Retinotopic order in the absence of axon competition

The retinotectal projection has long been studied experimentally and theoretically, as a model for the formation of topographic brain maps. Neighbouring retinal ganglion cells (RGCs) project their axons to neighbouring positions in the optic tectum, thus re-establishing a continuous neural representation of visual space. Mapping along this axis requires chemorepellent signalling from tectal cells, expressing ephrin-A ligands, to retinal growth cones, expressing EphA receptors. High concentrations of ephrin A, increasing from anterior to posterior, prevent temporal axons from invading the posterior tectum. However, the force that drives nasal axons to extend past the anterior tectum and terminate in posterior regions remains to be identified. We tested whether axon-axon interactions, such as competition, are required for posterior tectum innervation. By transplanting blastomeres from a wild-type (WT) zebrafish into a lakritz (lak) mutant, which lacks all RGCs, we created chimaeras with eyes that contained single RGCs. These solitary RGCs often extended axons into the tectum, where they branched to form a terminal arbor. Here we show that the distal tips of these arbors were positioned at retinotopically appropriate positions, ruling out an essential role for competition in innervation of the ephrin-A-rich posterior tectum. However, solitary arbors were larger and more complex than under normal, crowded conditions, owing to a lack of pruning of proximal branches during refinement of the retinotectal projection. We conclude that dense innervation is not required for targeting of retinal axons within the zebrafish tectum but serves to restrict arbor size and shape.     

Normal maturation involves systematic changes in binocular visual connections in Xenopus laevis

Systematic changes in neuronal connections have been observed during the development of many vertebrate neuronal systems. These changes have usually involved a refinement from an initial exuberance of connections or a response to some experimental perturbation. Here we report on a system of neuronal connections, which, during a protracted developmental period, undergo ordered changes in response to normally occurring changes in functional requirements. In the frog Xenopus laevis, interocular alignment changes markedly during late larval and post-metamorphic life, producing a progressive enlargement of the binocular portion of the visual field. An intertectal system links the two mid-brain optic tecta and is concerned with the neural representation of binocular visual space. In the adult animal, connections in this system link corresponding points (points receiving information from one locus of binocular visual space) on the two tecta. Changes in eye position with development, however, change the set of corresponding points. Therefore, if the intertectal connections link corresponding tectal points throughout development, they must undergo an ordered change with time. We present electrophysiological evidence that the intertectal connections do, indeed, undergo such changes in response to changes in eye alignment, and that the changes are major.     

Target neuron prespecification in the olfactory map of Drosophila.

In Drosophila and mice, olfactory receptor neurons (ORNs) expressing the same receptors have convergent axonal projections to specific glomerular targets in the antennal lobe/olfactory bulb, creating an odour map in this first olfactory structure of the central nervous system. Projection neurons of the Drosophila antennal lobe send dendrites into glomeruli and axons to higher brain centres, thereby transferring this odour map further into the brain. Here we use the MARCM method to perform a systematic clonal analysis of projection neurons, allowing us to correlate lineage and birth time of projection neurons with their glomerular choice. We demonstrate that projection neurons are prespecified by lineage and birth order to form synapses with specific incoming ORN axons, and therefore to carry specific olfactory information. This prespecification could be used to hardwire the fly's olfactory system, enabling stereotyped behavioural responses to odorants. Developmental studies lead us to hypothesize that recognition molecules ensure reciprocally specific connections of ORNs and projection neurons. These studies also imply a previously unanticipated role for precise dendritic targeting by postsynaptic neurons in determining connection specificity.     

Dynamic receptive field plasticity in rat spinal cord dorsal horn following C-primary afferent input

The central terminals of cutaneous primary afferent neurons are spatially ordered in the dorsal horn in a highly organized fashion such that a point-to-point map represents the body surface. This afferent terminal somatotopic map correlates with the map of the receptive fields of the cells on which they terminate. The location, size and modality of the cutaneous receptive fields of dorsal horn neurons necessarily depend upon the anatomical presence of afferent nerve fibres which deliver information from the periphery, directly or indirectly, to the cells. However the receptive field size and modality of a cell do not depend only on anatomical connections. Excitatory and inhibitory interneurons, descending influences and facilitations or depressions of synaptic contacts can alter receptive field properties. Here we show that prolonged and substantial cutaneous receptive field changes can be produced by brief inputs from peripheral unmyelinated afferent fibres.     

Retinotopic order appears before ocular separation in developing visual pathways

In mammals, the major subcortical visual structures receive projections from both eyes, with the uncrossed projection being smaller than the crossed. Each projection is arranged as a separate orderly map of one hemiretina. Although these hemiretinal maps are separate in the nuclei, they are aligned so that the representations of points in the visual field are in register, thus there is a continuity of visual field representation between them. During the early development of the binocular pathways, terminals from the two eyes overlap almost entirely. As development proceeds, terminals arising from each eye segregate to form the adult pattern. In the present study, local retinal lesions were made in ferrets at various stages in development before the separation of the projections from the two eyes. A neuronal tracer was then injected into the damaged eye, defining the pattern of projection from that eye. As reported here, the lesion resulted in a limited interruption in the pattern of terminal label on both sides of the brain, demonstrating that terminals from each eye are arranged in an orderly retinotopic manner at this stage. hence, during later development, as one projection is reduced relative to the other, the two maps must slide in relation to each other.     

Nerve fibre topography in the retinal projection to the tectum.

The orderly layout of visual fibres in the optic nerves of cichlid fishes suggests that they are guided most of the way to the brain by contact with their neighbours. Before they reach the visual map in the tectum, however, their arrangement in the cross-section of the nerve is reorganised in a way which requires longer-range guidance.     

Moving visual stimuli rapidly induce direction sensitivity of developing tectal neurons

During development of the visual system, the pattern of visual inputs may have an instructive role in refining developing neural circuits. How visual inputs of specific spatiotemporal patterns shape the circuit development remains largely unknown. We report here that, in the developing Xenopus retinotectal system, the receptive field of tectal neurons can be 'trained' to become direction-sensitive within minutes after repetitive exposure of the retina to moving bars in a particular direction. The induction of direction-sensitivity depends on the speed of the moving bar, can not be induced by random visual stimuli, and is accompanied by an asymmetric modification of the tectal neuron's receptive field. Furthermore, such training-induced changes require spiking of the tectal neuron and activation of a NMDA (N-methyl-D-aspartate) subtype of glutamate receptors during training, and are attributable to an activity-induced enhancement of glutamate-mediated inputs. Thus, developing neural circuits can be modified rapidly and specifically by visual inputs of defined spatiotemporal patterns, in a manner consistent with predictions based on spike-time-dependent synaptic modification.     

鱼类视神经损伤和再生的研究

综述了鱼类视网膜－顶盖系统的研究概况，包括视网膜、视神经和顶盖的组织结构特点；同时介绍了损伤视神经引起的视网膜神经节细胞的变化及其跨神经元的影响；最后综述了视神经再生与神经传入活性、相邻神经纤维间的相互作用及靶区选择的关系等方面的研究进展     

Receptive field dynamics in adult primary visual cortex.

The adult brain has a remarkable ability to adjust to changes in sensory input. Removal of afferent input to the somatosensory, auditory, motor or visual cortex results in a marked change of cortical topography. Changes in sensory activity can, over a period of months, alter receptive field size and cortical topography. Here we remove visual input by focal binocular retinal lesions and record from the same cortical sites before and within minutes after making the lesion and find immediate striking increases in receptive field size for cortical cells with receptive fields near the edge of the retinal scotoma. After a few months even the cortical areas that were initially silenced by the lesion recover visual activity, representing retinotopic loci surrounding the lesion. At the level of the lateral geniculate nucleus, which provides the visual input to the striate cortex, a large silent region remains. Furthermore, anatomical studies show that the spread of geniculocortical afferents is insufficient to account for the cortical recovery. The results indicate that the topographic reorganization within the cortex was largely due to synaptic changes intrinsic to the cortex, perhaps through the plexus of long-range horizontal connections.     

Rules for neural development revealed by chimaeric sensory systems in crickets

Many sensory systems are organized so that the afferent projection forms a topographic map of the sensory surface within the central nervous system (CNS). The information necessary to create such a map may be available to the neuronal cell body based on its position in the receptor array, and this 'positional information' is translated into an axonal arborization in the proper part of the CNS. To study how the location of a cell body within the sensory surface determines the termination pattern of its axon within the CNS, we have transplanted epidermis, containing identified sensory neurones, from a black cricket to a tan cricket. As we report here, when epidermis is transplanted to an unusual location in the receptor array, newly generated neurones are produced along the borders of the graft. These neurones arborize in locations that are appropriate neither to their new position nor to their original position in the array, but rather to a position somewhere in between. This is direct evidence for the idea that positional information guides the differentiation and ultimately the synaptic connections of insect sensory neurones.     

Changes in spinal cord reflexes after cross-anastomosis of cutaneous and muscle nerves in the adult rat

Evidence exists that the specification of afferent nerves and their central connections in the embryo may depend in part on influences from the peripheral target innervated. We have now investigated whether such peripheral determination persists in the adult rat using the unmyelinated afferent system of C fibres, which differ chemically in the adult depending on their target. We have previously shown that if the cutaneous sural nerve and the muscle gastrocnemius nerve are cross-anastomosed so that they grow to each other's target, the A fibres establish functional endings and the C fibres change their chemistry to that which is appropriate for the new target. Here we report that in normal adult rats, a short train of stimuli to the cutaneous sural nerve produced a brief facilitation of the flexion reflex, lasting on average only 5 min, whereas similar stimulation of the gastrocnemius-muscle nerve enhanced this reflex for an average of 54 min. In cross-anastomosed animals, stimulation of the gastrocnemius nerve (innervating skin) induced a brief potentiation of the flexion reflex, lasting on average only 3 min. By contrast, stimulation of sural nerve (innervating muscle) produced a potentiation of this reflex lasting 57 min. Thus the ability of adult afferent nerves to potentiate the flexion reflex depends on the target with which they make contact. We propose that tissue-specific factors influence some of the central actions of primary afferent neurons in the adult.     

Nogo-66 receptor antagonist peptide promotes axonal regeneration

Myelin-derived axon outgrowth inhibitors, such as Nogo, may account for the lack of axonal regeneration in the central nervous system (CNS) after trauma in adult mammals. A 66-residue domain of Nogo (Nogo-66) is expressed on the surface of oligodendrocytes and can inhibit axonal outgrowth through an axonal Nogo-66 receptor (NgR). The IN-1 monoclonal antibody recognizes Nogo-A and promotes corticospinal tract regeneration and locomotor recovery; however, the undefined nature of the IN-1 epitope in Nogo, the limited specificity of IN-1 for Nogo, and nonspecific anti-myelin effects have prevented a firm conclusion about the role of Nogo-66 or NgR. Here, we identify competitive antagonists of NgR derived from amino-terminal peptide fragments of Nogo-66. The Nogo-66(1 40) antagonist peptide (NEP1 40) blocks Nogo-66 or CNS myelin inhibition of axonal outgrowth in vitro, demonstrating that NgR mediates a significant portion of axonal outgrowth inhibition by myelin. Intrathecal administration of NEP1 40 to rats with mid-thoracic spinal cord hemisection results in significant axon growth of the corticospinal tract, and improves functional recovery. Thus, Nogo-66 and NgR have central roles in limiting axonal regeneration after CNS injury, and NEP1-40 provides a potential therapeutic agent.     

Dscam2 mediates axonal tiling in the Drosophila visual system

Sensory processing centres in both the vertebrate and the invertebrate brain are often organized into reiterated columns, thus facilitating an internal topographic representation of the external world. Cells within each column are arranged in a stereotyped fashion and form precise patterns of synaptic connections within discrete layers. These connections are largely confined to a single column, thereby preserving the spatial information from the periphery. Other neurons integrate this information by connecting to multiple columns. Restricting axons to columns is conceptually similar to tiling. Axons and dendrites of neighbouring neurons of the same class use tiling to form complete, yet non-overlapping, receptive fields. It is thought that, at the molecular level, cell-surface proteins mediate tiling through contact-dependent repulsive interactions, but proteins serving this function have not yet been identified. Here we show that the immunoglobulin superfamily member Dscam2 restricts the connections formed by L1 lamina neurons to columns in the Drosophila visual system. Our data support a model in which Dscam2 homophilic interactions mediate repulsion between neurites of L1 cells in neighbouring columns. We propose that Dscam2 is a tiling receptor for L1 neurons.     

Induction of visual orientation modules in auditory cortex

Modules of neurons sharing a common property are a basic organizational feature of mammalian sensory cortex. Primary visual cortex (V1) is characterized by orientation modules--groups of cells that share a preferred stimulus orientation--which are organized into a highly ordered orientation map. Here we show that in ferrets in which retinal projections are routed into the auditory pathway, visually responsive neurons in 'rewired' primary auditory cortex are also organized into orientation modules. The orientation tuning of neurons within these modules is comparable to the tuning of cells in V1 but the orientation map is less orderly. Horizontal connections in rewired cortex are more patchy and periodic than connections in normal auditory cortex, but less so than connections in V1. These data show that afferent activity has a profound influence on diverse components of cortical circuitry, including thalamocortical and local intracortical connections, which are involved in the generation of orientation tuning, and long-range horizontal connections, which are important in creating an orientation map.     

Inside polyomavirus at 25-A resolution.

Empty capsids and complete virions of polyomavirus crystallize isomorphously. Here we use difference Fourier analysis of X-ray diffraction data at 25-A resolution from these crystals to obtain an electron-density map of the inside of the virion. The polyomavirus capsid is built from 72 pentamers of VP1 that form three different types of connections in the T = 7d icosahedral surface lattice. Self-assembly of purified recombinant VP1 into capsid-like aggregates has shown that switching of the bonding specificity to form the unanticipated non-equivalent connections is an inherent property of the VP1 pentamers. Our map of the inside of the virion displays 72 prongs of electron density extending from the core into the axial cavities of the VP1 pentamers. We identify these prongs with the VP2 and VP3 molecules, which may function to guide the assembly of the highly ordered capsid on the nucleohistone core. The atomic structure of the closely related simian virus-40 capsid has been determined from the high-resolution diffraction data. Our polyomavirus map, calculated using all the low-resolution diffraction data, shows no indication of regular order inside the spherical core.     

A central role for denervated tissues in causing nerve sprouting

One of the oldest known forms of neuronal plasticity is the ability of peripheral nerves to grow and form functional connections after damage to neighbouring axons. Yet the source of the signal which elicits this "sprouting" remains unknown. In mammalian muscles, paralysis-which gives rise to many of the changes which occur in denervated muscles-causes motor nerve terminals to sprout. Could the inactive muscle fibres (rather than nerve degeneration products, another likely source) be responsible for some of the sprouting found in partial denervation? We confirm in this paper that direct stimulation of a partially denervated muscle inhibits sprouting and show that stimulation does so by activating the denervated fibres. Consequently after partial denervation the same signal as that which causes terminal sprouting in a paralysed muscle is able to spread from the denervated muscle fibres to the nerves on the innervated fibres and initiate terminal sprouting.     

Selective collateral elimination in early postnatal development restricts cortical distribution of rat pyramidal tract neurones

The pyramidal tract, comprising those axons which pass from the neocortex to the medulla and spinal cord, is among the most thoroughly studied projections of the mammalian cortex. Recent studies using anterograde axon tracing techniques have provided information concerning the time course of the growth of pyramidal tract fibres, yet much remains to be learned about its development. We have now begun to study the distribution of the neurones of origin of the pyramidal tract during the postnatal development of the rat neocortex using the recently introduced retrogradely transported fluorescent marker, True blue. During the first postnatal week, injections of True blue into the pyramidal decussation result inthe labelling of pyramidal tract neurones which are distributed virtually throughout the tangential extent of layer V of the neocortex, whereas after comparable injections during the fourth postnatal week the distribution of such cells is much more restricted and remains restricted into adult life. This developmental restriction is most dramatic in the occipital cortex: during the first postnatal week many pyramidal tract neurones are found throughout the visual cortex while none is seen in this area of the adult. When True blue is injected into the pyramidal decussation during the first postnatal week and the animals are allowed to survive until the fourth postnatal week, the distribution of pyramidal tract neurones is as widespread as in the immediate postnatal period and includes the entire visual cortex. This implies that many of the neurones in the occipital cortex initially send a collateral into the pyramidal tract which is later eliminated, although the neurones themselves persist. These findings, together with similar recent observations on the development of the callosal connections, indicate that the elimination of axon collaterals may be a general feature of the development of cortical projection systems, and that such transitory collaterals may traverse considerable distances.     

The optic tectum controls visually guided adaptive plasticity in the owl's auditory space map.

The midbrain contains an auditory map of space that is shaped by visual experience. When barn owls are raised wearing spectacles that horizontally displace the visual field, the auditory space map in the external nucleus of the inferior colliculus (ICX) shifts according to the optical displacement of the prisms. Topographic visual activity in the optic tectum could serve as the template that instructs the auditory space map. We studied the effects of a restricted, unilateral lesion in the portion of the optic tectum that represents frontal space. Here we show that such a lesion eliminates adaptive adjustments specifically in the portion of the auditory map that represents frontal space on the same side of the brain, while the rest of the map continues to adjust adaptively. Thus, activity in the tectum calibrates the auditory space map in a location-specific manner. Because the site of adaptive changes is the ICX, the results also indicate that the tectum provides a topographic instructive signal that controls adaptive auditory plasticity in the ICX.     

Retinal ganglion cells lose response to laminin with maturation

The decisive role played by adhesive interactions between neuronal processes and the culture substrate in determining the form and extent of neurite outgrowth in vitro has greatly influenced ideas about the mechanisms of axonal growth and guidance in the vertebrate nervous system. These studies have also helped to identify adhesive molecules that might be involved in guiding axonal growth in vivo. One candidate molecule is laminin, a major glycoprotein of basal laminae which has been shown to induce a wide variety of embryonic neurones to extend neurites in culture. Moreover, laminin is found in large amounts in injured nerves that can successfully regenerate but is absent from nerves where regeneration fails. However, it is unclear to what extent the mechanisms that regulate axonal regeneration also operate in the embryo when axon outgrowth is initiated. Here we have examined the substrate requirements for neurite outgrowth in vitro by chick embryo retinal ganglion cells, the only cells in the retina to send axons to the brain. We show that while retinal ganglion cells from embryonic day 6 (E6) chicks extend profuse neurites on laminin, those from E11 do not, although they retain the ability to extend neurites on astrocytes via a laminin-independent mechanism. This represents the first evidence that central nervous system neurones may undergo a change in their substrate requirements for neurite outgrowth as they mature.