Major advances in Neurobiology have shown that the central nervous system can regenerate and repair itself in response to cell damage due to ischemia and trauma, yet these innate recovery mechanisms remain limited and poorly understood. Recently, endogenous cell proliferation has been recognized as a mechanism to replenish lost neurons following injury, and that this phenomenon is age-dependent being much more pronounced in juvenile and young animals than elderly. Traumatic brain injury (TBI) is the major cause of death and disability in persons under the age of 45. Over 5.3 million Americans currently live with disabilities due to TBI, ranging from cognitive impairment to vegatative state. Studies have shown that endogenous cells from the subventricular zone and the hippocampal subgranular zone constantly generate new neurons throughout life, and that this process is enhanced after injury. Moreover, we and others have shown that newly-generated hippocampal dentate granular neurons can integrate and form synaptic connections to the existing hippocampal circuitry. We have also shown that this injury-enhanced endogenous neurogenic response is associated with the expression levels of several trophic factors following TBI. We have further shown that administration of exogenous trophic factors can not only enhance neurogenesis but also greatly improve recovery of cognitive function in adult animals following injury. In this proposal, we will specifically investigate how the endogenous neurogenic capacity of the brain can be enhanced to repair damaged neuronal circuitry. We will first examine the extent to which the newly- generated neurons establish connections to their target and communicate with neighboring cells through synaptic connections; Secondly, to further explore the effect of trophic factors on neurogenesis and functional recovery, we plan to assess expression levels of a broad spectrum of growth factors in the hippocampus following TBI in juvenile, adult and aged animals using antibody array methods. Thirdly, we will then utilize this information to manipulate endogenous neurogenesis and test the extent to which cognitive recovery in the adult and elderly brain following TBI can be improved by administering trophic factors that promote neurogenesis. Collectively, these studies will provide the mechanistic underpinning for rational construction of clinical trials on trophic factor administatrion for severely head injured patients who have sustained hippocampal damage - one of the most common patterns of cognitive impairment in this common, and currently untreatable condition. ? ? ?
