How Do Thalamic Axons Find Their Way to the Cortex?

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How Do Thalamic Axons Find Their Way to the Cortex? Z. Molnkr and C. Blakemore - Development of thalamocortical innervation CORTEX How do thalamic axons find their way to the cortex? Zolthn Molnhr and Colin Blakemore A cascade of simple mechanisms influences thalamic innervation of the neocortex. The cortex exerts a remote growth-promoting influence on thalamic axons when they start to grow out, becomes growth-permissive when the axons begin to invade, and later expresses a ‘stop signal’, causing termination in layer 4. However, any part of the thalamus will innervate any region of developing cortex in culture, and the precise topographic distribution of thalamic fibres in vivo is unlikely to depend exclusively on regional chemoaffinity. The ‘handshake hypothesis’ proposes that axons from the thalamus and from early-born cortical preplate cells meet and intermingle in the basal telencephalon, whereafter thalamic axons grow over the scaffold of preplate axons, and become ‘captured’ for a waiting period in the subplate layer below the corresponding part of the cortex. The bizarre pattern of development of thalamic innervation in the mutant reeler mouse provides strong evidence that thalamic axons are guided by preplate axons. Trends Neurosci. (1995) 18, 389-397 NY DEVELOPMENTAL NEUROSCIENTIST with a have small cerebral hemispheres in which adjacent A tendency to masochism is encouraged to contem- neocortical fields generally receive their projections plate the development of thalamocortical projections. from neighbouring thalamic nuclei2,3. Table 1 shows In general, each thalamic relay nucleus projects pre- the chronicle of thalamocortical development for rat cisely and topographically to a particular cortical terri- and mouse. As in all eutherian mammals, the major tory. However, the routes taken by individual fibres in events take place in utero, and are initiated before the the adult brain can be tortuous, with sharp bends and thalamus is innervated by the sensory pathways. even rotations of the array around one axis but not How the cortex is built the orthogonal. Moreover, single thalamic nuclei can project to more than one cortical area; each cortical The cells of the cerebral cortex originate in the pro- field can have several thalamic inputs; and the topo- liferative neuroepithelium that lines the forebrain graphic order of projections from a single nucleus can vesicle. From this mitotic factory, immature neurones change abruptly at the borders of neighbouring corti- migrate along the processes of radial glia towards the cal areas (such as the reversal of the retinotopic map pial surface to generate the layers of the cortex8. The between primary and secondary visual areas). first post-mitotic neurones form the primordial plexi- How could this bewildering complexity and preci- form zone or preplate, which is later split by the sion be generated by the simple mechanisms that are invasion of true cortical neurones that are generated familiar to developmental neuroscience, such as subsequentlyg-‘l. The latter are distributed in an trophism, selective adhesion and competitive interac- inside-out sequence to create layers 6-2 of the cortex, tion? This question assumes special significance which are sandwiched between the superficial and deep because of the growing evidence that the input from components of the original preplate [the marginal each major thalamic nucleus can act as a local ‘extrin- zone (cortical layer 1) and the subplate, respectively sic signal’, influencing the fate of the cortex it inner- (see below)]. vates by setting the boundaries of the cortical field, Neurones of the preplate mature precociously, send- delivering its afferent input, and influencing its ing out axons, and expressing a variety of transmitter regional differentiation’. and receptor systems, long before the cells of the corti- In considering how neural systems form, it is cal plate mature. However, a substantial proportion of important not to infer complexity during develop- these neurones die after the arrival of thalamic axons, ment from the appearance in the mature animal. and the completion of cortical neuronogenesisl’. Many of the perplexing features of thalamocortical These characteristics provide strong circumstantial organization (especially the convoluted paths taken evidence that preplate cells play a role in the devel- by individual axons, the rotations of axon arrays and opment of the cortex. Of particular interest is the Zoltrin Molntir and irregular topology between thalamus and cortex) mutant mouse reeler. In this autosomal-recessive Colin Blakemore are might be produced after the initial establishment of mutant, whose aberrant gene product has been cloned at the Laboratory of connections. The ultimate imbroglio of thalamocorti- very recently 12, the cortex forms in a roughly outside- Physiology, cal organization might be generated by a cascade of in sequence, leaving the entire preplate stranded as a University of individually simple mechanisms. ‘super-plate’ above the inverted layers of the cortical plate; Oxford, Parks Road, In an attempt to simplify the problem, a number of however, the basic topographic interrelations between Oxford, studies have been performed on rodents, since they thalamus and cortex develop essentially normally13. UK OXI 3PT. 0 1995, Elsevier Science Ltd TINS Vol. 18, No. 9, 1995 389 CORTEX Z. Molnir and C. Blakemore - Development of thalamocortical innervation TABLE I. Chronology of thalamocortical development in rat and mouse ing period of a few days before invasion of the cortex. Although the insensitivity of their methods led them Age Major events (for occipital cortex and LGN) to overestimate the age by a couple of days at each Rat Mouse stage, this general sequence has been confirmed in recent studies using the acutely sensitive carbocyanine El2 El1 Start of cortical neuronogenesis Early El4 Early E I3 First preplate cells complete their migration dyes’4,‘5 to trace axons in fixed fetal brainslh-” (see El4 El3 Commencement of axon outgrowth from preplate and Table 1). Catalan0 and colleague? also reported that thalamus fibres from the ventral thalamus arrive under the El5 El4 Arrival of first cells of the cortical plate somatosensory cortex early, and enter the cortical Early E I 5 Early E I4 Preplate and thalamic axons meet in basal telencephalon plate before birth, but they demonstrated axons that El6 El5 Thalamic axons arrive under cortex penetrate the lower layers of the cortex immediately El8-I9 El7-I8 Major invasion of the cortical plate begins after their arrival, and questioned the existence of a E211PO E2llPO Birth waiting period in rodents. However, the consensus PI PO Arrival of thalamic axons in layer 4 seems to be that many thalamic fibres accumulate under the true cortical plate but for a shorter time Approximate ages in rat and mouse (including the reeler mutant) are given for the main events in the development of the occipital cortex, and projections from the lateral geniculate nucleus than the prolonged waiting periods that are observed (LGN), the visual relay in the dorsal thalamus. The ‘plug date’ is taken as embryonic day zero (EO) in carnivores” and primatesz3. for the dating of fetuses, and the first postnatal day as PO. Cortical-cell generation finishes before The sequence and topography of initial outgrowth birth but migration into the upper layers continues until the end of the first postnatal week’? In from the dorsal thalamus to the occipital cortex is the tangential direction, across the developing cerebral cortex, there is another distinct neuro- illustrated in Figs 1 and 2. Figure 1 shows two bundles genetic gradient, the anteroventral areas of the hemisphere preceding the caudodorsal in maturity of axons that have been labelled by placement of by more than a day’,‘. small crystals of different dyes in neighbouring regions of the dorsal thalamus of an embryonic day 14.5 (E14.5) rat fetus. Even at this early stage, when The timing and pattern of thalamic-axon outgrowth the major nuclei of the thalamus are just beginning to be distinguishable, and the cortex consists of preplate In an early study, using degeneration techniques, alone, thalamic axons have grown down through the Lund and Mustads described the outgrowth of fibres diencephalon in reasonable topographic order, and from the fetal rat thalamus, and their accumulation out through the primitive internal capsule under the under the appropriate region of the cortex for a wait- anlage of the corpus striatum, and are coursing up into the intermediate zone of the telencephalon. Figure 2 illustrates the subsequent events for both normal and reeler mice. In the normal animal, thalamic axons ap- proach the cortex but then gather in the subplate layer. Very few thalamic axons penetrate the corti- cal plate until a couple of days before birth, when they suddenly turn and invade radially en masse, branching and terminating mainly in layer 4. The pattern seems very different in the reeler mutant, in which the neurones that are equivalent to the normal subplate remain above the gathering corti- cal plate. Thalamic fibres stream obliquely upwards in fascicles through the cortical plate, and accumulate for a few days in the superplate layer above. They then plunge down and terminate, pre- sumably on cells that are equiva- lent to the normal layer 4 (Refs 26 and 27). Could a single develop- mental programme explain both Fig. 1. Topographic outgrowth of axons from the thalamus. Two small crystals of different carbocyanine dyes were patterns of innervation? inserted 200
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