The research and career development plans proposed in this application will expand the applicant s expertise into neuropharmacology and integrative neuroscience as applied to studies of neuroplasticity and neuroprotection in animal models of neuropsychiatric disorders. The studies proposed will take advantage of the recent observation that exposure to brief, highly controlled seizures induced by low-intensity eLeciroconvulsive shock (ECS), confer a marked resistance to neuronal cell death induced by diverse insults This effect is accompanied by a marked induction of expression of specific neurotrophic factors in lhnbic system regions. The working hypothesis for the proposed studies is that enhanced receptor-mediated actions of the neurotrophic factors are a crucial component of the neuroprotective influence of ECS exposure. In particular, the extent to which receptors for two major neurotrophic factors, basic fibroblast growth factor (bFGF) and nerve growth factor (NGF), become activated and/or upregulated following repeated ECS treatment will be evaluated in specific brain areas of rats.
The Specific Aims will test whether I) repeated ECS results in activation and/or enhanced biosynthesis of receptors for bFGF and NGF in limbic system regions; 2) the neuroprotective action of repeated ECS is dependent upon activation of receptors for bFGF and/or NGF; 3) differential changes in expression of glutamate receptors will accompany the changes in bFGF and/or 4GF expression following repeated ECS; and 4) differential changes in expression of glutamate receptors are dependent upon activation of receptors for bFGF and/or NGF following repeated ECS. The experiments designed to pursue these Specific Aims will provide an ideal opportunity for the applicant to gain both theoretical and practical expertise in the combined use of pharmacological, physiological and neurohistological approaches to the study of animal models. The applicant's strong background in molecular approaches in vitro will be brought to bear on an analysis of changes occurring in vivo in the intact animal. The career development plan will facilitate a substantial shift in the applicant's research capabilities and focus, so that it will become possible for the applicant to build an independent research program devoted to elucidating molecular mechanisms that determine vulnerability to neuronal cell death in the brain of the intact animal. The ability to evaluate the multifactorial impact of therapeutic interventions in intact animal models will prepare the applicant to pursue research on animal models of neuropsychiatric disorders and place his molecular skills in the context of neurohistopathogy, pharmacology, anatomy and physiology. Structured mentored activities and short courses will guide the development of expertise in these areas necessary for the proposed studies and for the long-term career advancement of the applicant as a versatile neuroscientist.
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