P ERSPECTIVES ON DISEASEU. <strong>Bellugi</strong> <strong>et</strong> <strong>al</strong>. – Linking cognition <strong>and</strong> the brainAcknowledgmentsThe authors’research wassupported in part bygrants to U.B. fromthe Nation<strong>al</strong>Institutes of He<strong>al</strong>th(PO1 HD33113,P50 NS22343, P50DC01289), theJames McDonnellFoundation, <strong>and</strong> theOak TreePhilanthropicFoundation. Theauthors thank theNation<strong>al</strong> <strong>and</strong>Region<strong>al</strong> WilliamsSyndromeAssociations, <strong>and</strong>the Nation<strong>al</strong> <strong>and</strong>Region<strong>al</strong> DownSyndromeAssociations. Theauthors are gratefulto the subjects <strong>and</strong>their families fortheir participationin these studies.WMS (Refs 77,79). However, <strong>al</strong>though absence of onecopy of LIMK1 had been implicated in the spati<strong>al</strong> deficitcharacteristic of WMS (Ref. 60), recent work unexpectedlyreve<strong>al</strong>ed that the del<strong>et</strong>ion of this gene <strong>and</strong> othersin the region was compatible with norm<strong>al</strong> function 77 .Further, preliminary an<strong>al</strong>yses of individu<strong>al</strong>s with thefaci<strong>al</strong>, cardiac <strong>and</strong> ment<strong>al</strong> r<strong>et</strong>ardation features of WMSbut with a sm<strong>al</strong>ler del<strong>et</strong>ion, indicate that the region ofthe FZD3 gene might not be essenti<strong>al</strong> for the developmentof these typic<strong>al</strong> diagnostic features 69 . In summary,using this approach, it is now becoming possible to linkaspects of the phenotypic profile (specific cognitivefunctions, faci<strong>al</strong> features, sociability <strong>and</strong> spati<strong>al</strong> deficits)to their gen<strong>et</strong>ic origins (Fig. 8B).Important issues revolve, in part, around the definitionof the remaining genes in the common del<strong>et</strong>edregion 69,76,77 . Furthermore, it is essenti<strong>al</strong> to dissect WMScognitive features further <strong>and</strong> to d<strong>et</strong>ermine the contributionsof single genes <strong>and</strong> their interactions with othersin the del<strong>et</strong>ed regions, to each of these features<strong>and</strong> to the other characteristic embryologic<strong>al</strong>, neuroanatomic<strong>al</strong>,physiologic<strong>al</strong> <strong>and</strong> function<strong>al</strong> l<strong>and</strong>marks ofWMS, as well as to the gen<strong>et</strong>ic origins of variability inthese phenotypes. Future studies will focus on thosegenes mapping to regions that, when del<strong>et</strong>ed, are notcompatible with norm<strong>al</strong> phenotypes, but rather generatesubs<strong>et</strong>s of the features of particular interest inWMS. Anim<strong>al</strong> models of the WMS del<strong>et</strong>ion will be usefulbut it is expected that underst<strong>and</strong>ing many aspectsof human cognition <strong>and</strong> its gen<strong>et</strong>ic underpinnings willultimately rest on studying humans. Such human studiesmight depend on the need to define further rareindividu<strong>al</strong>s with WMS <strong>and</strong> sm<strong>al</strong>l del<strong>et</strong>ions, <strong>and</strong> to combin<strong>et</strong>heir molecular structures with a sophisticatedunderst<strong>and</strong>ing of their neurocognitive <strong>and</strong> behavior<strong>al</strong>phenotypes. Although many genes probably contribut<strong>et</strong>o the ment<strong>al</strong> r<strong>et</strong>ardation, it will without doubt be ofinterest to d<strong>et</strong>ermine wh<strong>et</strong>her specific genes could beresponsible for hypersociability, visu<strong>al</strong>–spati<strong>al</strong> deficitsor to the characteristic ERPs that might be markers forWMS. Hopefully, these new studies will provide th<strong>et</strong>ools for investigating human evolution <strong>and</strong>, ultimately,the clues to the pathways that lead to the cognitivefeatures of WMS <strong>and</strong> underlie norm<strong>al</strong> humancognition 80–82 .Concluding remarksOne of the greatest ch<strong>al</strong>lenges faced in underst<strong>and</strong>ingthe brain <strong>and</strong> cognition is the need to link investigationsacross disciplines within the neurosciences. Untilnow, this go<strong>al</strong> has remained unachievable. The studiesreviewed here using a specific neurogen<strong>et</strong>ic disorder,which presents unusu<strong>al</strong> dissociations in highercortic<strong>al</strong> functioning, might provide opportunities toexplore some of the centr<strong>al</strong> issues of cognitive neuroscienc<strong>et</strong>hat tie cognitive functions to brain organization<strong>and</strong>, ultimately, to the human genome.Selected references1 <strong>Bellugi</strong>, U. <strong>et</strong> <strong>al</strong>. in Neurodevelopment<strong>al</strong> Disorders: Contributionsto a New Framework from the Cognitive Neurosciences (Tager-Flusberg, H., ed.), MIT Press (in press)2 <strong>Bellugi</strong>, U., Klima, E.S. <strong>and</strong> Wang, P.P. (1996) in The Life-SpanDevelopment of Individu<strong>al</strong>s: Behavior<strong>al</strong>, Neurobiologic<strong>al</strong>, <strong>and</strong>Psychosoci<strong>al</strong> Perspectives. 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Abstr. 5, 1182 <strong>Bellugi</strong>, U., Lai, Z.C. <strong>and</strong> Korenberg, J. in Frontiere della Biologia:The <strong>Brain</strong> of Homo Sapiens (Vol. 3) (Bizzi, E., C<strong>al</strong>issano, P. <strong>and</strong>Volterra V., eds), Istituto della Enciclopedia It<strong>al</strong>iana (in press)What is the amygd<strong>al</strong>a?A comparative approachL ETTERS TO THE EDITORation he proposed but the use of a comparativeperspective, which is essenti<strong>al</strong> toelaborate solid hypotheses concerning theanatomic<strong>al</strong> <strong>and</strong> function<strong>al</strong> organization ofthe brain.In their exciting <strong>and</strong> provocative article 1 ,Swanson <strong>and</strong> P<strong>et</strong>rovich consider the term‘amygd<strong>al</strong>a’ to be an arbitrary namedescribing a series of structures that areh<strong>et</strong>erogeneous from both anatomic<strong>al</strong> <strong>and</strong>function<strong>al</strong> viewpoints. Function<strong>al</strong>ly, theysee the amygd<strong>al</strong>a as being made up ofnuclei that belong to the autonomicnervous system (centr<strong>al</strong> nucleus), thevomeronas<strong>al</strong> system (medi<strong>al</strong>, posteromedi<strong>al</strong>cortic<strong>al</strong> <strong>and</strong> posterior nuclei), theolfactory system (the cortic<strong>al</strong> olfactorecipientnuclei, the basomedi<strong>al</strong> nucleus<strong>and</strong> the posterior part of the basolater<strong>al</strong>nucleus) <strong>and</strong> the frontotempor<strong>al</strong> cortic<strong>al</strong>system (later<strong>al</strong> nucleus <strong>and</strong> anterior basolater<strong>al</strong>nucleus). Anatomic<strong>al</strong>ly, they considerthe amygd<strong>al</strong>a to be composed oftradition<strong>al</strong> cortic<strong>al</strong> (cortic<strong>al</strong> nuclei <strong>and</strong>areas receiving direct olfactory input),claustr<strong>al</strong> (basolater<strong>al</strong> amygd<strong>al</strong>a) <strong>and</strong> striat<strong>al</strong>elements (centr<strong>al</strong> <strong>and</strong> medi<strong>al</strong> nuclei).In the past, a combination of differentm<strong>et</strong>hods has demonstrated the role of thebasolater<strong>al</strong> <strong>and</strong> centr<strong>al</strong> amygd<strong>al</strong>a in fearconditioning <strong>and</strong> emotion<strong>al</strong> learning 2–4 .Therefore, the basolater<strong>al</strong> amygd<strong>al</strong>a(frontotempor<strong>al</strong>) <strong>and</strong> the centr<strong>al</strong> amygd<strong>al</strong>a(autonomic) appear to constitute a singlefunction<strong>al</strong> system that, according toanatomic<strong>al</strong> data from reptile studies 5–7 ,appears to have been well conservedduring vertebrate evolution. Although theremaining amygd<strong>al</strong>oid nuclei certainlybelong to the main <strong>and</strong> accessory olfactorysystems (in view of the large number ofafferents from the olfactory bulbs), evenSwanson <strong>and</strong> P<strong>et</strong>rovich recognize that theyhave a s<strong>et</strong> of intricate interconnectionswith the centr<strong>al</strong> <strong>and</strong> basolater<strong>al</strong> amygd<strong>al</strong>a.The activity in the chemosensory amygd<strong>al</strong>amust, therefore, have a strong influence onthe basolater<strong>al</strong> <strong>and</strong> centr<strong>al</strong> amygd<strong>al</strong>a, whichsuggests a function<strong>al</strong> interdependence of <strong>al</strong>lthe amygd<strong>al</strong>oid nuclei.Addition<strong>al</strong>ly, as is emphasized by theauthors 1 , their structur<strong>al</strong> classification ofthe amygd<strong>al</strong>a coincides essenti<strong>al</strong>ly withthat proposed by Johnston in 1923(Ref. 8). Using a comparative perspective,Johnston divided the amygd<strong>al</strong>a into a primitivegroup of nuclei, which includes the‘striat<strong>al</strong>’ <strong>and</strong> ‘olfactory’ nuclei, <strong>and</strong> a phylogen<strong>et</strong>ic<strong>al</strong>lynew group of nuclei, the ‘claustr<strong>al</strong>’amygd<strong>al</strong>a. However, recent connection<strong>al</strong><strong>and</strong> neurochemic<strong>al</strong> studies havereve<strong>al</strong>ed the presence of a putative homologu<strong>et</strong>o the mamm<strong>al</strong>ian basolater<strong>al</strong>amygd<strong>al</strong>a in the dors<strong>al</strong> ventricular ridge(DVR) of the reptilian brain 5–7 , which,following the view held by Swanson <strong>and</strong>P<strong>et</strong>rovich, would be claustr<strong>al</strong> <strong>and</strong>, therefore,isocortic<strong>al</strong> in nature. Were this true,the DVR would represent the reptiliancounterpart of the claustrum 9 <strong>and</strong> otherderivatives of the cortic<strong>al</strong> cell plate (layerVIb), even though the remaining layers ofthe isocortex are absent in the reptilianbrain. However, the reptilian DVR has asubcortic<strong>al</strong> origin 10,11 <strong>and</strong> occupies a subventricularposition in the adult. Thisstrongly suggests that the basolater<strong>al</strong>amygd<strong>al</strong>a is not a cortic<strong>al</strong> (claustr<strong>al</strong>) structure.Data on the expression of genes thatcontrol region<strong>al</strong> specification, morphogenesis<strong>and</strong> differentiation in the forebrainof embryonic vertebrates are urgentlyneeded in order to clarify this issue.The major legacy of Johnston’s work onthe amygd<strong>al</strong>a is not the compartment<strong>al</strong>iz-ReplyLanuza <strong>and</strong> his colleagues address two fundament<strong>al</strong>problems in their l<strong>et</strong>ter 1 : how areneur<strong>al</strong> systems defined <strong>and</strong> is there a basicplan of the vertebrate brain? Their excitingEnrique Lanuza<strong>Center</strong> for Neur<strong>al</strong> Science,New York University, NY 10012,USA.Alino Martínez-MarcosDept of Anatomy <strong>and</strong> Cell Biology,He<strong>al</strong>th Science <strong>Center</strong> at Brooklyn,SUNY, Brooklyn, NY 11203-2098,USA.Fern<strong>and</strong>o Martínez-GarcíaDept de Biologia Anim<strong>al</strong>, Fac. CC.Biològiques, Universitat de V<strong>al</strong>ència,Burjassot 46100, V<strong>al</strong>ència, Spain.References1 Swanson, L.W. <strong>and</strong> P<strong>et</strong>rovich, G.D.(1998) Trends Neurosci. 21, 323–3312 Davis, M. (1994) Int. Rev. Neurobiol. 36,225–2663 Ono, T., Nishijo, H. <strong>and</strong> Uwano, T.(1995) Prog. Neurobiol. 46, 401–4224 LeDoux, J.E. (1996) The Emotion<strong>al</strong> <strong>Brain</strong>,Simon & Schuster5 Bruce, L.L. <strong>and</strong> Neary, T.J. (1995) <strong>Brain</strong>Behav. Evol. 46, 224–2346 Lanuza, E. <strong>et</strong> <strong>al</strong>. (1997) J. Comp. Neurol.384, 537–5557 Lanuza, E. <strong>et</strong> <strong>al</strong>. (1998) Eur. J. Neurosci.10, 3517–35348 Johnston, J.B. (1923) J. Comp. Neurol.35, 337–4829 Striedter, G.F. (1997) <strong>Brain</strong> Behav. Evol.49, 179–21310 Yanes, C.M. <strong>et</strong> <strong>al</strong>. (1987) J. Morphol.194, 55–6411 Lohman, A.H.M. <strong>and</strong> Sme<strong>et</strong>s, W.J.A.J.(1990) in The Neocortex (Finley, B.L.,Innocenti, G. <strong>and</strong> Scheich, H., eds),pp. 59–74, Plenum Presswork on the connections of what appearsto be the amygd<strong>al</strong>a in reptiles refers to thelatter, classic<strong>al</strong> problem, which has beenreviewed thoroughly quite recently 2 .What is a neur<strong>al</strong> system? Perhaps thebest way to approach this problem isthrough a simple example. Essenti<strong>al</strong>TINS Vol. 22, No. 5, <strong>1999</strong> 207