Unraveling TBI-mediated Dysregulation of Adult Hippocampal Neurogenesis at Multiple Stages in the Neurogenic Cascade

Abstract Traumatic brain injury (TBI) afflicts an estimated 2.5 million people in the US each year, with as many as 5.3 million living with TBI-related disabilities. Chief among these are cognitive deficits, particularly in learning and memory functions that are highly dependent on the hippocampus. Structural and functional damage to the hippocampus resulting from TBI may be offset, in part, by neuroplasticity in the form of neurogenesis. TBI triggers an early wave of proliferation of neural progenitor cells (NPCs) in the subgranular zone (SGZ) of the hippocampal dentate gyrus. NPC proliferation supports an increase in the production of immature granule cell (GC) neurons, compensating for the early loss of immature GC neurons after TBI. In a traumatized brain, however, many proliferating NPCs fail to generate granule neurons and newborn neurons do not develop normal dendritic arbors. While therapeutics can boost posttraumatic neurogenesis in preclinical models, there remain concerns that stimulating excessive or aberrant neurogenesis could have negative consequences and could compromise longer term neuroplasticity. A more complete understanding of the effects of TBI on different stages of neurogenesis, from cell proliferation to neuronal maturation and survival, is needed to more effectively guide neurogenesis-targeted therapies. Using a novel transgenic mouse model in which a reporter molecule is conditionally expressed in the cytoplasm of neuronally committed NPCs, we will evaluate the effects of a cortical contusion injury on the morphological development of GC neurons born just before TBI, acutely after TBI during a phase of elevated proliferation, and subacutely (weeks) after TBI after the proliferative burst has subsided to identify the window of neurogenesis dysregulation. Our preliminary data suggests intriguing differences in the generation/survival and maturation of posttrauma-born neurons in male and female mice, pointing to more pronounced impairment of neurogenesis in males. Inclusion of male and female cohorts in the proposed studies will fill a gap in knowledge in the TBI neurogenesis field, which has been dominated by studies of exclusively male rodents. To determine if the TBI-induced proliferative wave compromises SGZ neurogenic potential and longer term, physiological neurogenesis, cell proliferation and NPC and immature neuron numbers will be quantified in the SGZ at 6 and 12 weeks. We hypothesize that TBI disrupts cell cycle exit of proliferating neuroblasts, contributing to decreased generation of postmitotic neurons and an increase in cellular senescence. We will use pulse labeling with proliferation markers to examine timing of cell cycle exit and will examine the extent and time course of cell senescence in the SGZ. Finally, we will test the efficacy of a drug which eliminates senescent cells to enhance neurogenesis and improve cognition following TBI in mice. Taken together, these studies will (1) yield new insights into how TBI affects critical stages of the neurogenesis process, including maintenance of the stem cell pool, cell cycle exit, neuronal maturation, axon and dendrite elaboration, and survival, (2) delineate sex-dependent neurogenic responses following TBI, and (3) provide initial efficacy data on an innovative therapeutic approach for restoring neurogenesis-related plasticity and cognitive function after TBI.