Down syndrome, Alzheimer's disease and the trisomy 16 mouse

Downsyndrome,Alzheimer'sdiseaseandthe somy 16 mouse Joseph T. Coyle, M a r y Lou Oster-Granite, Roger H. Reeves and John D. Gearhart

decade 6. Second, the gene encoding the 'precursor' protein for the 42 amino acid cerebrovascular A4[3 amyloid peptide 7, which accumulates in senile neuritic plaques and around blood vessels in AD, has been identified and mapped to chromosomal position HSA 218-1°. Third, recent molecular genetic studies have revealed a restriction fragment length polymorphism (RFLP) on HSA 21 that is genetically linked to the vulnerability to familial AD (FAD) in some families H. This form of AD exhibits an autosomal dominant pattern of inheritance and affects approximately 15-20% of the cases of AD, particularly those with an early age of onset. Finally, family studies of patients suffering from the senile form of AD suggest a pattern of vulnerability in first-degree relatives consistent An understanding of the pathophysiology of with an autosomal dominant pattern of inheritance ~2. Alzheimer's disease (AD) has been hindered by the Collectively, these results indicate that genes located lack of suitable animal models that could be subjected on HSA 21 may be involved in the etiology of the AD to rigorous molecular and cellular biological studies pathology of DS and in FAD and suggest that study of since such studies currently are not feasible with the regulation of the expression of genes located on humans. While the cognitive impairments observed in HSA 21 may prove informative about the pathogenaged rodents and primates may reflect compromised esis of AD. central cholinergic function 1, it is generally agreed that AD is a disease process with specific pathological Alzheimer's disease and Down syndrome features. Furthermore, the synaptic neurochemical DS is the most common form of mental retardation abnormalities of AD can be distinguished from those with a known genetic cause la. In most cases, DS associated with simple aging 2. Lesion-induced deficits results from the non-disjunction of HSA 21 during of basal forebrain cholinergic neurons in animals have meiosis, so that three copies of HSA 21 are present in been informative about the behavioral role and synap- the cells of the affected individual, instead of the usual tic pharmacology of this particularly vulnerable neur- two. Thus, the developmental anomalies seen in DS onal pathway in AD, but do not recreate the other do not result from the action of a mutant gene, but characteristic pathological features a. Several other rather from the expression of the additional copies of neurotransmitter systems, including noradrenergic and normal genes located on HSA 21. somatostatin-containing neurons, are also affected DS is frequently lethal early in development; an in AD4's. To date, only humans are known to develop estimated 75--90% of DS conceptuses die in utero. spontaneously the neuropathological and cognitive Virtually every organ system is affected in the manifestations of AD. complex phenotype that characterizes DS 14. For example, DS individuals suffer from a high incidence Genetics of Alzheimer's disease of a rare congenital heart anomaly, endocardial Recent studies have provided four lines of evidence cushion defects. Impairments in normal development that genetic factors are involved in the etiology of AD. of the gastrointestinal system occur frequently, and First, as discussed in greater detail below, most the risk of developing leukemia is 20-50 times greater individuals with Down syndrome (DS; trisomy 21) than in the normal population. However, the most develop the pathological features of AD by the fourth common phenotypic manifestation of DS is mental subnormality 1S. Histopathological studies indicate that TABLE I. Comparison between Alzheimer's disease and the Down syndrome- the brain of the DS individual is typically reduced in size, that its cortical convolutions are fewer and less Alzheimer's disease complex well-developed, and that the number of cortical AD DS-AD neurons and the degree of their dendritic complexity Age of onset 6th-Sth decade 4th decade are reduced when compared with those of normal Cognitive deterioration Yes ? individuals. Nevertheless, the precise mechanisms Neuritic plaques Yes Yes that account for the mental retardation of DS indiNeurofibrillary tangles Yes Yes viduals remain poorly understood. Amyloid Yes Yes Although the early age of onset of AD pathology in Cholinergic deficits Yes Yes individuals with DS was noted over 40 years ago 16, Noradrenergic deficits Some Yes the significance of this association has been appreciJoseph T.Coyle,Mary Lou Oster.Granite, RogerH. Reevesand John D. Oearhartare at the Departmentsof Psychiatry, Neuroscience, Physiology, Cell Biologyand Anatomy, Gynecologyand Obstetricsand the Developmental GeneticsLaboratory, TheJohnsHopkins UniversitySehoolof Medicine, Baltimore, MD 21205, USA.

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Recent findings have implicated genes on human chromosome 21 as important in the pathophysiology of Alzheimer's disease (ADJ. These include the high incidence of the pathological features characteristic of AD in individuals with Down syndrome (trisomy 21) and the localization of both a familial AD gene and the gene encoding amyloid precursor protein on chromosome 21. Substantial genetic homology exists between human chromosome 21 and mouse chromosome 16, including the gene encoding the amyloid precursor protein. Mice that are trisomic for chromosome 16 offer a genetic model.for studies relevant to Down syndrome that may also help to clarify molecular mechanisms involved in Alzheimer's disease.

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ated only recently. Wisniewski and her colleagues 6 conducted a detailed histopathological analysis of the brains of a hundred DS cases who died at various ages. They reported that, by the age of 40, pathology of the AD type was found in 100% of DS individuals examined. Histopathological studies indicate that, quantitatively and qualitatively, the distribution of neurofibrillary tangles and neuritic plaques in the DS individuals with AD pathology and in AD individuals is indistinguishable 17'18. Selective deficits occur in several neurotransmitter systems innervating or intrinsic to the cerebral cortex and hippocampus in AD. The most prominently affected systems are the basal forebrain cholinergic projections, the locus coeruleus noradrenergic neurons, and cortical somatostatincontaining neurons3. Yates et al. 19'2° have found significant reductions in presynaptic markers for cholinergic and noradrenergic neurons in the brains of DS individuals with AD pathology. Furthermore, the number of neurons in the nucleus basalis, the main source of cortical cholinergic projections, appears to be reductd in the brains of DS individuals21'22, although this finding is disputed23. Examination of histopathology and synaptic neurochemical abnormalities shows that triplication of genes located on HSA 21 results in an extremely high risk of developing the neurological features of AD at a remarkably early age (Table I). Nevertheless, there is debate as to whether all affected DS individuals exhibit the cognitive deterioration associated with the AD pathology24-26.

expression of the genes present in triplicate. Shared features of aneuploidy include a high frequency of lethality, resulting in intrauterine death in virtually all trisomies except trisomy 19, which involves triplication of the smallest autosome. Two other shared features of primary trisomies in mice are growth retardation and hypoplasia. The basis of this common generalized deficiency of cells remains unclear. Studies implicating alterations in the duration of cell cycle based on results from cultured trisomic cells remain controversial.

7

1 - -prin.1 (16), Prrn.2 7

~kv-2

AoI-1 (2z) 5

~-Igl-1 r -$mst

(3q)

11

Genetics of mouse chromosome 16 Gene mapping techniques have been greatly facilitated by recent advances in molecular genetics. As genetic maps in different species 8 have become more detailed, it has dW become clear that clusters of genes sometimes remain closely linked through evolution. For example, at least six genes mapped to HSA 21 are located on 16 MMU 16 (Fig. 1). However, MMU 16 is considerably larger than HSA 21 and contains genes that are located on at least three Mouse models of aneuploidy 2 1 ° Aneuploidy is a condition in which whole chromo- human chromosomes other than HSA 2129-32. In addition, some somes or parts of chromosomes are duplicated or deleted, leading to an unbalanced genetic comp- genes on HSA 21 are found on lement. Aneuploidy adversely affects developmental mouse chromosomes other than processes and often results in developmental failure MMU 1633. Ifrc * Given the genetic homology that and intrauterine death. The abnormalities associated with aneuploidy could be a consequence of excess exists between MMU 16 and HSA Pros * genetic material, or could, instead, be a result of 21, it is of considerable interest Cola - 2 (Tq) disruption in development due to the over- or under- that trisomy 16 (Tsl6) mice and Gap 43 (S) expression of specific genes encoded in the duplica- individuals with DS share several Fig. 1. Linkage map of mouse tion or the deletion. Since most mammals appear to characteristic (if not unique) fea- chromosome 16. The positions on the exhibit a very low spontaneous incidence of aneu- tures 2s. Both have endocardial genetic map of the genes listed ploidy compared with humans, this concern has been cushion defects and similar cranio- beneath the map have not been difficult to resolve until recently. The German patho- facial malformations, including par- determined. Genes mapped to HSA logist, Alfred Gropp, developed a novel breeding ficular audiovestibular anomalies, 21 are indicated by asterisks whereas scheme to generate aneuploidy for each of the 19 platybasia, midface hypoplasia and the human chromosomal Iocalizations autosomes of the mouse 27. The breeding scheme ocular defects34-36. Finally, the of other genes are given in parenuses naturally occurring robertsonian chromosome Tsl6 mouse exhibits significant theses. Abbreviations: rod, mahogtranslocations, which result from the fusion of two hematopoietic stem cell defects anoid; Prm 1, 2, protamines I and 2; Akv2, endogenous ecotropic acrocentric chromosomes at the centromeres (Fig. that may be analogous to some of pro-virus; Igl-1, immunoglobufin ~1 1). Animals containing two such chromosomes that the hematological abnormalities light chain; Igl-lr, immunoglobulin are homologous in one arm, but not the other, will observed in DS 14'~8. regulatory locus; Smst, somatostatin; produce normal, hypo- and hyper-haploid gametes. Bst, belly spot and tail; Mtv6, endogenous mouse mammary tumor When these gametes fuse with normal eggs or sperm The neurobiology of Ts 16 Reduced size is a striking fea- virus sequence; Mtv6r, Mtv reguladuring fertilization, embryos are produced that are eusomic, monosomic or trisomic for the genes on ture of the Tsl6 brain when com- tory locus; App, amyloid precursor Sod- 1, [Cu 2+, Zn 2+] pared with that of its euploid litter- protein; specific chromosomes. Using this breeding scheme, primary trisomies for mate, especially at mid- to late- superoxide dismutase, cytoplasmic each of the 19 autosomes in the mouse have been gestation, when the reduction in form; Mx, influenza virus resistance; Ets-2, proto-oncogene; wv, weaver; generated and examined. Some features are common weight approaches 30% (day 17 of Ifrc, ol- and r-interferon cell surface to several trisomies and may reflect the general gestation)a7. When Nissl-stained receptor; Prgs, phosphoribosyl glyconsequences of aneuploidy; in contrast, some fea- sections of the telencephalon of the cinamide synthetase; Cola-2, coltures appear to be unique to a particular trisomy28. Ts16 mouse at day 15 of gestation lagen type 1 and 2; Gap 43, growthSuch unique features may result from abnormal are examined, hypocellularity of associated protein. TINS, Vol. 11, No. 9, 1988

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TABLE II. Synaptic chemistry of Ts16 and Ts19 mice

littermates reveal significant reductions in the presynaptic markers of specific neurotransmitter systems z7'38. The cholinergic system in the brainstem Brain weight D D seems to be the system that is most affected; this in Brain protein D D part comprises lower motor neurons of the cranial Choline acetyltransferase nerves and neurons of the basal forebrain. A con~r Telencephalon N D comitant decrease in the specific activity of choline ,AMidbrain brainstem D N acetyltransferase in the striatal intrinsic cholinergic Glutamate decarboxylase N D neurons is not evident. Other neurotransmitter Serotonin D N systems affected include: the noradrenergic; to a ~r Dopamine N D lesser extent, the serotonergic; and variably, the Norepinephrine D D dopaminergic systems of the brainstem. However, Abbreviations: D, decreases in trisomic fetuses compared with euploid litterthe GABAergic system is spared, as no differences in mates; N, no significant alterations; ~, areas where there is disparity between the the specific activity of glutamate decarboxylase or the two trisomies. levels of GABA are observed in the Tsl6 brain as the cortical plate and subplate layer is accompanied by compared with euploid littermates. In addition, speciincreased thickness of the proliferative subventricular fic activities of DOPA decarboxy|ase and of catecholzone. Since the cortex is arranged in processing units O-methyltransferase are increased and the specific that subserve particular functions, such hypocel- activity of monoamine oxidase is unchanged in the lularity may affect not only the number of cells within a Tsl6 brain as compared with euploid littermate unit (its integrative capacity), but also the total controls. Combining acetylcholinesterase histochemistry number of units. Such a reduction of overall cell number, and perhaps of the ratio of interneurons to with [3H]thymidine autoradiography, it has been output neurons, is consistent with descriptions of the possible to show that the number of basal forebrain immature DS brain. The increased ratio of the cholinergic neurons is reduced in the Ts16 mouse, a thickness of the germinal zone relative to post-mitotic finding consistent with the quantitative reductions in cortical plate has been interpreted to indicate pro- choline acetyltransferase 36. In addition, the caudal-tolonged cell cycle duration; however, studies in the rostral sequence of cell division generating these Tsl6 mouse do not support this conclusion 36. cholinergic neurons appears to be altered in the Ts16 Whereas the total number of mitotic cells is reduced in brain. The reductions in choline acetyltransferase the Tsl6 mouse brain relative to that of littermate activity and in the number of basal forebrain cholinercontrols, the duration of the cell cycle in the gic neurons in the Ts16 brain appear consistent with developing hindbrain (cerebellum, etc.) is not changed the reports of reduced basal forebrain cholinergic significantly during mid-gestation. Analyses of pro- neurons in the DS brain and the vulnerability of the gressively younger gestational stages in the Tsl6 basal forebrain cholinergic neurons to AD pathology22. mouse demonstrate that cell numbers are already One critical issue requiring resolution with regard reduced by day 9 of gestation. Thus, it appears that if to the synaptic neurochemical alterations observed in changes in cell cycle duration affect Tsl6 mouse Tsl6 brains is whether these changes are the nondevelopment, they do so during gastrulation (day 6.5 specific consequence of aneuploidy disrupting overall to day 8 of gestation). embryogenesis, or whether the changes are the Detailed studies comparing the synaptic neuro- specific result of dosage effects of specific genes chemistry of the Tsl6 mouse brain with euploid located on MMU 16. To resolve this question, detailed synaptic neurochemical studies were conducted on mice with trisomy of MMU 1939. As shown WITH ¢~NVI~T IONAL IIE][O$1S Z K&RYOTYP[ -- ALL in Table II, the reductions in brain weight and protein ACAOCIBHTRIC content in the Tsl6 and Tsl9 fetuses were comparQt~I~I.I[NTS CONCI[PTU$1[S able; the synaptic neurochemical profile of the Ts19 ANAPHAS[ Z $[GI~GATION brain, however, differed considerably from that of the Tsl6 brain. Thus, the impairments in the development and differentiation of specific neurotransmitter systems in the Tsl6 brain appear to reflect gene dosage effects whereas the more non-specific hypoplasia appears to be a general consequence of aneuploidy. Ts16

Ts19

Disparity

Amyloid precursor protein and the trisomy 16 mouse Recently, the gene encoding amyloid precursor protein (App) has been mapped to HSA 21, band q21, supporting the hypothesis that abnormal expression of genes located on HSA 21 might predispose DS Fig. 2. Breeding scheme for the production of trisomic mice. The mouse doubly individuals to developing AD in mid-life7-1°. In the heterozygous for robertsonian chromosomes with monobrachial homology is mouse, the gene has been localized to the distal 20mated to an animal with all acrocentric chromosomes. The gametes generated 25% of MMU 16, based on concordant segregation of have O, 1 or 2 metacentric chromosomes. At fertilization, the gametes with the mouse gene with a translocated segment of MMU both or neither of the metacentric chromosomes result in trisomic and 16 in somatic cell hybrids 31'4°. Using interspecific monosomic conceptuses, respectively. backcrosses, Reeves et al. 31 determined the gene 392

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order from proximal to distal on MMU 16 to be App, Sod-1 (superoxide dismutase), Ets-2 (the proto-

amount of App mRNA extracted from the whole brain of the Ts16 mouse at day 14 of gestation as compared with its littermate controls. Thus, there appears to be a considerable increase in the level of App transcript in the Ts16 fetal brain that is disproportionately greater than that expected from the 1.5-fold gene dosage effect.

oncogene). Thus, these genes have remained linked in the same order since divergence of a common ancestor of mouse and man, approximately 80 × 106 years ago. A cDNA clone of the human App message was used to isolate a corresponding cDNA from a mouse brain cDNA library. This mouse App cDNA was used for in Concluding remarks Genetic mapping of HSA 21 and MMU 16 has situ hybridization to localize App mRNA expression in the brain41. As in human brain, levels of App mRNA revealed that these chromosomes share a number of varied markedly in different regions of the mouse genes, including those implicated in AD in humans. brain. When the sections were analysed by quantita- Thus, studies of the Tsl6 mouse may provide a better tive densitometry, expression was particularly high in understanding of the genetic mechanisms involved in the cerebral cortex and in subfields of the hippocampal the pathogenesis of neurological changes in both DS formation, especially overlying the pyramidal cells, and AD. Unfortunately, Tsl6 mice do not survive but low in the striatum, midbrain regions and remain- birth, which complicates studies of the effects of this Lug brainstem. Excitotoxin lesion of the pyramidal trisomy on postnatal brain maturation and aging. The cells in the hippocampal formation, which selectively formation of chimeras involving Tsl6 cells42, whether deletes neurons but does not affect glial cells, resulted in whole animals or through the exploitation of in a virtually complete elimination of the dense band of transplantation techniques for selected brain regions, hybridization signal overlying the pyramidal cells. and the use of primary cell cultures derived from fetal Thus, App mRNA appears to be markedly elevated in brain, may help to clarify the relationships between certain classes of neurons, although its expression in aneuploidy, regulation of gene expression and selecnon-neuronal cells in the brain and in the periphery is tive neuronal vulnerability associated with AD and DS. More specific roles played by genes on HSA 21 evident. Sections through the heads of Tsl6 mouse fetuses, can be defined by the creation of mice transgenic for littermate controls, and Tsl9 fetuses were also individual genes or groups of genes on HSA 21 and examined by in situ hybridization. The expression of MMU 16. App mRNA was increased markedly in the cortical plate of the Tsl6 mouse as compared with its euploid Selected references 1 Bartus, R., Dean, R.L., Beer, B. and LJppa, A.S. (1982) littermate (Fig. 3). Although Tsl9 and Tsl6 mice Science 217, 40~-417 showed a similar degree of cortical hypoplasia, no 2 Terry, R. and Davis, P. J. (1980) Annu. Rev. Neurosci. 3, 77increase in App mRNA was observed in comparison 95 with littermate controls. Furthermore, northern blot 3 Coyle, J. T., Price, D. and DeLong, M. (1983) Science 219, 1184-1190 analysis revealed a nearly threefold increase in the

Fig. 3. Expression o f A p p mRNA. Color-enhanced computer image of corona/section through the heads of normal and Ts16 mice at day 15 of gestation. Sections were hybridized with [35S]-Iabelled cDNA probe for mouse App. Note that the optical density varies from 0.00 to 2.41. There is a clear increase in hybridization signal but a similar distribution in various brain regions of Ts16 fetal mouse brain relative to the fittermate control.

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Acknowledgements We wish to thank the many collaborators, postdoctoral fellows and studentsinvolved in the Ts16pro]ect.

4 Rossor, M. and Iversen, L. (1986) Br. Med. Bull. 42, 70-74 5 Katzman, R. (1986) N. Engl. Med. J. 314, 964-973 6 Wisniewski, K. E., Wisniewski, H. M. and Wen, G. Y. (1985) Ann. Neurol. 17, 278-282 7 Glenner, G. G and Wong, C. W. (1984) Biochem. Biophys. Res. Commun. 120, 885-890 8 Kang, J. etaL (1979) Nature 325, 733-736 9 Robakis, N. K., Ramakrishna, N., Wolfe, G. and Wisniewski, H. M. (1987) Proc. Natl Acad. Sci. USA 84, 4190-4194 10 Goldgaber, D., Lerman, M. I., McBride, W. O., Saffiotti, U. and Gajdusek, D. C. (1987) Science 235, 887-880 11 St George-Hyslop, P. H. et aL (1987) Science 235, 885-890 12 Breitner, J. C., Folstein, M.F. and Murphy, E.A. (1986) J. Psychiatr. Res. 20, 31-43 13 Hook, E. B. (1981) in Trisomy 21 (Down Syndrome) (de la Cruz, F. F. and Geralk, P. S., eds), pp. 3-68, University Park Press 14 Epstein, C. J. (1986) The Consequences of Chromosomal Imbalance, Cambridge University Press 15 Coyle, J. T., Oster-Granite, M. L. and Gearhart, J. D. (1986) Brain Res. Bull. 16, 773-787 16 Jervis, G. A. (1948) Am. J. Psychiatr. 105, 102-106 17 Ball, M. J. and Nuttal, K. (1981) J. Neuropathol. Appl. Neurobiol. 7, 13-30 18 Burger, P. C. and Vogel, F. S. (1973) Am. J. Pathol. 73,457476 19 Yates, C. M. etal. (1983) Brain Res. 280, 119-126 20 Yates, C. M. etal. (1983) Brain Res. 258, 45-52 21 Mann, D. M. A., Yates, P.O. and Marcynicek, B. (1984) J. Neuropathol. Appl. Neurobiol. 10, 185-207 22 Casanova, M. F., Walker, L. C., Whitehouse, P. J. and Price, D. (1985) Ann. Neurol. 18, 310-313 23 Kirkpatrick, J. B. and Hicks, P. (1984) J. Neuropathol. Exp. Neurol. 43, 307

24 Ropper, A. H. and Williams, R. S. (1980) Neurology 30, 639644 25 Schwarz, M. et al. (1983) Science 221,781-783 26 Shapiro, M. B., Haxby, J. V., Grady, G. L. and Rapoport, S. I. (1986) in The Neurobiology of Down Syndrome (Epstein, D. J., ed.), pp. 89-108, Raven Press 27 Gropp, A., Kolbus, U. and Giers, D. (1975) Cytogenet. Cell Genet. 14, 42-62 28 Gearhart, J., Davisson, M. T. and Oster-Granite, M. L. (1986) Brain Res. Bull. 16, 789-801 29 Reeves, R. H., Gearhart, J. D. and Littlefield, J.W. (1986) Brain Res. Bull. 16, 803-814 30 Reeves, R. H., Callahan, D., O'Hara, B. F., Callahan, R. and Gearhart, J. D. (1987) Cytogenet. Cell Genet. 44, 76-81 31 Reeves, R. H. etal. (1987) Mol. Brain Res. 2, 215-221 32 Watson, D. K. et al. (1986) Proc. Natl Acad. Sci. USA 83, 1792-1796 33 Skow, L. C. and Donner, M. E. (1985) Genetics 110, 723732 34 Oster-Granite, M.L., Gearhart, J.D. and Reeves, R.H. (1986) in The Neurobiology of Down Syndrome (Epstein, D. J., ed.), pp. 137-151, Raven Press 35 Oster-Granite, M.L. et al. (1987) in Animal Model of Dementia (Coyle, J. T., ed.), pp. 279-307, Alan Liss 36 Oster-Granite, M. L. et al. (1987) Soc. Neurosci. Abstr. 13, 1121 37 Singer, H. S., Tiemeyer, M., Hedreen, J. C., Gearhart, J. and Coyle, J. T. (1984) Dev. Brain Res. 15, 155-166 38 Ozand, P. T. etal. (1984) J. Neurochem. 43,401-408 39 Saltarelli, M. D., Forloni, G-L., Oster-Granite, M. L., Gearhart, J. D. and Coyle, J. T. (1987) Dev. Genet. 8, 267-279 40 Lovett, M. et al. (1987) Biochem. Biophys. Res. Commun. 144, 1069-1075 41 Bendotti, C. etal. (1988) Proc. NatlAcad. Sci. USA 85, 36283632 42 Gearhart, J. D. et al. (1986) Brain Res. Bull. 16, 815-824

Probing visual cortical function with discrete chemical lesions William

T. N e w s o m e

a n d R o b e r t H. W u r t z

Recent anatomical and physiological experiments sugInitial glimpses into the functional roles played by gest that a neural pathway in primate visual cortex several of these visual areas emerged from single-unit selectively analyses visual motion information. By recordings in anesthetized monkeys. Zeki and cocreating small chemical lesions in identified visual workers reported that a striate-recipient zone of the areas of this pathway, a new link has been established superior temporal sulcus contained a preponderance between the physiological properties of cortical neurons of direction-selective neurons a, whereas other and the behavioral capabilities of rhesus monkeys. Such extrastriate areas appeared relatively enriched in lesions elevate psychophysical thresholds in motion- color-selective neurons 4'5. Zeki suggested that the Sensorimotor related tasks while leaving non-motion thresholds extrastriate visual areas function in parallel, with each Research,National unaffected. Small chemical lesions also impair a area being specialized for the analysis of a particular EyeInstitute, monkey's ability to employ motion information to guide aspect of the visual image such as motion, color, Bethesda,MD 20892. eye movements, but have no effect on eye movements to disparity, or orientation 6. More recently, the complex USA. static targets. This technique creates the opportunity for serial as well as parallel nature of extrastriate a detailed functional analysis of the motion pathway organization has been emphasized by the notion of and may be employed in other visual pathways as well. functionally specialized 'pathways' or 'streams of processing' in visual cortex 7'8. In this view, parallel One of the most intriguing developments in the study extrastriate pathways indeed process distinct types of of the mammalian visual system has been the discov- visual information, but serial principles are incorporery of multiple cortical areas that perform an exten- ated within each pathway as indicated by extensive sive analysis of the visual image beyond that carried feedforward and feedback connections within a pathout by the primary visual area (striate cortex, or V1). way and by progressively more complex response In the macaque monkey, investigators from a number properties at higher levels of a pathway (reviewed in of laboratories have identified more than 20 'extrastri- Ref. 2). ate' visual areas in the occipital, temporal and The most intensively studied pathway in primate parietal lobes. Many of these areas are illustrated in extrastfiate cortex appears to be devoted to the Fig. 1, and together they comprise roughly half of the analysis of visual motion. This pathway is characterneocortex of the m a c a q u e1 2' . A major task now ized at each stage by neurons that respond selectively confronting investigators in this field is to understand to the direction of motion of a visual stimulus while how these extrastriate visual areas contribute, indi- being relatively unselective for other aspects of the vidually and collectively, to visual perception and stimulus. The motion pathway originates in layer 4B of striate cortex, or V1, and may include the 'thick' visually guided behavior. William T. Newsome is at the Department of Neurobiology, StanfordUniversity Schoolof Medicine, Stanford, CA 94305, USAand RobertH. Wurtz is at the Laboratoryfor

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