Traumatic brain injury (TBI) is the leading cause of neurological disability and the primary risk factor for development of neurodegenerative diseases and dementia in the United States. Over 2 million TBI-related incidents occur each year, and 3-5 million people currently suffer from chronic TBI-related disabilities. With the incidence of TBI on the rise, it is increasingly important to understand the underlying injury mechanisms and develop treatments for current and future patients. This dissertation investigates two such mechanisms contributing to TBI-induced cognitive decline, broadens the scope of TBI research to understand the effect of aging, and describes a new mouse model for frontal lobe TBI.

In chapter 1, I investigated the effect of aging on TBI-induced cognitive deficits and inflammatory response with emphasis on the contribution of peripheral, infiltrating monocytes. Our mouse model of TBI showed significantly greater chronic impairment of spatial memory in aging mice. Aging also exacerbated the infiltration of the peripheral monocytes while impairing expression of anti-inflammatory markers in peripheral monocytes and resident microglia. Furthermore, I observed that a subpopulation of the peripheral monocytes regained proliferative capabilities after infiltrating the injured brain, and the effect was significantly more pronounced in the old mice. In chapter 2, I targeted the integrated stress response (ISR) pathway using a novel small molecule at a chronic timepoint after injury. Inhibition of the ISR during behavioral testing fully restored spatial learning and memory in two different mouse models of TBI. The treatment additionally rescued deficits in long-term potentiation in the hippocampus at the chronic timepoint. In chapter 3, I applied the controlled cortical impact method to develop a frontal lobe injury mouse model to better mimic TBIs commonly observed among human patients. Markedly, mice that had received the frontal lobe TBI displayed deficits in prefrontal cortex-driven behavior similar to symptoms seen in human TBI patients. These chapters collectively add to our understanding of the biology of TBIs with the hope that we are a step closer to providing effective treatment for a major health crisis in the future.