cortical layer vii and persistent subplate cells in mammalian brains

© 2000 S. KargerAG, Basel

Fax + 41 61 306 12 34E-Mail [email protected] Accessible online at:www.karger.com www.karger.com/journals/bbe

Cortical Layer VII and PersistentSubplate Cells in Mammalian Brains

Roger L. Reep

Department of Physiological Sciences, College of Veterinary Medicine and Brain Institute, University of Florida,Gainesville, Fla., USA

Dr. Roger L. ReepDepartment of Physiological Sciences, Box 100144, HSCUniversity of Florida, Gainesville, FL 32610 (USA)Tel. +1 352 392-4700, ext. 3859, Fax +1 352 392-5145E-Mail [email protected]

Key WordsCerebral cortex • Corticocortical • Cytoarchitecture •

Development • Evolution • Interstitial cells • Subplate

AbstractLayer VII is the deepest cortical layer in rats, and consistsof a thin layer of persistent subplate cells overlain bya cell-sparse, myelin-rich stratum through which manycorticocortical axons travel. Layer VII neurons participatein local and long-distance corticocortical connections.The present study was undertaken to determine whetherlayer VII is a typical feature in rodent brains, and to deter-mine which other mammalian taxa exhibit a layer VII.The adult brains of 144 species from 22 orders wereexamined. Of these, 43 species in 6 orders exhibit a layerVII. These include the sciurognath Rodentia, Insectivora,Paucituberculata, Paramelemorphia, some Xenarthra,and some Chiroptera. In all taxa interstitial cells wereobserved scattered throughout the white matter. Theobserved distribution of layer VII in this sample of mam-malian taxa suggests that layer VII is a typical feature insome orders, but is not present in most orders. The het-erogeneous distribution of layer VII in the Rodentia andChiroptera suggests that species-level developmentaldynamics are involved. It is hypothesized that the timingof subplate apoptosis in relation to the establishment ofcorticocortical connections is the major factor that deter-mines whether layer VII is present in the adult stage.

Copyright © 2000 S. Karger AG, Basel

Introduction

Isocortical regions of mammalian cerebral cortex areusually described as consisting of six cellular layersarranged tangential to the pial surface. Within this scheme,variations in the thickness, cellular density, and subdivisionsof specific layers are recognized; for example, the well-developed granular layer IV and sparse layer V of primarysensory areas, and a reversed condition in motor areas.Many earlier cytoarchitectural and myeloarchitectural stud-ies recognized more than six layers in a variety of mam-malian taxa [see Jones, 1984]. Rose [1928, 1929] referredto the deepest layer of mouse cortex as layer VII due to itsthin and compact appearance, and its separation from moresuperficial layers by a cell-sparse zone. Since Rose, mostauthors have followed the lead of Krieg [1946] in identi-fying Rose’s layer VII as layer VIb in rodents. However,recent studies on cortical development and connections inrats have substantiated our earlier hypothesis [Reep andGoodwin, 1988] that layer VII is a distinct entity, derivedfrom the subplate. Therefore, throughout the remainder ofthis report, our layer VII is synonymous with layer VIb ofmost other authors; our layer VI is likewise synonymouswith layer VIa of others.

The subplate is generated very early in cortical develop-ment (E12–13 in rats) [Valverde et al., 1989; Allendoerferand Shatz, 1994], and participates in pivotal events includ-ing guidance of thalamocortical and corticofugal axons[Ghosh et al., 1990; De Carlos and O’Leary, 1992; Allen-doerfer and Shatz, 1994]. In rats most subplate cells undergo

Original Paper

Brain Behav Evol 2000;56:212–234

apoptosis, but those that persist form layer VII and the inter-stitial cells of the white matter, whereas layers II–VI arederived from the cortical plate [Cobas et al., 1991; Valverdeet al., 1989, 1995; Spreafico et al., 1995]. Comparable datafrom mice indicate that although most subplate cells die,those that survive are found in layer VII [Smart and Smart,1982; Price et al., 1997], which is also the case in hamsters[Woo et al., 1991]. By contrast, in cats and rhesus monkeysthe subplate exists initially as a distinct stratum, then almostall subplate cells die and a remnant population becomes theinterstitial neurons scattered in the subcortical white matterwith no layer VII present [Kostovic and Rakic, 1980; Rakic,1981; Valverde and Facal-Valverde, 1988; Chun and Shatz,1989; Kostovic and Rakic, 1990; Meyer et al., 1992]. Inadults of these species the interstitial neurons participate insynaptic connections with the thalamus [Lund et al., 1975;Giguere and Goldman-Rakic, 1988] and isocortex [Sheringand Lowenstein, 1994].

Neurons of layer VII participate in local and long-dis-tance ipsilateral corticocortical connections in rats, andapparently do not send projections to subcortical regions[Divac et al., 1987, 1995; Reep et al., 1987, 1990, 1994;Reep and Goodwin, 1988; Valverde et al., 1989; Vande-velde et al., 1996; Clancy and Cauller, 1999]. This contrastswith the neurons of layer VI that project to the thalamus andhave sparse corticocortical connections [Divac et al., 1987;Reep et al., 1990, 1994; Staiger et al., 1996]. The cell-sparsestratum immediately superficial to layer VII was shown byVaz Ferreira [1951] to contain myelinated axons in the rat.Valverde et al. [1989] found that the axons of layer VII neu-rons often travel in this stratum and suggested that mostlayer VII cells were long projecting neurons. We reportedthat this zone contains many of the intrahemispheric cor-ticocortical axons linking cortical areas with each other,regardless of their lamina of origin [Vandevelde et al.,1996]. Subplate-derived interstitial neurons in rats also par-ticipate in corticocortical connections, but do not project tothe thalamus [Meyer et al., 1991].

Due to the dominant influence of Brodmann’s work onprimate brains, in which no distinct deep layer of the graymatter forms from persistent subplate cells, it has becomecommonly accepted that the typical mammalian plan of iso-cortical architecture is represented by six cellular layers[Jones, 1984]. Taxonomic variations in isocortical architec-ture usually have been interpreted as subdivision, fractiona-tion, loss, or compression of these six layers, often in theabsence of developmental data. However, as mentionedabove, it has become clear that taxonomic variations in thepresence or morphology of layer VII in adults represent dif-fering developmental histories, and thus divergent paths in

cortical evolution. The present study was undertaken inorder to determine the distribution and variation of layer VIIamong adult mammalian brains, and to elucidate the devel-opmental significance of the observed patterns.

Materials and Methods

Brain sections were examined from the adult brains of 144 mam-malian species representing 22 orders. The Comparative MammalianBrain Collections of Dr. W.I. Welker at the University of Wisconsin(UW) and Dr. J.I. Johnson at Michigan State University (MSU) wereused, as well as two specimens (Rousettus amplexicaudatus, Myotismontivagus)from the brain atlases in Baron et al. [1996]. Most speci-mens consist of celloidin-embedded brains sectioned at 30–40 µm inthe coronal plane with alternating series of sections stained for Nisslsubstance or myelinated axons. Some specimens were sectioned inthe horizontal or sagittal plane. In the cases of species represented bymultiple specimens, sections were usually available in more than oneplane. In addition, brains of prairie voles (Microtus ochrogaster)andgolden hamsters (Mesocrictus auratus)were examined using stainedfrozen sections from my own material (UF).

For each species, a spaced sample of Nissl-stained sections wasexamined for evidence of a layer VII. In brains exhibiting a layer VII,Nissl-stained sections were examined more thoroughly, to determinethe mediolateral and rostrocaudal extent of layer VII and the cell-sparse zone. In addition, myelin-stained sections (where available)were examined to assess the disposition of myelinated axons in thecell-sparse zone immediately superficial to layer VII.

A four-point scoring system was devised. A score of 3 was given tospecies having a well defined layer VII throughout most of the isocor-tex, appearing as a thin, densely packed cell layer located immediatelysuperficial to the subcortical white matter, and separated from layer VIby a distinct cell-sparse zone. A score of 2 was given to those speciesexhibiting a well-defined layer VII that was more restricted in rostro-caudal extent, usually also having a less-distinct overlying cell-sparsezone. A score of 1 represented cases with an indistinct or intermittentlayer VII, often lacking a cell-sparse zone. A score of 0 was given incases with no visible layer VII.

The taxonomic system used was that of Wilson and Reeder [1993].

Guinea Pig ExperimentsInjections of anterograde and retrograde axonal tracers were made

in the medial agranular, parietal and visual cortices of 8 adult guineapigs in order to determine the laminar distribution of neurons partici-pating in corticocortical connections, and to chart the trajectories ofcorticocortical axons. All animal procedures conformed to institutionalprotocols that meet or exceed the NIH and Society for Neuroscienceguidelines. For assessing retrograde labeling, 3% aqueous Fast Blue(Sigma) was injected in the right hemisphere via glass monofilamentmicropipettes of 20–30 µm tip diameter, using a Picospritzer (GeneralValve Corp). One pulse of 5–10 psi, 2–5 msec duration was made ateach of two depths. For assessing anterograde labeling, 10% aqueousFluororuby (D-1817, Molecular Probes, Inc.) was injected into the lefthemisphere, using two pulses at each of three depths. Following sur-vival times of 7 days, animals were deeply anesthetized and perfusedtranscardially with buffered saline followed by 4% buffered para-formaldehyde. The brains were removed and soaked in a cold 20%sucrose/phosphate-buffered paraformaldehyde solution 1–2 days. The

213Cortical Layer VII and Persistent SubplateCells in Mammals


hemispheres were separated, and sections were cut at 40 µm on a freez-ing microtome in the coronal plane for the right hemisphere and in thesagittal plane for the left hemisphere. Sections were collected in dilutefixative. Two spaced series were mounted, dehydrated and coverslippedwithout staining; these were viewed under epifluorescence illuminationon an Olympus BH-2 microscope. A third spaced series of sections wasstained with cresyl violet and used for cytoarchitectural orientation.

Results

Distribution of Layer VII across TaxaOf the brains examined (from 144 species, representing

22 orders), those of 43 species from 6 orders exhibited alayer VII, distributed as shown in tables 1 and 2. In thosetaxa lacking a layer VII, the border of the gray and whitematter may be well-defined or vague. Generally, this borderis sharply defined at the depths of sulci and is indistinct atgyral crowns (fig. 1). Interstitial cells (identifiable by theirlarge sizes compared to oligodendroglia) were seen in thewhite matter of most taxa, regardless of the presence oflayer VII.

Within the order Rodentia, 21 of 26 species exhibit alayer VII, and the pattern of incidence is consistent with thedivision of rodents into the suborders Hystricognathi andSciurognathi (table 2). None of the hystricognath familiesexamined have a layer VII, as illustrated by the guinea pig(fig. 1E, F). In contrast, all of the sciurognath families pos-sess a well-defined layer VII, and many of the sciurognathsexhibit the maximally elaborated condition consisting of adistinct and widespread cellular layer VII together with acell sparse, myelin-rich zone superficially (fig. 2). Speciesin the family Muridae are uniform in possessing a maxi-mally elaborated layer VII (score of 3), but those in thefamily Sciuridae are more heterogeneous. However, in allrodent brains having a layer VII with a score of 2 or 3,myelinated axons are dense in the cell-sparse zone. Amongall rodents, the gray squirrel possesses the most distinctivelayer VII and overlying cell-sparse zone, and both of thesefeatures extend from the forceps minor of the corpus callo-sum to the splenium (fig. 2F). Some other species in the sub-order Sciurognathi display a layer VII and cell-sparse zonethat are as distinct as those of the gray squirrel, but are morerestricted in rostrocaudal extent.

All species examined in the order Insectivora (8/8) pos-sess a layer VII (table 2), with most being moderately elab-orated (score of 2). The European hedgehog is endowedwith a very prominent layer VII compared to the otherInsectivora (fig. 3).

Within the order Chiroptera, fewer than half the speciesexamined (8/18) possess a layer VII, and no species exhibits

the maximally elaborate condition (table 2). However,all members of the family Vespertilionidae exhibit themoderately elaborated condition, represented by a score of2 (fig. 4A). The three species examined in the family Rhi-nolophidae exhibit a range of conditions (scores of 0–2); thegreater horseshoe bat had the most elaborated layer VIIamong the Rhinolophidae (fig. 4B). One phyllostomid andone pteropid each exhibited a poorly developed layer VII(score of 1).

Members of the order Xenarthra present a mixed picture,with two of four species examined possessing a poorlydeveloped layer VII (table 2). Nevertheless, the nine-bandedarmadillo possesses a well-defined myelinated zone superfi-cial to its rudimentary layer VII (fig. 5).

Among the marsupials only the bandicoots (order Para-melemorphia) and shrew opossums (order Paucitubercu-lata) exhibit a moderately well defined layer VII (table 2;fig. 6).

In taxa having an attenuated layer VII, the dorsofrontalregion lateral to the cingulum bundle is the site where layerVII is the most distinct.

The Claustrum and Layer VIIIn many taxa with a well developed layer VII it is unclear

whether the lateral portion of layer VII is distinct from theclaustrum. However, in several species (shrew opossum,European hedgehog (fig. 3A), short-tailed shrew, streakedtenrec (fig. 3B), common tenrec, mountain beaver (fig. 2G),and eastern flying squirrel) layer VII was obviously sepa-rated from the more superficially located claustrum.

A Cryptic Layer VII in Some Taxa?In several taxa lacking an obvious layer VII, scattered

dark cells are seen adjacent to the white matter. An exem-plary case is shown by guinea pigs, a species that lacks alayer VII (fig. 1F). In some chiropterans lacking a layer VII,dark cells are present in deep layer VI and as a scatteredinterstitial population in the superficial white matter (fig. 7).This raises the possibility that in some cortical areas in sometaxa, subplate survivors are present in the gray matter, butblend in rather inconspicuously with the deep portion oflayer VI rather than forming a separate layer VII. This cryp-tic population of subplate survivors might also participate inlong distance cortical connections, as do layer VII neuronsin rats and prairie voles [Divac et al., 1987, 1995; Vande-velde et al., 1996; Reep and Kirkpatrick, 1999].

In order to investigate these possibilities further, injec-tions of retrograde axonal tracers were made into the medialagranular, parietal or visual cortex of guinea pigs. Theseinjections produced widespread labeling in the deepest part

214 Brain Behav Evol 2000;56:212–234 Reep



Table 1. Incidence of layer VII in 144 species of 22 mammalian orders. Species names are shown for orders lacking a layer VII; table 2 givesspecies names for orders in which layer VII appears

Number of No. species Gestationspecies examined with layer VII time (days)1

Subclass PrototheriaMonotremata 2 0 18–27

Ornithorhynchus anatinus,duckbill platypusTachyglossus aculeatus,spiny anteater

Subclass TheriaInfraclass Metatheria

Dasyuromorphia 8 0 12–31Antechinus flavipes,yellow-footed marsupial mouseCaluromys lanatus,wooly opossumDasyurus viverrinus,quollMarmosa mexicana,murine opossumMarmosa (Thylamys)sp., cuicaMarmosasp., cuicaPhilander opossum,four-eyed opossumSminthopsis murina,common dunnartSarcophilus harrisii,Tasmanian devil

Didelphimorphia 2 0 13Didelphis albiventris,white-eared opossumDidelphis virginiana,Virginia opossum

Diprotodontia 14 0 16–37Macropus eugenii,Tammar wallabyMacropus rufogriseus fruticus,Bennet's wallabyMacropus rufus,red kangarooMacropus fuliginosus,western grey kangarooMacropus giganteus,great grey kangarooPetaurus breviceps,sugar gliderPetaurus norfolcensis,squirrel gliderPotorous tridactylus,potorooPseudocheirus peregrinus,ringtailSchoinobates volans,dusky gliderSetonix brachyurus,quokkaThylogale billardierii,Tasmanian pademelonTrichosurus vulpecula,brushtailed opossumVombatus ursinus,common wombat

Microbiotheria 1 0 N/ADromiciops australis,Monito del Monte

Paramelemorphia 2 2 12Paucituberculata 2 2 N/A

Infraclass EutheriaArtiodactyla 8 0 120–400

Bos indicus,zebuCamelus dromedarius,dromedary camelCapra hircus,domestic goatLama peruana,llamaOdocoileus virginianus,white-tailed deerOvis aries,domestic sheepSus scrofa,domestic pigTayassu tajacu,collared peccary

Carnivora 23 0 28–100Ailurus fulgens,lesser pandaBassaricyon gabbii,olingoCallorhinus ursinus,Alaskan fur sealCanis latrans,coyoteCanis familiaris,domestic dogCynictis penicillata,yellow mongooseEumetopias jubatus,Steller sea lion


Table 1. (Continued)

Number of No. species Gestationspecies examined with layer VII time (days)1

Felis catus,domestic catFelis leo,African lionFelis pardus,leopardFennecus zerda,fennec foxGrisonsp., Grison, HuronMephitis mephitis,skunkMustela nigriceps,ferretMustela nivalis,least weaselNasua narica,coatimundiPhoca vitulina,harbor sealPotos flavus,kinkajouProcyon lotor,raccoonTaxidea taxus,badgerUrsus arctos,polar bearVulpes fulves,red foxZalophus californianus,California sea lion

Cetacea 1 0 >330Tursiops truncatus,Atlantic bottle-nosed dolphin

Chiroptera 18 8 35–150Dermoptera 1 0 ~150

Cynocephalus volans,flying lemurHyracoidea 1 0 >200

Procavia capensis,rock hyraxInsectivora 8 8 20–55Lagomorpha 2 0 20–30

Lepus mexicanus,jack rabbitOryctolagus cuniculus,old world rabbit

Macroscelidea 1 0 ~57Elephantulus rufescens,elephant shrew

Perissodactyla 1 0 ~360Equus burchelli,Grant’s zebra

Primates 17 0 >100Alouatta palliata,howler monkeyAteles geoffroyi,spider monkeyCercocebus torquatus,sooty mangabeyCercopithecussp., guenonGalago senegalensis,lesser bushbabyHomo sapiens,humanHylobates lar,gibbonLemu mongoz,mongoose lemurMacaca mulatta,rhesus macaqueMandrillus sphinx,mandrillMicrocebus murinus,mouse lemurNycticebus coucang,slow lorisPresbytis langur,langurSaguinussp., tamarinSaimiri sciureus,squirrel monkeyTarsius spectrum,tarsier

Rodentia 26 21 16–210Scandentia 1 0 ~45

Tupaia glis,tree shrewSirenia 1 0 ~270

Trichechus manatus latirostris,Florida manateeXenarthra 4 2 130–225

1 Data on gestation time are from Hayssen et al. [1993].



Table 2. Layer VII scores by species examined, for orders with species having a layer VII (scores range from 0-absent to 3-well developed)

Layer VII score Gestation time (days)

Infraclass MetatheriaOrder Paramelemorphia

Isodon obesulus,short-nosed bandicoot 2 12Parameles nasuta,long-nosed bandicoot 3 12

Order PaucituberculataCaenolestes obscurus,raton runcho, shrew opossum 2 NALestoros inca,raton runcho peruano, shrew opossum 2 NA

Infraclass EutheriaOrder Chiroptera

(Suborder Megachiroptera)Family Pteropodidae

Pteropus giganteus,flying fox 0 140–150Rousettus amplexicaudatus,rousette fruit bat 1 ~120

(Suborder Microchiroptera)Family Emballonuridae

Saccopteryx bilineata,white-lined bat 0 ~120Family Molossidae

Molossus major,velvety free-tailed bat 0 ~105Family Natalidae

Natalus micropus,funnel-eared bat 0 ~270*Family Noctilionidae

Noctilio labialis,bulldog bat 0 NAFamily Phyllostomidae

Brachyphylla cavernarum 0 ~110*Carollia perspicillata,short-tailed leaf-nosed bat 0 ~110Monophyllus redmani 0 ~110*Trachops cirrhosus,fringe-lipped bat 1 ~110*Vampyrum spectrum,false vampire bat 0 ~110*

Family RhinolophidaeHipposideros armiger,Asian leaf-nosed bat 0 ~90Rhinolophus ferrumequinum,greater horseshoe bat 2 ~300Rhinolophus hipposideros,lesser horseshoe bat 1 75

Family VespertilionidaeEptesicus fuscus,big brown bat 2 35Myotis lucifugus,little brown bat 2 50–60Myotis myotis,little brown bat 2 60Myotis montivagus,little brown bat 2 ~60*

Order InsectivoraFamily Erinaceidae

Erinaceus europaeus,European hedgehog 3 35–40Family Soricidae

Blarina brevicauda,short-tailed shrew 2 15–20Sorex araneus,common shrew 1 19–21

Family TalpidaeCondylura cristata,star-nosed mole 2 ~42*Scalopus aquaticus,Eastern American mole 2 42

Family TenrecidaeHemicentetes heminspinosus,streaked tenrec 2 ~55Setifer setosus, large Madagascar hedgehog 2 50–65Tenrec eucaudatus,common tenrec 2 53–60


Table 2. (Continued)

Layer VII score Gestation time (days)

Order Rodentia(Suborder Hystricognathi)

Family CaviidaeCavia porcellus,guinea pig 0 65–68

Family ChinchillidaeChinchilla laniger,chinchilla 0 111

Family DasyproctidaeDasyprocta aguti,agouti 0 ~104*

Family ErethizontidaeErethizon dorsatum,North American porcupine 0 ~210

Family HydrochaeridaeHydrochaeris hydrochaeris,capybara 0 ~120

(Suborder Sciurognathi)Family Aplodontidae

Aplodontia rufa,mountain beaver 2 30Family Castoridae

Castor canadensis,beaver 2 ~120Family Geomyidae

Geomys bursarius,pocket gopher 2 19Family Heteromyidae

Dipodomys merriami, Merriam’s kangaroo rat 3 33Dipodomys spectabilis,banner-tailed kangaroo rat 3 ~27

Family MuridaeGerbillus gerbillus,pygmy gerbil 3 ~20*Meriones unguiculatus,Mongolian gerbil 3 25Mesocricetus auratus,Syrian hamster 3 16Microtus ochrogaster,prairie vole 3 ~21*Mus musculus, house mouse 3 20Ondatra zibethicus,muskrat 3 21–28Peromyscus eremicus,cactus mouse 3 21–28Peromyscus floridanus,Florida mouse 3 20–30*Peromyscus gossypinus,cotton mouse 3 23Peromyscus leucopus,white-footed mouse 3 25Rattus norvegicus,Norway rat 3 21

Family MyoxidaeGlis glis,common dormouse 3 ~21*

Family SciuridaeGlaucomys volans,eastern flying squirrel 2 40Marmota monax,woodchuck 2 33Sciurus carolinensis,gray squirrel 3 44Spermophilus tridecemlineatus,thirteen-lined ground squirrel 2 28

Order XenarthraFamily Dasypodidae

Dasypus novemcinctus,nine-banded armadillo 1 ~135Family Bradypodidae

Choloepus hoffmanni,two-toed sloth 0 ~225Family Myrmecophagidae

Myrmecophaga tridactyla,giant anteater 0 ~180Tamandua tatradactyla,lesser anteater 1 130–190

Data on gestation time are from Hayssen et al. [1993]. Asterisks denote probable gestation times based on known values for closely relatedspecies.



1(For legend, see p. 221.)



Fig. 1. Most mammals lack a layer VII. Sections from four representative species illustrate the manner in which layerVI merges with the white matter in most mammals. Cells visible in the white matter (wm) are mostly oligodendroglia.Thionin cell stain here and in succeeding figures. A Echidna, specimen UW 62-455. B Flying lemur, specimen UW 63-271. C, D California sea lion, specimen UW 62-294. E, F Guinea pig, specimen UW 60-1.Fig. 2. Most rodents have a well developed layer VII. A Parasagittal section of a cactus mouse brain, frontal pole to theleft, specimen MSU 66216. In this and subsequent figures, arrows point to layer VII and asterisks denote the cell-sparsezone superficial to it. B–E Pairs of adjacent horizontal sections in the cotton mouse (specimen MSU 71259) and Mer-riam’s kangaroo rat (specimen MSU 70238), frontal pole toward the left. Cell stains on the left, myelinated fiber stainson the right. In C and E, note the myelinated axons present in the cell-sparse zone. F The gray squirrel has the most exten-sive layer VII seen in any mammal. Parasagittal section, frontal pole to the left, specimen UW 60-144. G Parasagittalsection of the mountain beaver brain, specimen UW 64-99. Note that layer VII is visible deep to the dorsal portion of theclaustrum. H Layer VII is visible in the developing rat brain from E18 onward. Specimen UW 61-837.

2


Fig. 3. Insectivores have a layer VII. A–B The European hedgehog (specimen UW 61-559) and streaked tenrec (spec-imen UW 69-503) exhibit a very clear separation between layer VII and the claustrum (CL), and a cell-sparse zone is vis-ible in both. C No cell-sparse zone is visible in the Eastern American mole (specimen MSU 70240). Horizontal section,frontal pole to the left. D Layer VII and a cell-sparse zone are visible in the Madagascar hedgehog. The cingulum bun-dle is denoted by cg.

of layer VI, both in the vicinity of the injection site and indistant cortical areas containing labeled cells in layers IIIand V as well (fig. 8A–C). However, there was no involve-ment of the main portion of layer VI in this species. Corticalinjections of the anterograde axonal tracer Fluororubyrevealed that most corticocortical axons in guinea pigstravel in layer VI of the gray matter rather than in the whitematter (fig. 8D–E).

Discussion

Taxonomic Distribution of Layer VIIThe present results suggest that most mammalian species

do not possess a layer VII, but that it is characteristic ofother taxa, most notably the sciurognath rodents. Presenceof a layer VII also appears to be the rule for the orders Para-melemorphia, Paucituberculata, and Insectivora. The pat-terns observed in rodents and chiropterans also demonstratethat layer VII can exhibit variations within a family, sug-gesting that there are species-level differences in the devel-opmental history of the subplate. These observations raisethe question of the relative importance of lineage-specificdevelopmental dynamics compared to life history variables,such as gestation times, that vary within lineages. The

strongest hypotheses generated from this line of questioningcould be tested through comparative experimental studieson the dynamics of subplate development in hystricognathand sciurognath rodents. No member of the Hystricognathihas a layer VII, whereas all members of the Sciurognathiexhibit a well developed layer VII.

Cryptic Subplate Survivors?The presence of dark cells in deep layer VI in some taxa

lacking a layer VII, together with the experimental findingsin guinea pigs, suggest that in these cases subplate survivorsare scattered throughout deep layer VI rather than beingorganized into a separate layer VII. These deep layer VIcells participate in long distance corticocortical connectionsin guinea pigs, as do layer VII cells in rats and prairie voles[Divac et al., 1987, 1995; Vandevelde et al., 1996; Reep andKirkpatrick, 1999]. Furthermore, as in rats and prairie voles,the majority of corticocortical axons in guinea pigs travel inthe deep gray matter rather than in the white matter [Vande-velde et al., 1996; Reep and Kirkpatrick, 1999]. This orga-nization of corticocortical connections is not seen in othertaxa that lack a layer VII. In cats and monkeys, deep layerVI cells do not seem to preferentially participate in cortico-cortical connections [Caminiti et al., 1985; Cavada andReinoso-Suarez, 1985; Olson and Jeffers, 1987; Avendaño



Fig. 4. Little brown bats and the greater horseshoe bat both exhibit a layer VII but no pronounced cell-sparse zone.A Coronal section, specimen UW 59-57. B Parasagittal section, specimen UW 62-125.


Fig. 5. A Nine-banded armadillos exhibit a reduced layer VII, with no pronounced cell-sparse zone. B Nevertheless, aprominent myelinated fiber bundle is present superficial to layer VII. Adjacent coronal sections; cell stain on the left,myelin stain on the right. Specimen UW 60-465. C–E Three spaced coronal sections from specimen UF DN1, arrangedrostral to caudal. Layer VII is present only in D, demonstrating its restricted spatial extent.



Fig. 6. Marsupials having a layer VII include the bandicoots and shrew opossums. A well-defined layer VII and cell-sparse zone are present in the long-nosed bandicoot, as seen in A coronal and B parasagittal (frontal pole to the left) sec-tions from specimen MSU 65043. C The shrew opossums exhibit a thin layer VII with no discernable cell-sparse zone.Parasagittal section, frontal pole to the right, specimen MSU 69089.


Fig. 7. Cryptic layer VII cells? Arrows denote some of the dark cells visible in the superficial white matter in twomicrochiropterans (specimens MSU P50 and MSU P258, respectively). Coronal sections, midline to the left.

et al., 1988; Cavada and Goldman-Rakic, 1989; Andersen etal., 1990; Neal et al., 1990; Barbas and Rempel-Clower,1997], and long distance corticocortical axons travel in thewhite matter rather than in the deep gray matter [Kawamuraand Otani, 1970; Voneida and Royce, 1974; Squatrito et al.,1981; Rockland, 1992, 1995]. These observations are con-sistent with the fact that in adult cats and monkeys subplatesurvivors are present only as interstitial cells in the whitematter and are not found in the deep gray matter [Kostovicand Rakic, 1980, 1990; Rakic, 1981; Valverde and Facal-Valverde, 1988; Chun and Shatz, 1989; Meyer et al., 1992].

Layer VII and the ClaustrumIn most taxa having a layer VII, it merges imperceptibly

with the claustrum laterally. However, a distinction between

the claustrum and layer VII is supported by four lines of evi-dence. First, as reported in the present study, layer VII isvisibly separated from, and lies deep to the claustrum in sev-eral taxa. Second, claustral cells are generated on embryonicdays (ED) 15-16 in rats [Bayer and Altman, 1991], whereasthe subplate-derived cells of layer VII originate on E12-13[Valverde et al., 1995]. Third, the subplate is visibly sepa-rated from the claustrum in embryonic stages of the rat brain[Altman and Bayer, 1995], even though layer VII and theclaustrum appear merged in the adult. Finally, the claustrumis present in taxa lacking a layer VII.

Layer VII, Gestation Time and NeurogenesisThe present observations raise the issue of how extensive

persisting subplate cells are among various mammaliantaxa, and why in some taxa they are coalesced into a distinctlayer VII, whereas in others they are found dispersed in thewhite matter. Important variables would appear to be: dura-tion of subplate existence prior to apoptosis, length of theapoptotic phase, and onset and duration of white matterdevelopment relative to these events. If the lifetime of thesubplate were relatively prolonged during the period ofdevelopment of corticopetal, corticofugal and corticocorti-cal connections, then the subplate cells would be morelikely to become dispersed. Because the intermediate zoneis transformed into the white matter during this time, manysubplate cells would become located within it, and thosesubplate cells that survive would remain there, as seen in car-nivoresand primates. In contrast, in taxa with a layer VII,subplate apoptosis could occur so rapidly in relation to thetime during which axonal connections are established thatmany subplate survivors remain located in a single band, as


Table 3. Developmental data for seven species

Gestation length Day eyes open Neurogenesis ED of peak neurogenesis,(days)1 (ED + PD)2 duration (days)3 layers II–III3

Hamster (Mesocricetus auratus) 16 28 7 16Mouse (Mus musculus) 19 32 9 17Rat (Rattus rattus = R. norvegicus) 21 36 8 19Spiny mouse (Acomys cahinnus) 38 38 16 29Ferret (Mustela furo) 41 69 34 45Cat (Felis domestica = F. catus) 65 74 43 56Rhesus monkey (Macaca mulatta) 165 165 60 90

1 Most gestation length values are taken from Hayssen et al. [1993]; ferret data is from Jackson et al. [1989].2 Eye opening data obtained from Eisenberg [1981]. ED = Embryonic day; PD = postnatal day.3 Most values for total duration of neurogenesis and peak days of neurogenesis for cortical layers II–III were taken from Finlay and Darling-ton [1995]. Ferret data is from Jackson et al. [1989]; spiny mouse data is from Brunjes et al. [1989].

Fig. 8. In the guinea pig, which lacks a layer VII, neurons in the deep-est portion of layer VI participate in local and long distance corticocor-tical connections. An injection of Fast Blue in visual cortex area Oc2Mproduced retrograde labeling in cortical areas rostral and caudal to theinjection site, with prominent labeling of neurons in the deepest part ofthe gray matter as shown on three representative sections (A–C). CaseUF GP7R, coronal frozen sections 40 µm thick, arranged from rostralto caudal. White matter is denoted by wm, cortical layers by Romannumerals. D–E Corticocortical axons travel largely in the deep graymatter in the guinea pig. An injection of fluororuby in parietal cortexarea Par 1 produced anterograde axonal labeling rostral and caudal tothe injection site. A prominent contingent of axons descends into thestriatum (str) to subcortical targets. Many other axons travel longitudi-nally in the deep gray matter until arriving at their cortical terminationzones, where they turn upward. Many fewer corticocortical axonstravel in the white matter. Case UF GP7L, parasagittal frozen sections,E is more medial than D; frontal pole is toward the left. Lines representlabeled axons; forceps minor of the white matter denoted by fm.

in sciurognath rodents, rather than all subplate survivorsbeing dispersed throughout the white matter as interstitialcells. In these species, it might be appropriate to considerthe cell-sparse, myelin-rich zone superficial to layer VII asthe most superficial portion of the white matter, and layerVII as a compacted sheet of interstitial cells. This view isconsistent with the observations that the rodent cell-sparsezone contains numerous corticocortical axons [Vandeveldeet al., 1996; Reep and Kirkpatrick, 1999], and that in carni-vores and primates most corticocortical axons travel super-ficially in the white matter [Jones et al., 1978; Schwark andJones, 1989]. The findings of Barbara Clancy and col-leagues [Clancy et al., 1997; Clancy and Cauller, 1999] sug-gest that rat layer VII neurons are morphologically andfunctionally similar to interstitial neurons deeper in thewhite matter of rats, cats and other mammals.

The importance of neurogenesis dynamics for under-standing comparative brain development has been empha-sized through the work of Finlay and Darlington [1995] andFinlay et al. [1998]. Could the status of layer VII among allmammalian taxa be simply related to the duration of neuro-genesis, so that prolonged neurogenesis results in interstitialcells, whereas shorter neurogenesis leads to establishmentof a layer VII? Data on duration of neurogenesis are knownfor very few taxa. However, as one might expect, the dura-tion of neurogenesis is related to the duration of gestation,as shown in table 3 and figure 9A. Choosing a specific eventduring neurogenesis (peak neurogenesis for cortical layersII–III) results in a better correlation with gestation time(fig. 9B). Parturition, the endpoint of gestation time, mightbe viewed as an arbitrary event, especially in the context ofaltricial versus precocial taxa. Therefore, time of eye open-ing is a useful alternative referent of developmental status[Darlington et al., 1999]. Indeed, plotting peak neurogenesisof layers II–III against total time to eye opening producesthe best fit (fig. 9C). Thus, data from these admittedly fewtaxa suggest that the duration of neurogenesis and the tim-ing of specific neurogenetic events are closely tied to theoverall duration of early development. Therefore, gestationtime or time of eye opening appear to be useful surrogatevariables for neurogenesis duration in the absence of data onthe latter. A more detailed analysis of these relationships isprovided by Darlington et al. [1999].

An examination of the current dataset reveals that mosteutherian taxa possessing a layer VII have gestation times inthe range of 16–60 days (table 2), and they also possesssmall absolute body and brain sizes [Mace et al., 1981;Nowak and Paradiso, 1983; Baron et al., 1996]. However,duration of development cannot be the only variable ofimportance, because some taxa (e.g. Lagomorpha, Macros-



Fig. 9. Relationship between neurogenesis and developmental dura-tion, for the species listed in table 3. Total duration of neurogenesisis significantly correlated with gestation time (r2 = 0.82, n = 7, p =0.005) (A). The time of peak neurogenesis of cortical layers II–III iscorrelated with gestation time (r2 = 0.92, n = 7, p = 0.0006) (B), andmore tightly with duration to eye opening (r2 = 0.95, n = 7, p = 0.0002)(C).

celidea, Scandentia) having gestation times < 60 days donot exhibit a layer VII. Perhaps the most striking example isthat of the least weasel, Mustela nivalis,which has a gesta-tion time of 35 days. Conversely, some species havingextended gestation times do possess a well developed layerVII; examples include the beaver, Castor canadensis(~120days), and the greater horseshoe bat (~300 days). Theseobservations suggest that taxon-specific developmentalconstraints could be as important as variables tied to theabsolute duration of cortical neurogenesis in determiningthe fate of persisting subplate cells. One such taxon-specificconstraint may be the aforementioned timing and durationof subplate apoptosis.

Rodents and BatsRodents and bats offer insight into the relationship

between the presence of layer VII and gestation time. Thesciurognath rodents examined in this study are generallysmall bodied [< 500 g excepting the beaver and woodchuck;Eisenberg, 1981; Nowak and Paradiso, 1983], have gesta-tion times of 16–44 days [with the exception of the beaver,Castor canadensis;Hayssen et al., 1993], and all possess awell-developed layer VII (table 2). In contrast, the hystri-cognath rodents examined in this study are relatively large

bodied [> 500 g; Eisenberg, 1981; Nowak and Paradiso,1983], have much longer gestation times [65–210 days;Hayssen et al., 1993] and none has a layer VII. This rela-tionship among body size, gestation time and status of layerVII is not related to relative brain size; known encephaliza-tion quotients for the rodents examined in this study aver-aged 0.9 for the hystricognaths and 1.0 for the sciurognaths[Eisenberg, 1981], and these group means were not signifi-cantly different (t = –0.79, n = 16, p < 0.44). However, as agroup the hystricognaths have significantly larger absolutebrain sizes than the sciurognaths [Mace et al., 1981], sup-porting the contention that among rodents the absolute dura-tion of neurogenesis is a critical variable.

Within Chiroptera, the Phyllostomidae (layer VII absent;rudimentary in one species) and Vespertilionidae (layer VIIpresent) have overlapping body size ranges [Nowak, 1994],but the phyllostomids have larger absolute brain sizes, muchhigher encephalization quotients, and larger telencephalicand neocortical size indices than the vespertilionids [Baronet al., 1996]. Phyllostomids generally have gestation timesof 3.5–4 months, whereas vespertilionids are in the range of1–2 months [Hayssen et al., 1993]. These facts suggest thatthere is a prolonged period of neurogenesis in the phyllosto-mids, resulting in the development of a larger brain with


Table 4. Comparative timing of eventsduring cortical development Rat Cat Rhesus

monkey

Gestation time E22 E65 E165Subplate born1 E12 E24–30 E542

Subplate apoptosis P0-3 (mouse)3 P0-305 E104-P72

none4

Cell proliferation and migration E13-21 E19-60 E40-1006

Thalamocortical connections established* E16-P77, 8 E38 (sp)9 E78 (sp)6

E50-P7 (cp) E91-144 (cp)Corticocortical connections established P3-1510, 11 E43-12 E95-15013

Subcortical efferents (E14)7 E45-12 E69-15513

E18-P7Eyes open14 P15 P9 P0Total days to eyes open 37 74 165

(percentage of cat) (50) – –(percentage of monkey) (22) (45) –

Note: E and P refer to embryonic and postnatal days, respectively.* For thalamocortical connections, sp and cp refer to the time afferents reach the subplate andcortical plate, respectively.

1 Allendoerfer and Shatz [1994]; 2 Kostovic and Rakic [1990]; 3 Price et al. [1997](mouse); 4 Valverde et al. [1995]; 5 Valverde and Valverde [1988], Chun and Shatz [1989]; 6

Rakic [1981]; 7 De Carlos and O’Leary [1992]; 8 Molnar and Blakemore [1995]; 9 Ghosh et al.[1990]; 10 Barbe and Levitt [1995], Hogan and Berman [1990]; 11 Kingsbury et al. [1998],Prasad et al. [1999]; 12 Payne et al. [1988]; 13 Goldman-Rakic [1981]; 14 Eisenberg [1981].



Fig. 10. Relative timing of subplate dynam-ics and the establishment of cortical connec-tions in rats, cats and rhesus monkeys. Hori-zontal lines represent the duration of fiveevents, including lifetime of the subplate,proliferation and migration of prospectiveneurons, establishment of thalamocortical,subcortical and corticocortical connections.Dashed line for subplate represents the apop-totic phase; dashed line for thalamocorticalrepresents the waiting period of afferents atthe subplate prior to entry into the corticalplate. Arrowheads indicate processes thatcontinue further into the postnatal period. Eand P refer to embryonic and postnatal days,respectively.

an interstitial population of subplate survivors rather thana layer VII. Alternatively, there could be more extensivesubplate apoptosis in this group, or a different time courseinvolving the establishment of neuronal connections that aredependent upon the subplate.

Corticocortical Connections and the SubplateGiven the general trend for layer VII to be present in taxa

with short gestation times, what variables could result in lin-eage-specific trends across a wide range of gestation times,as in carnivores? I hypothesize that a critical variable isthe timing of establishment of corticocortical connections inrelation to subplate apoptosis. Developmental data on cor-ticocortical connections are quite rare across taxa, and thoseof relevance to the present issue pertain mostly to inter-hemispheric (callosal) projections rather than intrahemi-spheric connections. However, within these limitations it isinteresting to note that in rats, that have a layer VII, thereis a very abbreviated period of contemporaneity betweenthe subplate and the establishment of callosal connections(~4 days) compared to domestic cats (~40 days) and rhesusmonkeys (~60 days), neither of which retains a layer VII(table 4; fig. 10).

The present theory suggests that the critical variabledetermining the distribution of subplate survivors in theadult is the temporal overlap between subplate existenceprior to and during apoptosis, and the establishment ofcorticocortical connections. In this scheme, gestation time,duration of neurogenesis, and absolute brain size are corre-lated, but not determinate, variables. Thus, the least weaselmay exhibit the carnivore pattern (no layer VII) because ofa carnivore-specific time course of subplate apoptosis andconsequent overlap with the development of corticocorticalaxons, rather than being constrained by its short gestationtime [35 days; Hayssen et al., 1993] or small absolute brainsize (~3.5 g). The duration of overlap would appear todepend critically on how long the subplate persists prior toapoptosis and how long the apoptotic phase lasts. If thesevariables were taxon-specific, it could explain the patternsobserved.

In primates, the subplate is thickest and persists longestbeneath those cortical areas that develop the most extensivecorticocortical connections, suggesting that the subplatemight play a role in directing the pattern of corticocorticalconnections [Kostovic and Rakic, 1990]. In taxa with anattenuated or intermittent layer VII, the most distinct portionof layer VII is invariably located in the dorsofrontal cortexlateral to the cingulum bundle. This is also the location of alarge number of corticocortical axons linking the frontal andparietal cortices [Vandevelde et al., 1996]. Perhaps in these

species there is greater regional variation in the pre-apop-totic lifetime of the subplate compared to taxa with anextensive layer VII. Layer VII could persist longer in thedorsofrontal region in relation to the establishment of cor-ticocortical connections, although not long enough to makethe transformation from a lamina into a scattered interstitialpopulation.

Future DirectionsGiven the paucity of developmental data for most of the

taxa examined in the present study, there is substantialopportunity to explore further the hypotheses raised, and todiscover whether there are significant differences in thefunctional organization of the adult cortex in brains with alayer VII compared to those without. In particular, it wouldbe very interesting to compare the relative timing of sub-plate duration and apoptosis in relation to the establishmentof corticocortical connections, in a variety of species. Doesa similar proportion of subplate cells persist across taxa,regardless of whether they become interstitial cells in thewhite matter exclusively, or also include cells in layer VII?Does the time course of subplate apoptosis exhibit variationacross closely related taxa, and how does this depend onfactors such as the duration of neurogenesis? Understandingthese dynamic processes will bring about a deeper apprecia-tion for the significance of taxonomic variations in adultcortical morphology.

Acknowledgements

This work was supported by NSF grant IBN-9120450, the Univer-sity of Florida College of Veterinary Medicine, and the Maxwell Fund.I appreciate the generosity of Jack Johnson and Wally Welker foraccess to the Comparative Mammalian Brain Collections at MichiganState University (MSU) and the University of Wisconsin (UW), andfor ongoing conversations related to the issues herein. Thanks also toBarb Clancy, John Eisenberg and Barbara Finlay for their discussion ofissues related to this manuscript. I greatly appreciate the hospitalityand technical support of John Morris at Michigan State University;Carol Dizack, Jo Ann Eckleberry, Joan Meister, Inge Sigglekow andTerry Stewart at the University of Wisconsin.




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cortical layer vii and persistent subplate cells in mammalian brains

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