The absence of a neurogenic response to a repeated concussive-like injury in mice

Abstract

AbstractIn response to traumatic brain injury (TBI), the brain increases its generation of new neurons (neurogenesis) within the hippocampus, a brain region critical for learning and memory. Because neurogenesis plays important roles in learning and memory, post-traumatic neurogenesis may represent an adaptive response contributing to cognitive recovery. In contrast to increases in neurogenesis acutely after injury, levels of neurogenesis become impaired long after TBI. And although chronic deficits in neurogenesis after TBI have been reported by multiple groups, it is unknown whether the hippocampus remains capable of eliciting another neurogenic response to a repeated injury. To address this lack of knowledge, we used a closed head injury model that reflects a concussive-like injury or a mild TBI (mTBI) and assessed levels of neurogenesis in male and female adult mice. Mice received one or two mTBI or sham treatments 3 weeks apart. Compared to mice with a single mTBI, proliferation and neurogenesis were blunted in mice that received a second mTBI. This impaired response was unlikely due to a short recovery time between the two mTBIs as the proliferative response to a second mTBI was also impaired when two months were allowed between injuries. We further found that proliferation was impaired in the radial-glia like cells despite an intact pool. The mice that received two mTBIs also had a blunted intensity in their GFAP staining. In contrast to reports of aberrant post-TBI neurogenesis, we found that the neurons born after mTBI had normal dendritic branches. Lastly, we found that impairments in the inability to mount a neurogenic response after a second mTBI were associated with deficits in neurogenesisstrategy flexibility in the reversal water maze task. Our data suggests that a loss in the neurogenic response could in part contribute to worse cognitive recovery after a repeated concussion. These data may expose a novel target to help improve long-term cognitive outcome following repeated brain injury.