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Quantitative studies of ontogenetic changes in the levels of brain-derived neurotrophic factor (BDNF) mRNA and its effector, BDNF protein, are not available for the retinal projection system. We used an electrochemiluminescence immunoassay to measure developmental changes in the tissue concentration of BDNF within the hamster retina and superior colliculus (SC). In the SC, we first detected BDNF (about 9 pg/mg tissue) on embryonic day 14 (E14). BDNF protein concentration in the SC rises about fourfold between (E14) and postnatal day 4 (P4), remains at a plateau through P15, then declines by about one-third to attain its adult level by P18. By contrast, BDNF protein concentration in the retina remains low (about 1 pg/mg tissue) through P12, then increases 4.5-fold to attain its adult level on P18. The developmental changes in retinal and collicular BDNF protein concentrations are temporally correlated with multiple events in the structural and functional maturation of the hamster retinal projection system. Our data suggest roles for BDNF in the cellular mechanisms underlying some of these events and are crucial to the design of experiments to examine those roles.

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Neurotrophins are a family of secreted molecules that have multiple, profound actions on the structure and function of both developing and mature neurons. Neurotrophins exert their influences by signaling through the trk family of receptor tyrosine kinases and the p75 low affinity neurotrophin receptor. Here we review the contributions of neurotrophins to the development of neural circuitry in the mammalian visual system. We emphasize: (1) the role of neurotrophins as components of the cellular mechanisms by which neuroelectric activity sculpts pattern of brain connectivity; and (2) the results of recent experiments suggesting that the trafficking of neurotrophin proteins may be activity dependent.

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We studied visually guided behavior and the visual response properties of single auditory cortex (A1) neurons in neonatally operated hamsters with surgically induced, permanent, ectopic retinal projections to auditory thalamic nuclei and to visual thalamic nuclei which normally receive little direct retinal input. The surgically induced retino-thalamo-cortical pathways can mediate visual guided behaviors whose normal substrate, the pathway from the retina to the primary visual cortex via the primary thalamic visual nucleus, is missing. The visually evoked response properties of A1 neurons resemble in many respects those of neurons in V1 of normal hamsters: many A1 neurons have well-defined visual receptive fields and preferences for orientation or direction of movement. In addition, some visually responsive cells in A1 are bimodal--they also respond to auditory stimuli. The visually responsive neurons in A1 probably account for the capacity of the auditory cortex to mediate visual behavior in 'rewired hamsters'.

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The expression of brain-derived neurotrophic factor (BDNF) mRNA and the secretion of BDNF protein are tightly regulated by neuronal activity. Thus, BDNF has been proposed as a mediator of activity-dependent neural plasticity. Previous studies showed that dark rearing (DR) reduces BDNF mRNA levels in the primary visual cortex (V1), but the effects of visual experience on BDNF protein levels are unknown. We report that rearing in constant light or DR alters BDNF mRNA and protein levels in the retina, superior colliculus (SC), V1, hippocampus (HIPP), and cerebellum (CBL), although the changes in mRNA and protein are not always correlated. Most notably, DR increases BDNF protein levels in V1 although BDNF mRNA is decreased. BDNF protein levels also undergo diurnal changes. In the retina, V1, and SC, BDNF protein levels are higher during the light phase of the circadian cycle than during the dark phase. By contrast, in HIPP and CBL, the tissue concentration of BDNF protein is higher during the dark phase. The discrepancies between the experience-dependent changes in BDNF mRNA and protein suggest that via its effects on neuronal activity, early sensory experience alters the trafficking, as well as the synthesis, of BDNF protein. The circadian changes in BDNF protein suggest that BDNF could cause the diurnal modulation of synaptic efficacy in some neural circuits. The fluctuations in BDNF levels in nonvisual structures suggest a potential role of BDNF in mediating plasticity induced by hormones or motor activity.

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Exposure of the developing brain to methamphetamine has well-studied biochemical and behavioral consequences. We review: (1) the effects of methamphetamine on mature serotonergic and dopaminergic pathways; (2) the mechanisms of methamphetamine neurotoxicity and (3) the role of serotonergic and dopaminergic signaling in sculpting developing neural circuitry. Consideration of these data suggest the types of neural circuit alterations that may result from exposure of the developing brain to methamphetamine and that may underlie functional defects.

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Combined lesions of retinal targets and ascending auditory pathways can induce, in developing animals, permanent retinal projections to auditory thalamic nuclei and to visual thalamic nuclei that normally receive little direct retinal input. Neurons in the auditory cortex of such animals have visual response properties that resemble those of neurons in the primary visual cortex of normal animals. Therefore, we investigated the behavioral function of the surgically induced retino-thalamo-cortical pathways. We showed that both surgically induced pathways can mediate visually guided behaviors whose normal substrate, the pathway from the retina to the primary visual cortex via the primary thalamic visual nucleus, is missing.

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Permanent, novel retinal projections to the principal thalamic somatosensory (ventrobasal) or auditory (medial geniculate) nuclei can be produced in adult hamsters if the superior colliculus is ablated bilaterally and the somatosensory and auditory lemniscal axons are transected unilaterally on the day of birth. We studied the development of those novel projections by labeling retinal axons with the fluorescent tracer 1,1'-dioctadecyl-3,3,3', 3'-tetramethylindocarbocyanine perchlorate to examine the relative roles of intrinsic factors and axon-target interactions in the specification of retinal axon connections. Our principal findings are as follows: (1) In hamsters operated on the day of birth to produce the novel retinal projections, retinal ganglion cell axons projecting to the ventrobasal or medial geniculate nuclei develop in three morphologically distinct stages, i.e., elongation, collateralization, and arborization, as do retinal axons projecting to the dorsal lateral geniculate nucleus, the principal thalamic visual nucleus, in normal hamsters. (2) In both the ventrobasal and medial geniculate nuclei of operated hamsters, as in the dorsal lateral geniculate nucleus of normal hamsters, collateral branches were initially formed by retinal ganglion cell axons in both the superficial and internal components of the optic tract and only collaterals from the superficial component formed permanent projections. (3) The retinofugal axon terminal arbors in the ventrobasal and medial geniculate nuclei of mature, operated hamsters resemble the same three morphologic classes that are observed in the lateral geniculate nucleus of normal hamsters, although their absolute size appears to be altered. These data suggest that both superficial and internal optic tract axons can produce thalamic collaterals during development but that only superficial optic tract axons can permanently retain thalamic collaterals. Furthermore, the same morphologic types of retinofugal axons appear to contribute to normal and surgically induced retinal projections.

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Lesions of cerebral targets of the retina in newborn hamsters, when combined with transection of lemniscal pathways to the primary auditory or somatosensory thalamic nuclei or the secondary thalamic visual nucleus, can induce the formation of permanent retinal projections to the deafferented non-visual structures. These projections are retinotopically organized and form functional synapses. Consequently, neurons in the auditory or somatosensory cortices, which normally are not driven by visual stimuli, become visually responsive and have receptive field properties that ressemble, in several important ways, those of neurons in the visual cortex of normal animals. The surgically-induced retinothalamo-cortical pathways can mediate visually guided behaviors whose normal substrate, the pathway from the retina to the primary visual cortex via the thalamic dorsal lateral geniculate nucleus, is missing.

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The role of neurotrophins as survival factors for developing CNS neurons, including retinal ganglion cells (RGCs), is uncertain. Null mutations for brain-derived neurotrophic factor (BDNF) or neurotrophin 4 (NT4), individually or together, are without apparent effect on the number of RGCs that survive beyond the period of normal, developmental RGC death. This contrasts with the BDNF dependence of RGCs in vitro and the effectiveness of BDNF in reducing RGC loss after axotomy. To investigate the effect of target-derived neurotrophins on the survival of developing RGCs, we injected BDNF into the superior colliculus (SC) of neonatal hamsters. At the age when the rate of developmental RGC death is greatest, BDNF produces, 20 hr after injection, a 13-15-fold reduction in the rate of RGC pyknosis compared with the rates in vehicle-injected and untreated hamsters. There is no effect 8 hr after injection. Electrochemiluminescence immunoassay measurements of BDNF protein in the retinae and SC of normal and BDNF-treated hamsters demonstrate that the time course of BDNF transport to RGCs supports a role for target-derived BDNF in promoting RGC survival. The effectiveness of pharmacological doses of BDNF in reducing developmental RGC death may be useful in further studies of the mechanisms of stabilization and elimination of immature central neurons.

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We examined the number, spatial distribution, and size of ganglion cells in the retinae of normal Syrian hamsters and hamsters with retinal projections to the auditory and somatosensory nuclei of the thalamus, induced by neonatal surgery. As revealed by retrograde filling with horseradish peroxidase, there are about 64,600 contralaterally projecting retinal ganglion cells (RGCs) and 1,700 ipsilaterally projecting RGCs in the retinae of normal adult hamsters. Contralaterally projecting RGCs are distributed throughout the retina and have two local density peaks located within a central streak of high RGC density that is oriented approximately along the nasal-temporal axis. RGC density falls above and below the central streak, with a steeper gradient towards the upper retina. Ipsilaterally projecting RGCs are diffusely distributed within a crescent at the inferotemporal retinal periphery and are most dense at the internal border of the crescent. The soma diameter of contralaterally projecting RGCs ranges from 6 to 25 microns; the diameter distribution is unimodal, with a peak in the 10-13 microns range and is skewed toward smaller values, with an elongated tail towards higher values. Contralaterally projecting RGCs tend to be smaller in regions of higher density. Ipsilaterally projecting RGCs tend to be larger than contralaterally projecting RGCs both globally and within the temporal crescent, and their size distributions tend to be less regular and less well related to local density. The retinae of neonatally operated hamsters with novel retinal projections to the auditory. and somatosensory systems contain about one-fourth the normal number of contralaterally projecting RGCs, whose relative density distribution is approximately normal despite the drastic reduction of absolute RGC density. The range and distribution of RGC soma diameters are similar in normal and neonatally operated hamsters, and, in operated as in normal hamsters, contralaterally projecting RGC somata tend to be smaller in regions of higher density. Our results in normal hamsters suggest a role for intraretinal mechanisms in the determination of RGC size. Our findings in neonatally operated hamsters suggest that, despite the reduced number of RGCs in these animals, the same types of RGCs are found in the retinae of normal and neonatally operated hamsters.

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During normal postnatal development, there is an overproduction and subsequent partial elimination of the callosal projections of cortical areas 17 and 18 in the cat. In the present study, we investigated how neonatal splitting of the optic chiasm affects this process. Our results indicate that neonatal splitting of the optic chiasm exaggerates the normally occurring partial elimination of immature callosal projections: it causes a significant reduction in the total number of neurons in the supragranular layers that send an axon through the corpus callosum. It does not, however, cause a significant change in the number of callosally projecting neurons in the infragranular layers. These data suggest that in addition to other factors previously described, the level or spatial distribution of correlated binocular input to visual cortical neurons may influence the stabilization/elimination of immature callosal connections.

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We examined the specificity and developmental time course of the labelling of retinal ganglion cells in Syrian hamsters by a monoclonal antibody AB5. In adult hamsters, AB5 selectively labelled somata in the ganglion cell layer, dendrites in the inner plexiform layer and axons in the nerve fibre layer. When retinal ganglion cells were retrogradely labelled with DiI prior to AB5 immunocytochemistry, all of the retrogradely labelled retinal ganglion cells in the ganglion cell layer were AB5 immunoreactive, indicating that AB5 labels all classes of ganglion cell in that layer. In retinae depleted of retinal ganglion cells by neonatal optic nerve transections, AB5 did not label any somata or processes, indicating that AB5 specifically labels retinal ganglion cells. During development, AB5 labelling first appeared as a weak staining of cell bodies in the ganglion cell layer on postnatal day 12 (P12; PO = first 24 h following birth) and acquired the staining pattern seen in the adult by postnatal day 14. From the onset of AB5 immunoreactivity, AB5-labelled somata of varying sizes were present across the entire retinal surface. Although AB5 labelled retinal ganglion cell axons in the nerve fibre layer of the retina it did not label the optic nerve or retinal ganglion cell axons in the brain at any age examined. AB5 labelling was also found to be compatible with bromodeoxyuridine immunocytochemistry and, therefore, useful for determining the time of generation of hamster retinal ganglion cells.

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During development, there is a transient overproduction of axons in the corpus callosum; this overproduction of axons is due, in part, to a transient excess of neurons that send an axon through the corpus callosum. However, transient axonal branching could also contribute to the developmental overproduction of callosal axons. To investigate this possibility, we filled developing callosal axons in the Syrian hamster with the carbocyanine dye 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil). Light microscopic analysis showed that, indeed, developing callosal axons branch transiently in the hamster: branching was robust on postnatal day 0 (P0) and P3 (P0 = the first 24 hr after birth), less prominent on P6 and P8, and absent by P11. Immature callosal axons branched before or after crossing the midline and at all rostral-caudal and medial-lateral levels within the corpus callosum. The majority of callosal axon collaterals that were contained within individual 100-micron-thick sections were relatively short (mean = 15.1 microns) but some collaterals extended up to approximately 135 microns from the main axon trunk before passing out of the section in which they were observed. Nearly all of the collaterals emanated from the main axon trunk; higher-order collaterals were rare. Some callosal axon trunks had multiple collaterals. Branching callosal axons originated from multiple cortical areas, including area 17. Electron microscopic observations indicated that the processes designated as axon collaterals by light microscopic criteria would have been included in electron microscopic counts of developing callosal axons. Some callosal axon trunks and branches had ultrastructural features that suggested they were degenerating. In cats, developing callosal axons branch on embryonic day 57 (E57; the first 24 hr after conception = E0) and P0. Thus, it is likely that transient branching of immature callosal axons is a generalized feature of mammalian cortical development and that it contributes to the overproduction of callosal axons, albeit perhaps to varying degrees, in multiple species.

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Insights into the mechanisms of normal and pathological neural development may be gained by studying the reorganization of developing neural connections, caused experimentally or by disease. Many reorganized connections are assumed to arise by the anomalous stabilization of transient connections that occur during normal development. We report that, although the retina projects transiently to the somatosensory system in normal developing hamsters, the permanent retinal projections to the somatosensory system that arise as a consequence of early brain lesions are not formed by the stabilization of the normally transient projection. Instead, the transient retinal axons are replaced by retinal axons that do not normally project to the somatosensory system. The distinction between anomalous stabilization and substitution is significant for determining the cellular mechanisms underlying the development of neural connectivity.

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We have studied the postnatal development of individual axons in the optic tract and thalamus of the Syrian hamster, concentrating attention on retinal ganglion cell axons that make a transient projection to the main somatosensory nucleus, the ventrobasal complex. We bulk-filled axons with horseradish peroxidase in hemithalami maintained en bloc, in vitro. After processing and reaction with diaminobenzidine, we reconstructed individual axons from serial sections. In hamsters and other rodents, the optic tract is composed of superficial and internal components, either or both being possible sources of the retino-ventrobasal projection. Both project to the midbrain, but in normal adults only the superficial optic tract maintains collaterals in the thalamus. We found that the axons of the internal component bear numerous transient thalamic collaterals on postnatal days 0, 1, and 2, and some of these extend into the ventrobasal complex. Axons in the superficial optic tract also bear collaterals on days 0 to 2, but these are confined to the superficial half of the dorsal lateral geniculate nucleus. Thus the transient retino-ventrobasal projection comprises solely transient collaterals originating from axon trunks in the internal optic tract. On days 1 and 2, some collaterals from the superficial optic tract appear to have begun to arborize in the lateral geniculate nucleus. In contrast, collaterals from internal optic tract axons to the ventrobasal complex branch little if at all as they traverse the lateral geniculate nucleus, and at no time prior to their elimination do they develop an appreciable terminal arbor. These long collaterals often terminate in growth cones that include lamellopodia. Our HRP-impregnation method also revealed some transient non-retinofugal axons that pass medially from the ventral lateral geniculate nucleus to the ventrobasal complex but then return without terminating or branching. By day 4, they are absent, as are collaterals from the internal optic tract to the ventrobasal complex.

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Neurons in many regions of the CNS (e.g., cortical areas, thalamic nuclei) are heterogeneous with regard to their afferent and efferent connections. Using the hamster retinofugal system as a model, we investigated the mechanisms by which such connectional heterogeneity arises during ontogeny. Retinal ganglion cell axons were labeled with 1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (Dil) in paraformaldehyde-fixed tissue. The fluorescent label was photoconverted to a diaminobenzidine reaction product. The morphology of the axons, including their trajectories, branching patterns, and growth cones, was studied at the level of the dorsal lateral geniculate nucleus (LGd) from embryonic day 14 to adulthood. In adult hamsters, axons of retinal ganglion cells (RGCs) are spatially segregated at the level of the lateral geniculate nucleus into a superficial optic tract, situated just beneath the pia, and an internal optic tract consisting of fascicles running parallel to the pia within the geniculate. All retinofugal axons project to the midbrain, but only superficial optic tract axons emit collaterals to the LGd. During development, axons in both divisions of the optic tract emit collaterals to the LGd, but by postnatal day 15, collaterals of internal optic tract axons are virtually entirely eliminated, whereas those of superficial optic tract axons have elaborated terminal arbors. Thus, the heterogeneity among different classes of RGCs with respect to their efferent connections emerges by the selective stabilization, by each class, of a unique subset of connections from an initially widespread set shared by all classes. Thalamic collaterals of RGC axons emerge along established axon trunks, not by bifurcation of the growing tip. This occurs after the axons have grown past the thalamus and, presumably, entered their targets in the midbrain. Growth cones at the tips of elongating axon trunks are larger in size and have a more "complex" morphology compared to the growth cones on collaterals. Axons of RGCs develop in 3 morphologically distinct growth states. First, they elongate to their most distant targets in the midbrain. Then, they simultaneously emit unbranched or poorly branched collaterals to multiple targets. Finally, they elaborate terminal arbors in their definitive targets and eliminate their other collaterals. This developmental strategy may be paradigmatic for the formation of long CNS pathways with multiple targets. Furthermore, these data document, at the single-axon level, the steps in the elaboration and withdrawal of transient neuronal projections.

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During normal postnatal development there is a partial elimination of the callosal projections of cortical areas 17 and 18 in the cat. Visual experience early in life can modulate this process. In the present study, we investigated how restricting visual experience to alternating monocular occlusion affects the development of the callosal connections of cortical areas 17 and 18. Alternating monocular occlusion exaggerates the normally occurring partial elimination of immature callosal projection: it causes a significant reduction in the total number of neurons in the supragranular layers that send an axon through the corpus callosum and marginally increases the distribution of these neurons across areas 17 and 18. Examination of these data in the context of the effects of other types of abnormal early visual experience on the corpus callosum and on the anatomy and physiology of areas 17 and 18 indicates that the postnatal development of the corpus callosum is under the control of multiple, interacting influences which differ in the magnitude and quality of their effects. The data also support the conclusion, drawn from our results in prior studies, that normal visual stimulation is necessary for the stabilization of the normal complement of callosal projections.

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