We propose to investigate the mechanisms underlying brain dysfunction following traumatic brain injury (TBI) and to clarify recovery processes that may be targeted for therapeutic intervention. In Part 1 of this project, we propose to combine in vitro neurophysiological techniques with cognitive neurobehavioral assessment to evaluate the temporal course of alterations in hippocampal inhibitory circuitry after trauma and to document evidence for aberrant spatial and movement selective hippocampal cellular discharge. The strength of the relationship between cognitive behavior and these indices of hippocampal circuit dysfunction will clarify the role of the hippocampus in generating the functional deficits associated with TBI and whether hippocampal reorganization contributes to functional recovery. In Part 2, we will investigate the effects of TBI on hippocampal long-term potentiation (LTP) and long-term depression (LTD), using the hippocampal slice preparation. Experiments are proposed that will determine whether TBI-induced over activation of NMDA receptors in hippocampus mediates the suppression of LTP and whether NMDA receptor overactivation in vitro will mimic TBI-induced LTP suppression. In Part 3, we will use a newly developed three-dimensional autoradiographic imaging averaging method of expressing local glucose utilization combined with somatosensory circuit activation to quantitatively pinpoint areas of circuit reorganization after TBI. These functional data will be complemented by immunocytochemical and in situ hybridization studies to assess local alterations in pre- and postsynaptic markers and gene expression associated with circuit remodeling. Finally, slowly developing thalamic retrograde degeneration will be targeted for treatment using basic fibroblast growth factor in an attempt to protect somatosensory circuit structure and function. Together, these studies should contribute new information concerning the response of the nervous system to TBI as well as clarifying recovery mechanisms that may be targeted for therapeutic intervention.
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