J. PhysioL 424, 513-531 17 Davies, C. H., Starkey, S. J., Pozza, M. F. and Collingridge, G. L. (1991) Nature 349, 609-611 18 Seabrook, G. R., Howson, W. and Lacey, M. G. (1990) Br. J. PharmacoL 101,949-957 19 Gahwiler, B. H. and Brown, D. A. (1985) Proc. NatlAcad. Sci. USA 82, 1558-1562 20 Heinemann, U., Hamon, B. and Konnerth, A. (1984) Neurosci. Left. 47, 295-300 21 Padjen, A. L. and Mitsoglou, G. M. (1990) Brain Res. 516, 201-207 22 Misgeld, U., Muller, W. and Brunner, H. (1989) PfliJgers Arch. 414, 139-144 23 Lambert, N. A., Harrison, N. L. and Teyler, T. J. (1991) Brain Res. 547, 349-352 24 Saint, D. A., Thomas, T. and Gage, P. W. (1990) Neurosci. Left. 118, 9-13 25 Rudy, B. (1988) Neuroscience 25, 729-749 26 Login, I. S., Pancrazio, J. J. and Kim, Y. I. (1990) Brain Res. 506, 331-334 27 Atkins, P. T., Surmeier, D. J. and Kitai, S. T. (1990) Nature 344, 240-242 28 Alger, B. E. (1984) J. Neurophysiol. 52, 892-910 29 Newberry, N. R. and Nicoll, R. A. (1984) Nature 308, 450-452 30 Inoue, M., Matsuo, T. and Ogata, N. (1985) Br. J. Pharmacol. 84, 833-841 31 Andrade, R., Malenka, R. C. and Nicoll, R. A. (1986) Science 234, 1261-1265 32 Hablitz, J. J. and Thalrnann, R. H. (1987) J. NeurophysioL 58,

160-179

33 Dutar, P. and Nicoll, R. A. (1988) Nature 332, 156-158 34 Innis, R. B., Nestler, E. J. and Aghajanian, G. K. (1988) Brain Res. 459, 27-36 35 Newberry, N. R. and Nicoll, R. A. (1985) 1. Physiol. 360, 161-185 36 Newberry, N. R. and Nicoll, R. A. (1984) J. Physiol. 348, 239-254 37 Thalmann, R. H. (1987) Neurosci. Lett. 82, 41-46 38 Rovira, C., Gho, M. and Ben-Ari, Y. (1990) PfliJgers Arch, 415, 471-478 39 VanDongen, A. M. J. et aL (1988)Science 242, 1433-1437 40 Premkumar, L. S., Chung, S-H. and Gage, P. W. (1990) Proc. R. 5oc. London 5er. B 241, 153-158 41 Chung, S-H., Moore, J. B., Xia, L., Premkumar, L. S. and Gage, P. W. (1990) Phil Trans. R. 5oc. London 5er. B 239,

Acknowledgements Many of the ideas presentedin this review were discussed and developed with co~leagues,especially S-H. Chung and L. Premkumar. I am grateful to M. Robe~on for help in preparing the manuscript.

265-285

42 Krouse, M. E., Schneider, G. T. and Gage, P. W. (1986) Nature 319, 58-60 43 Axelrod, J. A., Burch, R. M. and Jelsema, C. L. (1988) Trends Neurosci. 11, 117-123 44 Piomelli, D. and Greengard, P. (1990) Trends PharmacoL Sci. 11, 367-373 45 Bormann, J. (1988) Trends Neurosci. 11, 112-116 46 Enna, S. J. and Karbon, E. W. (1987) Trends Pharmacol. 5ci. 8, 21-24 47 Premkumar, L. S., Gage, P. W. and Chung, S-H. (1990) Proc. R. Soc. London Ser. B 242, 17-22 48 Dunwiddie, T. V., Taylor, M., Cass, W. A., Fitzpatrick, F. A. and Zahniser, N. R. (1990) Brain Res. 527, 76-80

Australian marsupialsas modelsfor the developing mammalian visualsystem R. F. M a r k a n d L. R. M a r o t t e

This article makes two points. First, the diprotodont marsupials, including the kangaroos, wallabies and the Australian possum are not primitive mammals, and their brains make as good a general model of the higher mammals such as monkeys and humans as do those of the more common laboratory mammals such as cats and rats. Second, the peculiarities of marsapial reproduction, which comprises a very short period of intrauterine development, followed by a relatively protracted period o/development in the pouch, provide unparalleled advantages for research into mammalian neuroembryology. Examples will be provided of how such research has made a contribution to our understanding o/neural development, concentrating primarily on the visual system. The evolutionary tree in Fig. 1 shows that the marsupials (metatherian mammals) diverged from eutherian mammals some 135 million years ago - so early that there may not have even been a common mammalian ancestor ~. Macropodoids, the most advanced marsupials, exemplified by the kangaroos, have adapted rapidly to different ecological opportunities and have produced large radiations with a wide diversity of forms. There are more than 60 living species in this group alone. The development of such a diversity of mammalian forms with similar characteristics that have descended separately from metatherian and eutherian mammals is the classical example of convergent evolution. It is natural to think that the marTINS, Vol. 15, NO. 2, 1992

supials converged with the other mammals, but it may equally well be put the other way around. When considering the nervous system, it might be thought that in such a long independent history, this convergence might have failed at one or many points and that the brains of marsupial mammals would be rather different from those of the eutherians.., they are not. Comparative neurological studies have shown them to be typical mammalian brains in most respects. Most of the details of neuroanatomy are so similar to those found in representatives of the placental mammals that they cannot be distinguished on histological grounds 2-4. There are differences within the marsupials, particularly between the more primitive ones such as the American opossum and the advanced Australian diprotodonts, but the differences between members of the placental and marsupial groups are in general no greater than variations within either one. Electrophysiological experiments have shown that between the two groups there are similar parallels in the organization of the pyramidal tract 5'6, the auditory cortex 7, the visual thalamus8'9, the somatosensory thalamus 1° and the visual cortex 11. The major exception came to light as soon as the first specimens of kangaroo brains were sent to England for examination. Owen 12 recognized the striking gross neuroanatomical peculiarity of the marsupials - the absence of the corpus caUosum directly linking the cerebral hemispheres (Fig. 2). His descriptions, recorded in 1837, are interesting in their

© 1992, ElsevierScience PublishersLtd, (UK) 0166- 2236192/$05.00

R. F. Mark and L. R. Marotte are at the Developmental Neurobiology Group and Centre for Visual Science, Research Schoolof Biolog;cal Sciences,Australian National University, CanberraACT2601, Australia.

51

physiological evidence for the functional homology of the fasciculus aberrans and the corpus callosum Kangaroos& Wallabies in the visual cortex, completing yet I another striking story of converDIPROTODONTA [ Aust. Possum gent evolution. The neuroembryological reasons for the selection of 135 76 Koala either the dorsal or the ventral route for interhemispheric conMAMMAL- LIKE nections have not yet been studied, I OTHER AUST. MARSUPIALS Bandicoot 149 METATHERIA [ 128 but it seems that functionally it REPTILES American Opossum does not matter. In ferrets, which are born relatively early in development compared to other MONOTREMATA Platypus eutherians, a transient interhemispheric connection of the dorsal Birds & Reptiles neocortices via the anterior commissure has been detected early in Fig. 1. The separation of marsupials is very ancient; numbers on the diagram indicate millions of postnatal life, so this route is not years. The diprotodonta, koalas, Australian (Aust.) possums and kangaroos are the most advanced. completely prohibited in eutherian brains 15. Despite being neurologically determination to paint the marsupials as primitive and typical mammals, the method of reproduction of inferior to placental mammals, even going so far as to marsupials is quite different from that of eutherians. 'associate the greater perfection of the brain resulting When the young are born, most parts of the nervous from the development of the great commissure with system are at a very early stage of development; this the placental mode of development of the true development is completed during a very long stay in Mammalia.' He also mentions his 'attentive study of the pouch, during which the young are nurtured by the manners of different Marsupiata in confinement', the mother's milk rather than by a placental cirand alludes to 'an inferiority of intelligence and a low culation16. Attached to the teat, development proceeds development of the cerebral organ.' Just what you at a rate that is much slower than in most placental would expect of the fauna of a penal colony! It is hard laboratory mammals but similar to that of the higher to believe that the unfortunate captive creatures were primates. For example, the time from conception to given a fair hearing, given the prejudices of their eye opening in humans and monkeys is 182 and 123 inquisitor. Surprisingly, this attitude is still prevalent days, respectively17, in the tammar it is 163 days TM, while in the rat it is only 36 days 17. This slower today. Owen concludes his analysis by proposing that the maturation has the important experimental advantage marsupials led an easy existence in Australia, and in that events that might happen apparently simulrelates his perception of the more perfect placental taneously in, for example, the rodent foetus, are brain to performance in 'a larger theatre in which the spread out in time, so that an underlying sequence avoidance of more numerous and powerful enemies, might become obvious. The major part of the or the capture of more varied and subtle prey, development of the central visual nervous structures, demands the manifestation of more courage, the that is, from the invasion of the primary visual centres practice of more address, and the possession of more by optic axons to the genesis of cells of the visual resources than appear to be called for by the cortex and eye opening, takes place after birth but exigencies of the Marsupiata in their more limited before the head emerges from the pouch and visual sphere.' In spite of the ringing prose this view does experiences first impinge on the brain 19-21. not accord with the realities of drought, fire and flood The pouch young is a robust little creature. In the of the Australian climate, nor with the efficiency of tammar wallaby (Macropus eugenii), which is comcrocodiles, eagles, dingos and humans as predators, monly used for laboratory research and in other and not at all with the real menace of an angry red similar species, the pouch young may be removed at kangaroo! any time from the day of birth onwards, anaesthetized Owen did comment on the greatly enlarged anterior separately from the mother, revived and reattached commissure in marsupials without realizing that this to the teat with effectively no mortality22. It is a freewas related to the absence of the corpus callosum. living foetus and poses no greater experimental Examining kangaroo brains 65 years later, Elliot- problems than those that are encountered in the freeSmith 13 found the related peculiarity of the fasciculus living larvae of the non-mammalian vertebrates upon aberrans. This structure runs from the dorsal neocor- which most of our knowledge of neuroembryology tex via the internal capsule to cross the midline in the rests. It is not difficult to perform experiments that anterior commissure, and thus accompanies fibres require quite precise manipulation of the foetus in the from the more ventral cortex that reach the anterior course of development, injection of tracer substances commissure by the normal route of the external into the PNS 19 ' 20 ' 2 3 - 3 0 or CNS 18 ' 31 , microsurgicalopercapsule. Heath and Jones 14 showed anatomically that ations 23 ' 2 5 - 3 0 or electrophysiological recording92.33 "'. the fasciculus aberrans carries interhemispheric fibres If prolonged survival is not required, the pouch young that cross-connect symmetrical neocortical regions, can be kept in a humid artificial pouch and fed through and that the combination of this and the expanded the mouth. Furthermore, the adults breed enthusianterior commissure had replaced the corpus callo- astically in captivity and their reproductive endocrinsum. Crewther et al. 11 have provided additional ology is well understood. Methods for timing birth to EUTHERIA

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Hacental Mammals

TINS, Vol. 15, No. 2, 1992

the day and inducing successive pregnancies throughout most of the year are routine 22'34. It is the combination of birth relatively early in development, making the pouch young accessible to experimental manipulation, along with its protracted development that has enabled the following work to be done.

A

B

The visual pathway i ] The retina of the diprotodont wallabies 35'36 and kangaroo 37, like many eutherian mammals, has a well-developed visual streak containing a temporally placed area centralis, which has the highest density of ganglion cells. Furthermore, the well-laminated lateral geniculate nucleus with its separate eye-specific bands, which is a ZC¢',,t l'e','" ,/l~t,,i,/¢t,"e,'o feature of eutherian mammals such as the cat and the monkey, is also a feature of the diprotodont mar- Fig. 2. Richard Owen's diagrams of partially dissected brains of (A) beaver supial s,as. In fact, the kangaroo (Castor fiber) and (13) kangaroo (Macropus sp.). The corpus callosum (labelled holds, at ten, the world record I) is present in the brain of the beaver but absent in the brain of the kangaroo. for the greatest number of eye- (Reproduced from Ref. 12.) specific bands in a mammal 38. The physiological characteristics of the receptive fields and the streaming of different The first of the two phases involves all ganglion response properties through different subdivisions of cells, all of the displaced and some of the nonthe nucleus are reminiscent of the cat 8'9. Projections displaced amacrine cells, horizontal cells and cone to other primary visual centres such as the colliculus, photoreceptors, and occurs between three days accessory optic system and hypothalamus19"2°'24"z5 before birth and 25 days after pouch life begins. The are similar to eutherian mammals. The visual cortex second phase occurs between 50 and 100 days of comprises the histologically recognizable areas 17 and pouch life and involves the rod photoreceptors, 18 (Refs 3, 18), along with connections to the bipolar cells, Mfiller cells, and probably some nonthalamus similar to those found in placental mam- displaced amacrine cells. The second phase is centred mals 2,18. initially on a region extending from the future area centralis to the optic nerve head and then extends Development of the retina peripherally from the future area centralis. It was The protracted development of the retina of the suggested that this phase contributes to variations in quokka (Setonix brachyurus), a cat-sized macropod retinal ganglion cell density that are seen in all native to Western Australia, has been described at the mammals possessing a high-resolution visual system level of the light microscope 35'39, while both light and and that the two phases can, to a considerable extent, electron microscopy have been used to describe that explain the formation of density gradients of the of the tammar 4°. However, the research that has individual cell types in the retina 45. provided t h e most interesting new insights into At the time, the only other mammalian species for mammalian retinal development has been that by which sufficient data were available for comparison Beazley and her collaborators on the quantitative was the mouse 48'49, since studies in other species analysis of the regional patterns of cell numbers concentrated on a limited number of cell types including cell birth and death of retinal cells 35'41"46. largely on cells in the ganglion cell layer. In mice, the The ability to determine cell birth dates at relatively corresponding period of development is 16 days, closely spaced intervals throughout the whole pro- comprising ten intrauterine and six postnatal, which is tracted development has revealed that there are two one sixth of the 100 days required for development of waves of cell birth and death, which are centred first the quokka retina. Although the two phases are on the optic disc and the area centralis and later recognizable with the hindsight provided by the around the visual streak 45 (Fig. 3), a pattern not marsupial experiments, they do overlap. Harman and previously described in other mammals. An important Beazley suggested that the two phases may be feature of these studies was that the gang~on cells indicative of two processes that are common to the that project to the optic nerve could be unambiguously formation of regional differences in many retinas, but identified at all stages of development by injection of a that they are only seen as occurring in separate stages tracer into the optic tract to label the cell bodies in species with a protracted development a5. Recently retrogradely 41'45. This eliminated the difficulty com- published work concerning the monkey supports their mon to many previous studies on the placental retina suggestion: cell birth in the retina shows a proof trying to decide which cell bodies in the inner retina nounced biphasic pattern 5°, as first demonstrated in actually belonged to ganglion cells47. the quokka. TINS, Vol, 15, No. 2, 1992

53

Phase 1

Phase 2

Ganglion cells Amacrine cells Displaced amacrine cells Horizontal cells Cones

Amacrine cells Bipolar cells M011er gila Rods

the segregation of eye-specific terminal bands. These experiments show that a rudimentary retinotopic order is apparent in the primary visual projections from a very early stage, and it seems likely that it may be a feature of the projections from the time the first axons reach their targets. Interestingly, the magnification factor, or the size of target tissue occupied by axons from a given retinal area, was always greatest for ganglion cells from the central retina in the future visual streak and area centralis. This was the case even before the formation of these specializations; that is, when the density of ganglion cells was uniform across the retina. This suggests a mechanism that may contribute to the unequal distribution of ganglion cells found in the adult. Cells from the peripheral retina have less area in which to form connections, which may result in decreased access to targetderived growth factors and subsequent decreased survival. What happens to the retinotopy of these projections if the outgrowth of developing axons from the eye is perturbed? Because few optic nerve axons have left the eye and none has reached the visual centres on 0 20 40 60 80 100 120 the day of birth, it was possible to rotate the eye at this stage of development and force ganglion cell Days postnatal axons to grow into the brain with the eye misaligned Fig. :1. Patterns of cell birth (B) and of cell death (D) in the with respect to the optic stalk 26. This was a version developing retina of the quokka (Setonix brachyurus). of Sperry's classical experiment on the growth of reThere are two phases of cell birth and two of cell death. In generating axons after eye rotation in lower the first phase of cell birth, cells undergo their final division in a chronological sequence from the central retina or the optic disk (OD) to the periphery. In the second phase of cell birth, the sequence is from mid-temporal [at the area centralis (AC) in the mature retina] to peripheral retina. Each phase of cell birth is followed by a corresponding phase of cell death that, in the quokka, takes place approximately 40 days later. The cells that are born in the first phase of cell birth are ganglion cells, displaced and non-displaced amacrine cells, horizontal cells and cones. Some non-displaced amacrine cells, bipolar cells, MOiler gila, and rods are born in the second phase. The cell types affected by each phase of cell death seem to match those generated in the corresponding phase of cell birth. These patterns are thought to underlie changes in cell density that transform the distribution of ganglion cells from being essentially uniform in young animals to being graded in adults.

/B,\ ,_\' J

\',.

Development of the primary visual pathways In the adult mammal there is a precise retinotopic organization of ganglion cell axons in the superior colliculus and lateral geniculate nucleus, but what of the disposition of these axons in the developing targets during early development? Are they initially ordered or does this arise later in development? The accessibility of the wallaby young has made possible the use of anterograde tracer techniques combined with retinal lesions to follow the retinotopic development of these projectionsa°. Retinotopic order could be detected soon after optic axons extended throughout the colliculus and geniculate nuclei, at a time when afferents from the two eyes still overlapped in the geniculate. The projection was less precise than in the adult at this time. There was an increase in precision over time, with refinement in projections from the temporal retina preceding those from the nasal retina. In the geniculate, refinement occurred concomitantly with 54

Fig. 4. Summary diagram showing the regional pattern of neurogenesis plotted onto lateral and medial views of the possum neocortex, with the dorsal surface of the brain represented adjacent in the two views in the middle of the figure. The regional neurogenetic gradients in the lateral and medial walls of the hemisphere integrate into a single simple pattern of neurogenesis. The numbers represent approximate ages in postnatal days of completion of neurogenesis in the neocortex, and are separated by 'contour lines', which were made by joining those points at which neurogenesis concluded at the same time. Zones 60-68 are the primary visual cortex. (Taken, with permission, from Ref. 21.) TINS, Vol. 15, No. 2, 1992

vertebrates 51, the results of which led to his theory of chemosl~ecificity in the formation of neural connections~2. Anatomical analysis showed that, as in the lower vertebrates, optic axons had terminated in the colliculus and geniculate nuclei in the correct retinotopic order, despite the rotation. They must have corrected their path at some point between the back of the eye and their targets. The optic chiasm, where pathway choice is made during normal development, was one such site where correction took place. In some cases, the optic stalk degenerated and axons entered the brain via the oculomotor root. They still specifically innervated only their correct targets, although in reduced numbers, and approached targets such as the colliculus quite directly over long distances. These results support the idea of a number of levels of specific interactions involving growing axons, the paths they grow along and their targets 26. Even if all pathway cues are eliminated, axon-target interactions operate to ensure that growing axons innervate their appropriately matched target no matter from which direction and in what disorder they arrive.

D e v e l o p m e n t of the cerebral cortex The cells that form the cortex of both eutherians 53'~4 and marsupials S~ are born in an insideout sequence with respect to their final laminar position. The cells that are born first lie more deeply, while the more superficial layers are formed by cells that leave the mitotic cycle in the ventricular layer later. What about the tangential dimensions? Sanderson and Weller 21 have exploited the slow pace of marsupial development in a study of the patterns of histogenesis in the cerebral cortex, including the visual cortex, of the Australian possum (Trichosurus vulpecula) to produce a more detailed picture of the regional neurogenetic gradient than has been produced in any other mammal. As is shown in Fig. 4, the first part of the neocortex to be born is the ventromedial region adjacent to the paleocortex and archicortex, and there is a simple orderly wave of cell genesis from rostral and ventral to caudal and medial, with strips of cortex called isogenetic strips, which lie roughly parallel to the rhinal fissure, developing more or less synchronously. This whole process takes place over 9-10 weeks - about the same period of time as that taken for neurogenesis of the monkey cortex 53, for which a spatial sequence has not yet been described. This same pattern of cell genesis can also be seen within the primary visual cortex (zones 60-68 in Fig. 4). In the developing cat primary visual cortex ~4, a weak anteroposterior gradient of cell genesis could be detected, but no dorsoventral (central to peripheral visual field) gradient was observed, although this was specifically looked for. The authors thought that such a gradient probably existed but was not detected because of the small dorsoventral extent of cortex involved. Its detection in the possum was presumably aided by the protracted development in this species. D e v e l o p m e n t of connections with the cerebral cortex From the onset of their ingrowth, developing thalamocortical axons in the wallaby (Macropus eugenii) are found to be distributed densely and ~NS, Vol. 15, No. 2, 1992

A P22

P40

P65

P82

P99

Pl18

E39

E46

E55

P0

P25

Mz CGZ sP? IZ svz vz o2smm

B

0 2 5 mm

W

Fig. 5. Comparison of the distribution of thalamic afferents in the visual cortex

of(A) the wallaby and (B) the cat during development. Data from the wallaby were obtained using anterograde labelling of thalamic afferents and retrograde labelling of corticothalamic cell bodies by injection of HRP directly into the visual thalamus. Data from the cat were obtained using autoradiography after transneuronal labelling of geniculocortical afferents by injection of tritiated proline into the eye. E and P denote embryonic and postnatal days, respectively. White sections designate areas where no label was detected, and black sections designate areas of highest density of label. Dark and light shading designate intermediate levels of labelling. Black dots represent the position of cell bodies in the wallaby cortex. Throughout development, afferents are more widely distributed in the depth of the cortex in the wallaby than in the cat. They extend up to the compact cell zone (CCZ) of the cortical plate (CP) from the earliest times studied (P22), a few days after the first axons reach the cortex from the thalamus, while in the cat they are confined to the subplate (SP) for a considerable period. In the wallaby, how far the subplate at the top of the intermediate zone (IZ) extends into the less densely packed zone of cells below the compact cell zone, or whether it extends into this zone at all cannot be determined with certainty before P40. However, at P40, the first labelled cell bodies projecting to the visual thalamus are seen, presumably defining the extent of the cortical plate. These cell bodies are in two bands: one in the compact cell zone and the other at the base of the cortical plate in the less densely packed region of the lower cortical plate (CPI). The two bands of cells are always seen when both the lateral geniculate nucleus and the lateral posterior nucleus are injected, and by P65 they are both within the CPI. By P76 (not illustrated), the two bands of cells are located within cytoarchitectonically identifiable layers V and VI. Over this period afferents are densely distributed throughout the CPI up to the base of the compact cell zone. In contrast, in the cat at E55, labelling is still heaviest over the subplate, and layers V and Vl in the Iower part of the cortical plate are only lightly labelled. By P82 in the wallaby, with the emergence of layers III and IV, the previously, evenly distributed label begins to show variations in density, and by P99 is heaviest over layer IV and, to a lesser extent, over layer Vl. By P118 the cortical lamination pattern and the distribution of afferents resembles those seen in the adult after a similar thalamic injection covering the geniculate and lateral posterior nuclei. By PO in the cat, afferents are found through most of the cortical plate but the deeper cortical layers and the subplate are still the most heavily labelled. By P25 the adult-fike lamination pattern has emerged. Abbreviations: MZ, marginal zone; SVZ, subventricular zone; VZ, ventricular zone. [Part (A) taken, with permission, from Ref. 18, and part (B) taken, with permission, from Ref. 57.] 55

evenly in much of the entire depth of the cortex, right up to the thin compact cell zone at the top of the cortical plate, and this is observed long before lamination emerges beneath this zone 18 (Fig. 5A). This is a dramatically different picture from that previously described in the placental monkey and cats6'sT, where it appears that thalamocortical axons undergo a waiting period, during which they innervate a transient layer of ceils deep to the developing cortical plate, the subplate, for a period prior to their ingrowth into the cortical laminae (Fig. 5B). At later stages, when cortical layers are forming, the distribution of afferents is also more dense and widespread in the wallaby compared to the cat (Fig. 5). The results from studies of the wallaby suggest that either there may be no waiting period or it is relatively short compared to that described in the cat and the monkey. Until very recently (see below), the experiments on monkey and cat, on which this view is based, have been performed by injecting radioactive tracers into the eye to label, via transneuronal transport, thalamocortical fibres56's7. This is a less sensitive method than that used in the experiments on marsupials, during which thalamic afferents were labelled directly in vivo by direct injection of HRP into the thalamus 18. What accounts for these differences? Has the more sensitive method revealed that during the growth of thalamic axons into the mammalian cortex, afferents may be much more widely distributed in the depth of the cortex than previously thought? Alternatively, are there differences between mammals in the mechanisms of development of the cortex? More recently, experiments have been done in the rat and the cat using direct labelling of thalamocortical afferents in fixed tissue with a fluorescent dye. The results in the cat visual cortex confirm the previous results from studies of this species 58, but in the rat somatosensory cortexs9 ingrowth of thalamic afferents is more similar to what occurs in the wallaby. There appears to be no waiting period and the authors question whether a subplate exists in the rat. The basis of the differences between these findings remains to be resolved, but the results in the wallaby and the rat suggest thalamic afferents play an important role in cortical laminar differentiation.

The future One aspect of marsupial developmental research electrophysiological recording from the intact CNS has scarcely begun, mainly because of all the background work that had to go into establishing developmental timetables by anatomical methods. There are few technical difficulties: respiration is maintained under surgical anaesthesia, evoked potentials are easy to record, and long duration sequences of unit activity are not difficult to make. In the pouch young of the tammar wallaby, Mark and Chung32 have recorded evoked potentials in the superior colliculus after stimulation of the optic nerve to determine the changing laminar distribution of optic input during development. Waite et al.33 have used the cortical evoked potential as a result of stimulation of a whisker follicle to follow the morphological development of projections to the somatosensory 'barrel' cortex. How the impulse activity in neurones of the developing nervous system might direct the formation of interneuronal connections is now an 56

important line of research, especially in vision. One question that springs to mind is the role of spontaneous impulse activity in the refinement of the projections of retinal ganglion cells to the lateral geniculate nucleus. Spontaneous activity has been recorded from developing retinas in eutherian mammals such as the neonatal ferret and the late foetal kitten6°. It will be necessary to take recordings from the CNS in order to find out whether impulses generated in the retina reach the lateral geniculate nucleus and whether neighbouring terminals have temporally correlated activity, as has been reported for the retinal ganglion cells.

The importance of good breeding Almost every article on the marsupial nervous system, and certainly every review, points out the potential usefulness of these animals for neuroembryological research. However, the number of papers describing actual experiments (not just observations) that deal directly with development are less than the number of admonishments to write them. The reason is the lack of reliable breeding colonies: unless a supply of young of exactly known age is guaranteed, a programme on development cannot be mounted. Of the work reviewed above, that on the quokka and the tammar was reliant upon such colonies. Even work on the Australian possum that has so far been reported is still largely carried out on animals caught in the wild on the chance that they will have a pouch young of suitable age. Laboratory colonies of the small American marsupial Monodelphis domestica have been established, but this is a primitive animal compared with the kangaroos and wallabies, which have the advantages of a very reliable reproductive process and a highly differentiated brain.

Selected references 1 walton, D. W. and Richardson, B. J. (eds) (1989) Fauna of Austra/ia: Mamma/ia, Australian Government Publishing Service (Vol. 1B) 2 Haight, J. R., Sanderson, K. J., Neylon, L. and Patten, G. S. (1980) J. Anat. 131,387-413 3 Mayner, L. (1989) Brain Behav. Evo/. 33,303-316 4 Mayner, L. (1989) Brain Behav. Evo/. 33, 342-355 5 Rees, S. and Hore, J. (1970) Brain Res. 20, 439451 6 Hore, J. and Porter, R. (1971) Brain Res. 30, 232-234 7 Gates, G. R. and Aitkin, L. M. (1982) Hear. Res. 7, 1-12 8 Wye-Dvorak, J., Levick, W. R. and Mark, R. F. (1987) J. Comp. Neuro/. 263, 198-213 9 Henry, G. H. and Mark, R. F. Brain Behav. Evo/, (in press) 10 Faulks, I. J. and Mark, R. F. (1983) Neurosci. Left. (Suppl.) 11, $43 11 Crewther, D. P., Crewther, S. G. and Sanderson, K. J. (1984) Brain Behav. Evo/. 24, 184-197 12 Owen, R. (1837) Phi/. Trans. R. Soc. London Set B 127, 87-96 13 Elliot-Smith, G. (1902) Proc. R. Soc. London Set. B 70, 226-231 14 Heath, C. J. and Jones, E. G. (1971) J. Anat. 109, 253-270 15 Dehay, C., Kennedy, H. and Meissiret, C. (1988) J. Physiol.

300, 45 16 Tyndale-Biscoe,C. H. and Janssens, P. A. (eds) (1988) The Developing Marsupial: Models for Biomedica/ Research, 17 18 19 20 21

Springer-Verlag Dreher, B. and Robinson, S. R. (1988) Brain Behav. Evol. 31, 369-390 Sheng, X-M., Marotte, L. R. and Mark, R. F. (1991) J. Comp. Neurol. 307, 17-38 Wye-Dvorak, J. (1984) J. Comp. NeuroL 228, 491-508 Harman, A. M. and Beazley, L. D. (1986) Anat. Embryol. 177, 123-130 Sanderson, K. J. and Weller, W. L. (1990) Dev. Brain Res. 55, TINS, Vol. 15, No. 2, 1992

269-274 22 Renfree, M. B. and Tyndale-Biscoe, C. H. (1978) in Methods in Mammalian Reproduction (Daniel, J. C., Jr, ed.), pp. 307-331, Academic Press 23 Sanderson, K. J., Pearson, L. J. and Dixon, P. G. (1978) J. Comp. Neurol. 180, 841-868 24 Sanderson, K. J., Dixon, P. G. and Pearson, C. P. (1982) Dev. Brain Res. 5, 161-180 25 Coleman L-A. and Beazley, L. D. (1988) J. Comp. Neurol. 273, 359-376 26 Marotte L. R. and Mark, R. F. (1988) J. Comp. Neurol. 271, 274-292 27 Coleman L-A. and Beazley, L. D. (1989) Dev. Brain Res. 48, 273-291 28 Coleman L-A. and Beazley, L. D. (1989) Dev. Brain Res. 48, 293-307 29 Marotte L. R., Ftett, D. L. and Mark, R. F. (1989)J. Comp. Neurol. 282, 535-554 30 Marotte L. R. (1990) J. Cornp. Neurol. 293, 524-539 31 Sheng, X-M., Marotte, L. R. and Mark, R. F. (1990)J. Comp. Neurol. 300, 196-210 32 Mark, R. F. and Chung, S-H. (1990) Proc. Aust. Neurosci. Soc. 1, 105 33 Waite, P. M. E., Marotte, L. R. and Mark, R. F. (1991) Dev. Brain Res. 58, 35-41 34 Tyndale-Biscoe, C. H. and Hinds, L. A. (1984) Gen. Comp. Endocrinol. 53, 58-68 35 Beazley, L. D. and Dunlop, S. A. (1983) J. Comp. Neurol. 216, 211-231 36 Wong, R. O. L., Wye-Dvorak, J. and Henry, G. H. (1986) J. Comp. Neurol. 253, 1-12 37 Dunlop, S. A., Longley, W. A. and Beazley, L. D. (1987) Vision Res. 27, 151-164 38 Sanderson, K. J., Haight, J. R. and Pettigrew, J. D. (1984) J. Comp. Neurol. 224, 85-106 39 Dunlop, S. A. (1990) J. Comp. Neurol. 293, 425-447

40 Spira, A. W. and Marotte, L. R. (1989) Anat. EmbryoL 179, 571-585 41 Dunlop, S. A. and Beazley, L. D. (1985) Dev. Brain Res. 23, 81-90 42 Braekevelt, C. R., Beazley, L. D., Dunlop, S. A. and Darby, J. E. (1986) Dev. Brain Res. 25, 117-125 43 Dunlop, S. A. and Beazley, L. D. (1987) J. Comp. Neurol. 264, 14-23 44 Harrnan, A. M. and Beazley, L. D. (1987)Anat. Embryol. 177, 123-130 45 Harman, A. M. and Beazley, L. D. (1989) Neuroscience 28, 219-232 46 Harman, A. M., Snell, L. L. and Beaztey, L. D. (1990) J. Comp. Neurol. 289, 1-10 47 Wong, R. O. L. and Hughes, A. (1987) J. Comp. Neurol. 255, 159-177 48 Sidman, R. L. (1961) in The Structure of the Eye (Smelser, G. K., ed.), pp. 487-506, Academic Press 49 Young, R. W. (1985) Anat. Rec. 212, 199-205 50 LaVail, M. M., Rapaport, D. H. and Rakic, P. (1991) J. Comp. Neurol. 309, 86-114 51 Sperry, R. W. (1943) J. Comp. Neurol. 79, 33-55 52 Sperry, R. W. (1963) Proc. NatlAcad. Sci. USA 50, 703-710 53 Rakic, P. (1974) Science 183,425-427 54 Luskin, M. B. and Shatz, C. J. (1985) J. Comp. Neurol. 242, 611-631 55 Reynolds, M. L. etal. (1985)Anat. Embryol. 173, 81-94 56 Rakic, P. (1977) Phil Trans. R. Soc. London Ser. B 278, 245-260 57 Shatz, C. J. and Luskin, M. B. (1986) J. Neurosci. 6, 3655-3668 58 Gosh, A. and Shatz, C. J. J. Neurosci. (in press) 59 Catalano, S. M., Robertson, R. T. and Killackey, H. P. (1991) Proc. Natl Acad. Sci. USA 88, 2999-3003 60 Meister, M., Wong, R. O. L., Baylor, D. A. and Shatz, C. J. (1991) Science 252,939-943

Acknowledgements We wouldlike to thank Drs L. D. Beazleyand C E. Hill for criticismof the manuscnpt,and M. Donohuefor word processing.

Mechanicalpreprocessingin the mammaliancochlea Graeme

K. Y a t e s , B r i a n M . J o h n s t o n e ,

The mammalian cochlea responds with exquisite sensitivity to the small fluctuations in air pressure that make up the stimulus of sound. Moreover, it responds to pressure fluctuations that occur extremely rapidly and that vary over a wide range of intensities - in both cases, to an extent outside the capabilities of unaided nerve fibres. Research performed during the past decade has shown that these properties are dependent on a physiological source o f mechanical energy that operates probably within the outer hair cells of the organ of Corti. These cells, which are anatomically and functionally similar to the primary receptor cells, the inner hair cells, are believed to function as a source of mechanical power to assist the mechanical sensitivity of the cochlea, by mechanisms that currently are not understood. Several possible mechanisms have been proposed, but each has limitations that may make it an unsuitable candidate. Recent work has also demonstrated the likely role of mechanoelectrical transduction in outer hair cells in controlling the power source and thereby influencing the sensitivity and amplitude range of the cochlea. The cochlea responds to sound by transducing minor fluctuations in atmospheric pressure into a train of action potentials along the auditory nerve. Acoustic signals that are interesting to an animal may be very fast, on a timescale of tens of microseconds, and may vary over many decades in intensity. They cannot be encoded by nerve fibres without some additional TINS, VoL 15, No. 2, 1992

R o b e r t B. P a t u z z i a n d D o n a l d R o b e r t s o n

processing, which the cochlea provides by performing a partial Fourier transformation on the incoming mechanical energy, filtering the mechanical vibrations through a large number of filters of narrow bandwidth. Essentially, the single stream of rapidly changing information is transformed into a large number of streams of information that fluctuate more slowly and that are encoded by separate neurones. Experimental measurement has shown this sharp filtering process to be present at the level of the mechanical vibration of the basilar membrane z'2. Mathematical models question whether the observed vibration is possible without a source of energy to cancel internal viscosity in the basilar membrane3. Sharp filtering requires low friction, or damping, but estimates of the effects of viscosity in the cochlea suggest that the damping may be too great. It has therefore been suggested4 that the presence of an internal source of mechanical power could overcome the viscous damping and simultaneously provide the filtering and sensitivity known to be present in the cochlea. However, the mathematical models do not suggest what the mechanism for generating the power might be, although they do place constraints upon it. The basilar membrane operates faster than any muscle known in biology (on timescales of microseconds), and it must be able to detect and react to mechanical vibrations as small as 1A.

© 1992.ElsevierSciencePublishersLtd,(UK) 0166- 2236/92/$05.00

GraemeK. Yates, BrianM. Johnstone, RobertB. Patuzziand DonaldRobertsonare at the Auditory Laboratory, Deptof Physiology, The Universityof Western Australia, Nedlands 6009, Western Australia.

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Australian marsupials as models for the developing mammalian visual system.

This article makes two points. First, the diprotodont marsupials, including the kangaroos, wallabies and the Australian possum are not primitive mamma...
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