The objective of our Neurotrauma Research Center at the University of Miami Miller School of Medicine is to carry out a program of integrated multidisciplinary experimental research into the mechanisms and therapies for traumatic brain injury (TBI). The ultimate goal is to identify factors resulting from TBI that may be amenable to specific therapeutic interventions in the acute, subacute and chronic stages. This current Program Project consists of investigative proposals directed at developing strategies and providing new data concerning recovery of function after TBI. These investigations are supported by Core facilities in the areas of animal physiology, neuropathology, molecular biology, electrophysiology, image processing and behavior. Established animal models including fluid-percussion (F-P) injury and cortical impact injury in rats and mice are utilized. Project 1 will examine the role of B-class ephrins and their respective receptors in the hippocampus following TBI. These studies will examine the role of ephrins and Eph receptors on astrocyte function and astrocyte-synaptic interactions. Project 2 will investigate molecular mechanisms of synaptic hyper-excitability and epileptic susceptibility after TBI. This project will test the hypothesis that activation of TrkB and ephrin B receptors plays a key role in posttraumatic seizure susceptibility. Project 3 will investigate the effects of injury severity on chronic circuit function and changes in synaptic plasticity after TBI. The use of an enriched environment (EE) as well as novel therapies and interventions to enhance behavioral and synaptic plasticity will be investigated. Finally, Project 4 will investigate the beneficial effects of transplantation of neuroprogenitor cells expressing a multi-neurotrophin. Studies will investigate underlying mechanisms for observed improvement and affects on synaptic plasticity. Potential detrimental side effects of this cell therapy will also be assessed including post-traumatic seizure potential and aberrant axonal sprouting. The Program Project is supported by an established group of scientists who provide the expertise necessary to conduct this multi-disciplinary program in TBI. Together, these experimental studies should enhance our understanding of the critical events associated with acute and more chronic brain trauma and help identify novel treatment strategies to promote neuroprotection, cellular replacement, remyelination and recovery of function in human TBI.