Contribution of neurogenesis to recovery of function following brain trauma

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DESCRIPTION (provided by applicant): Despite years of research, the current neurotrauma field is unable to offer any treatment to address the persistent loss of function that can often occur after a traumatic brain injury (TBI). Stem cells may offer some potential in this regard. Our understanding of the interaction between injury and neurogenesis comes largely from studies on stroke and cortical lesion models where differences in pathophysiology to experimental TBI do not always make it appropriate to extrapolate data to the trauma model. There is currently no information on which cells in the neurogenic subventricular zone (SVZ) are affected by TBI and whether the number of self-renewing stem cells increases in addition to more committed progenitor cells. Resolution of this is important since an increase in stem cell number would indicate that injury induces in vivo cues that allow them to leave their normally quiescent state. If this were to be the case, it would imply a much greater potential for the genesis of new cells in the injured brain than previously thought. We propose four aims to begin to address the nature of the interaction between TBI and the SVZ. Aims 1 and 2: To determine whether cellular proliferation and neural stem cell self-renewal in the SVZ increases following TBI. We propose to look both in vivo (aim 1), using a thymidine-labeling system to label dividing cells before and after injury, and in vitro (aim 2), using a clonal neurosphere-forming assay. Aims 3 and 4: To determine the contribution of proliferating progenitors and GFAP-expressing neural stem cells to increases in SVZ cell proliferation and to spontaneous behavioral recovery following TBI. We propose to ablate the populations of proliferating progenitor and GFAP-expressing stem cells in order to assess their contribution to injury-induced SVZ cell proliferation (aim 3) and to functional recovery (aim 4). This project is of considerable relevance to the public health community as we seek to address fundamental questions on neurogenic control as a first step in determining the potential of stem cells to promote functional recovery after brain trauma.