos, P., Bouras, C., Perl, D. P.,

Morrison, J. H., and Hof, P. R. 2003. Progressive degenera-

tion of nonphosphorylated neurofilament protein-enriched

pyramidal neurons predicts cognitive impairment inAlzheimer’s disease: A stereologic analysis of prefrontal cor-

tex area 9. J. Comp. Neurol. 463, 281–302.Campbell, M. J. and Morrison, J. H. 1989. A monoclonal

antibody to neurofilament protein (SMI-32) labels a subpo-

pulation of pyramidal neurons in the human and monkey

neocortex. J. Comp. Neurol. 282, 191–205.Campbell, M. J., Hof, P. R., and Morrison, J. H. 1991. A

subpopulation of primate corticocortical neurons is distin-guished by somatodendritic distribution of neurofilament

protein. Brain Res. 539, 133–136.

Carmichael, S. T. and Price, J. L. 1994. Architectonic subdivision

of the orbital and medial prefrontal cortex in the macaquemonkey. J. Comp. Neurol. 346, 366–402.

Conde, F., Lund, J. S., Jacobowitz, D. M., Baimbridge, K. G., andLewis, D. A. 1994. Local circuit neurons immunoreactive for

calretinin, calbindin D-28k or parvalbumin in monkey pre-

frontal cortex: Distribution and morphology. J. Comp.Neurol. 341, 95–116.

DeFelipe, J. 1997. Types of neurons, synaptic connections and

chemical characteristics of cells immunoreactive for calbin-din-D28k, parvalbumin and calretinin in the neocortex.

J. Chem. Neuroanat. 14, 1–19.Glezer, I. I. and Morgane, P. J. 1990. Ultrastructure of synapses

and Golgi analysis of neurons in neocortex of the lateral gyrus

(visual cortex) of the dolphin and pilot whale. Brain Res. Bull.24, 401–427.

Glezer, I. I., Jacobs, M. S., and Morgane, P. J. 1988. The ‘initial’

brain concept and its implications for brain evolution in ceta-cea. Behav. Brain Sci. 11, 75–116.

Glezer, I. I., Hof, P. R., and Morgane, P. J. 1992. Calretinin-immunoreactive neurons in the primary visual cortex of dol-

phin and human brains. Brain Res. 595, 181–188.Glezer, I. I., Hof, P. R., Leranth, C., and Morgane, P. J. 1993.

Calcium-binding protein-containing neuronal populations in

mammalian visual cortex: A comparative study in whales, insec-

tivores, bats, rodents, and primates. Cereb. Cortex 3, 249–272.Glezer, I. I., Hof, P. R., and Morgane, P. J. 1998. Comparative

analysis of calcium-binding protein-immunoreactive neuronalpopulations in the auditory and visual systems of the bottle-

nose dolphin (Tursiops truncatus) and the macaque monkey

(Macaca fascicularis). J. Chem. Neuroanat. 15, 203–237.Gonchar, Y. and Burkhalter, A. 1997. Three distinct families of,

GABAergic neurons in rat visual cortex. Cereb. Cortex 7,347–358.

Hassiotis, M., Paxinos, G., and Ashwell, K. W. 2004. Cyto- andchemoarchitecture of the cerebral cortex of the Australian

echidna (Tachyglossus aculeatus). I: Areal organization.

J. Comp. Neurol. 475, 493–517.Hendry, S. H. C., Jones, E. G., Emson, P. C., Lawson, D. E. M.,

Heizmann, C. W., and Streit, P. 1989. Two classes of cortical,

GABA neurons defined by differential calcium-binding pro-tein immunoreactivities. Exp. Brain Res. 76, 467–472.

Hof, P. R. and Morrison, J. H. 1995. Neurofilament protein definesregional patterns of cortical organization in the macaque

monkey visual system: A quantitative immunohistochemical

analysis. J. Comp. Neurol. 352, 161–186.Hof, P. R. and Morrison, J. H. 2004. The aging brain:

Morphomolecular senescence of cortical circuits. TrendsNeurosci. 27, 607–613.

Hof, P. R. and Nimchinsky, E. A. 1992. Regional distribution of

neurofilament and calcium-binding proteins in the cingulatecortex of the macaque monkey. Cereb. Cortex 2, 456–467.

Hof, P. R. and Sherwood, C. C. 2005. Morphomolecular neuro-nal phenotypes in the neocortex reflect phylogenetic

relationships among certain mammalian orders. Anat. Rec.A 287, 1153–1163.

Hof, P. R., Glezer, I. I., Archin, N., Janssen, W. G.,

Morgane, P. J., and Morrison, J. H. 1992. The primary audi-

tory cortex in cetacean and human brain: A comparativeanalysis of neurofilament protein-containing pyramidal neu-

rons. Neurosci. Lett. 146, 91–95.Hof, P. R., Mufson, E. J., and Morrison, J. H. 1995a. The

human orbitofrontal cortex: Cytoarchitecture and quanti-

tative immunohistochemical parcellation. J. Comp.Neurol. 359, 48–68.


Hof, P. R., Nimchinsky, E. A., and Morrison, J. H. 1995b.

Neurochemical phenotype of corticocortical connections inthe macaque monkey: Quantitative analysis of a subset of

neurofilament protein-immunoreactive projection neurons in

frontal, parietal, temporal, and cingulate cortices. J. Comp.Neurol. 362, 109–133.

Hof, P. R., Bogaert, Y. E., Rosenthal, R. E., and Fiskum, G. 1996.

Distribution of neuronal populations containing neurofila-ment protein and calcium-binding proteins in the canine

neocortex: Regional analysis and cell typology. J. Chem.Neuroanat. 11, 81–98.

Hof, P. R., Glezer, I. I., Conde, F., et al. 1999. Cellular distribu-

tion of the calcium-binding proteins parvalbumin, calbindin,

and calretinin in the neocortex of mammals: Phylogenetic anddevelopmental patterns. J. Chem. Neuroanat. 16, 77–116.

Hof, P. R., Glezer, I. I., Nimchinsky, E. A., and Erwin, J. M.2000. Neurochemical and cellular specializations in the mam-

malian neocortex reflect phylogenetic relationships: Evidence

from cetaceans, artiodactyls, and primates. Brain Behav.Evol. 55, 300–310.

Hof, P. R., Nimchinsky, E. A., Perl, D. P., and Erwin, J. M. 2001.An unusual population of pyramidal neurons in the anterior

cingulate cortex of hominids contains the calcium-binding

protein calretinin. Neurosci. Lett. 307, 139–142.Kirkcaldie, M. T., Dickson, T. C., King, C. E., Grasby, D.,

Riederer, B. M., and Vickers, J. C. 2002. Neurofilament

triplet proteins are restricted to a subset of neurons in the ratneocortex. J. Chem. Neuroanat. 24, 163–171.

Marino, L., McShea, D. W., and Uhen, M. D. 2005. Origin andevolution of large brains in toothed whales. Anat. Rec. A 281,

1247–1255.Markram, H., Toledo-Rodriguez, M., Wang, Y., Gupta, A.,

Silberberg, G., and Wu, C. 2004. Interneurons of the neocor-

tical inhibitory system. Nat. Rev. Neurosci. 5, 793–807.Morgane, P. J., Glezer, I. I., and Jacobs, M. S. 1988. Visual cortex

of the dolphin: An image analysis study. J. Comp. Neurol.273, 3–25.

Morgane, P. J., Glezer, I. I., and Jacobs, M. S. 1990. Comparative

and evolutionary anatomy of the visual cortex of the dolphin.In: Comparative Structure and Evolution of Cerebral Cortex,

Part, II (eds. E. G. Jones and A. Peters), Cerebral Cortex, vol.

8B, pp. 215–262. Plenum.Morrison, J. H., Hof, P. R., and Huntley, G. W. 1998.

Neurochemical organization of the primate visual cortex.

In: The Primate Nervous System (eds. F. E. Bloom, A.Bjorklund, and T. Hokfelt), Handbook of Chemical

Neuroanatomy, vol. 14, Part II, pp. 299–430. Elsevier.Murphy, W. M., Eizirik, E., Johnson, W. E., Zhang, Y. P.,

Ryder, O. A., and O’Brien, S. J. 2001a. Molecular phyloge-

netics and the origin of placental mammals. Nature 409,

614–618.Murphy, W. M., Eizirik, E., O’Brien, S. J., et al. 2001b.

Resolution of the early placental mammal radiation usingBayesian phylogenetics. Science 294, 2348–2351.

Nimchinsky, E. A., Vogt, B. A., Morrison, J. H., and Hof, P. R.1995. Spindle neurons of the human anterior cingulate cortex.

J. Comp. Neurol. 355, 27–37.Nimchinsky, E. A., Hof, P. R., Young, W. G., and Morrison, J. H.

1996. Neurochemical, morphologic and laminar characteri-

zation of cortical projection neurons in the cingulate motor

areas of the macaque monkey. J. Comp. Neurol. 374,136–160.

Nimchinsky, E. A., Vogt, B. A., Morrison, J. H., and Hof, P. R.1997. Neurofilament and calcium-binding proteins in the

human cingulate cortex. J. Comp. Neurol. 384, 597–620.

Nimchinsky, E. A., Gilissen, E., Allman, J. M., Perl, D. P.,

Erwin, J. M., and Hof, P. R. 1999. A neuronal morphologictype unique to humans and great apes. Proc. Natl. Acad. Sci.USA 96, 5268–5273.

Preuss, T. M. and Kaas, J. H. 1996. Parvalbumin-like immunor-

eactivity of layer V pyramidal cells in the motor and

somatosensory cortex of adult primates. Brain Res. 712,

353–357.Preuss, T. M., Stepniewska, I., Jain, N., and Kaas, J. H. 1997.

Multiple divisions of macaque precentral motor cortex identifiedwith neurofilament antibody, SMI-32. Brain Res. 767, 148–153.

Preuss, T. M., Qi, H., and Kaas, J. H. 1999. Distinctive compart-mental organization of human primary visual cortex. Proc.Natl. Acad. Sci. USA 96, 11601–11606.

Rogers, J. H. 1992. Immunohistochemical markers in rat cortex:

Colocalization of calretinin and calbindin-D28k with neuro-

peptides and GABA. Brain Res. 587, 147–157.Sherwood, C. C., Broadfield, D. C., Holloway, R. L.,

Gannon, P. J., and Hof, P. R. 2003a. Variability of Broca’s

area homologue in African great apes: Implications for lan-guage evolution. Anat. Rec. 271A, 276–285.

Sherwood, C. C., Lee, P. W. H., Rivara, C. B., et al. 2003b.Evolution of specialized pyramidal neurons in primate visual

and motor cortex. Brain Behav. Evol. 61, 28–44.Sherwood, C. C., Holloway, R. L., Erwin, J. M., and Hof, P. R.

2004. Cortical orofacial motor representation in Old World

monkeys, great apes, and humans. II: Stereologic analysis of

chemoarchitecture. Brain Behav. Evol. 63, 82–106.Van Brederode, J. F. M., Mulligan, K. A., and Hendrickson, A. E.

1990. Calcium-binding proteins as markers for subpopula-tions of GABAergic neurons in monkey striate cortex.

J. Comp. Neurol. 298, 1–22.van der Gucht, E., Vandesande, F., and Arckens, L. 2001.

Neurofilament protein: A selective marker for the architec-

tonic parcellation of the visual cortex in adult cat brain.J. Comp. Neurol. 441, 345–368.

van der Gucht, E., Clerens, S., Jacobs, S., and Arckens, L. 2005.

Light-induced Fos expression in phosphate-activated glutami-nase- and neurofilament protein-immunoreactive neurons in

cat primary visual cortex. Brain Res. 1035, 60–66.Vogt, B. A., Nimchinsky, E. A., Vogt, L. J., and Hof, P. R. 1995.

Human cingulate cortex: Surface features, flat maps, and

cytoarchitecture. J. Comp. Neurol. 359, 490–506.Vogt, B. A., Vogt, L. J., Perl, D. P., and Hof, P. R. 2001.

Cytoarchitecture of human caudomedial cingulate, retrosple-nial, and caudal parahippocampal cortices. J. Comp. Neurol.438, 353–376.

Vogt, B. A., Vogt, L. J., Farber, N. B., and Bush, G. 2005.

Architecture and neurocytology of monkey cingulate gyrus.

J. Comp. Neurol. 485, 218–239.

Further Reading

Ballesteros Yanez, I., Munoz, A., Contreras, J., Gonzalez, J.,Rodriguez-Veiga, E., and DeFelipe, J. 2005. Double bouquet

cell in the human cerebral cortex and a comparison with other

mammals. J. Comp. Neurol. 486, 344–360.

DeFelipe, J. 1997. Types of neurons, synaptic connections andchemical characteristics of cells immunoreactive for calbin-

din-D28k, parvalbumin and calretinin in the neocortex.

J. Chem. Neuroanat. 14, 1–19.

DeFelipe, J., Alonso-Nanclares, L., and Arellano, J. I. 2002.Microstructure of the neocortex: Comparative aspects.

J. Neurocytol. 31, 299–316.


Glezer, I. I., Hof, P. R., Leranth, C., and Morgane, P. J. 1993.

Calcium-binding protein-containing neuronal populations inmammalian visual cortex: A comparative study in whales, insec-

tivores, bats, rodents, and primates. Cereb. Cortex 3, 249–272.

Glezer, I. I., Hof, P. R., and Morgane, P. J. 1998. Comparative

analysis of calcium-binding protein-immunoreactive neuronalpopulations in the auditory and visual systems of the bottle-

nose dolphin (Tursiops truncatus) and the macaque monkey

(Macaca fascicularis). J. Chem. Neuroanat. 15, 203–237.

Hof, P. R. and Sherwood, C. C. 2005. Morphomolecular neuro-

nal phenotypes in the neocortex reflect phylogeneticrelationships among certain mammalian orders. Anat. Rec.A 287, 1153–1163.

Hof, P. R., Glezer, I. I., Conde, F., et al. 1999. Cellular

distribution of the calcium-binding proteins parvalbumin,calbindin, and calretinin in the neocortex of mammals:

Phylogenetic and developmental patterns. J. Chem.Neuroanat. 16, 77–116.

3.08 the evolution of neuron classes in the neocortex of

Documents