NEUROTROPHIN CONTROL OF THALAMOCORTICAL DEVELOPMENT

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Normal development of ordered representations of the craniofacial periphery (whisker pattern in rodents) in the primary somatosensory (SmI) cortex requires peripheral input. Although it is clear that competition between cortical pattern formation. Thus, competitive interactions may not be based upon electrical events, but rather, access to a growth-promoting substance(s) that (are) produce in the central nervous system. Here, we propose to evaluate the actions of neurotrophins, normally present in these areas, upon the development of thalamocortical afferents (TCAs). Based upon observations in the developing visual system (Cabelli et al., 1995) and trigeminal primary afferents (Project 1), we hypothesize that TCAs compete for access to a limited supply of particular neurotrophins during critical periods of development, and that the spatial and temporal distribution of neurotrophins during critical periods of development, and that the spatial and temporal distribution of neurotrophins is an important determinant of thalamocortical structure and function. Specifically, NT-3 will produce axon arborization and BDNF will produce axon elongation. Augmented delivery of NT-3 and BDNF will be accomplished using three corroborative approaches that include impregnated Elvax implants (Experiment 1a), transgenic over- expression (Experiment 1b), and transplantation of neural induced ES cells containing transgenes designed to conditionally over-express each neurotrophin (Experiment 2). In Experiments 1 & 2, the dependent variable assess TCA morphologic indices including single fiber and total production analysis using neurobiotin and DiI post-mortem anterograde labeling. Experiment 2 will assess integration and differentiation of neural ES cells containing transgenes to over-express the neurotrophins. Experiment 3 will compare cortical barrel patterns to individual TCA morphologic and topographic changes observed in Experiments 1 & 2. Core A will perform labeling of TCAs and layer IV neurons and stereologic ultrastructural analysis of TCA synapses upon ES cells. Core B will produce the tetracycline regulated NT-3/BDNF transgenic mice. Core C will quantify TCA morphology and cortical C confocal microscope and quantified using stereologic methods in Core C. These studies will provide insights with transplanted ES cells will be relevant to therapeutic strategies using transplantation to restore function lost whether individual non-regionally committed neural precursors are capable of being integrated into the normal somatotopic organization of the SmI cortex and if a critical-sensitive period exists.