Therapeutic Enhancement of neurogenesis following traumatic brain injury

DESCRIPTION (provided by applicant): Following traumatic brain injury (TBI), patients often develop significant disability in cognition, communication, and behavioral or emotional stability. Problems with memory commonly occur following TBI and underlie some of the morbidity accompanying each of these affected areas. In addition, there is some spontaneous recovery after brain injury that occurs largely by unknown remodeling processes. It has been known for some time that TBI elicits increased generation of new neurons in the hippocampus; the significance of this, however, has not been clear. We have recently demonstrated that injury-induced neurogenesis underlies at least some of the spontaneous recovery associated with TBI. As such, the promotion of hippocampal neurogenesis represents an important therapeutic target for developing new treatments for victims of TBI. If injury-induced activation of hippocampal progenitors is useful at improving functional outcome, one reasonable approach to enhancing recovery would be to increase the proliferation of early progenitors. We have recently developed, characterized, and validated a novel transgenic mouse that allows for ganciclovir-induced ablation of actively dividing early neural progenitors, enabling us to precisely attribute any positive effects of pro-neurogenic strategies to their effects on neurogenesis. The overall goal of this project is to determine whether enhancing neurogenesis improves outcome following TBI. In Specific Aim 1, we will enhance hippocampal neurogenesis using pharmacologic means. We will test an FDA-approved medication commonly used to treat Alzheimer disease and determine whether it specifically enhances neurogenesis in the hippocampus following injury. For Specific Aim 2, we will utilize temporally regulated and progenitor-specific genetic deletion of the tumor suppressor gene PTEN that also specifically increases hippocampal neurons. For both of these, we will study the effects of increasing neurogenesis following controlled cortical impact (CCI) injury to determine whether enhancing neurogenesis improves recovery after TBI.