Cerebral hypoperfusion exacerbates traumatic brain injury in male but not female mice

Abstract Mild-moderate traumatic brain injuries are common and while many individuals recover fully there is mounting clinical and epidemiological evidence that for a substantial subset, even when the acute TBI symptoms resolve, long term health can still be impacted. Individuals with a history of TBI are disproportionately vulnerable to many disease conditions including age-related neurodegeneration. These relationships are difficult to predict but these outcomes very likely interact with other disease risk factors such as cardiovascular disease. Here we tested the hypothesis that a mild pre-injury reduction in cerebral blood flow (bilateral carotid artery stenosis; BCAS) would impair recovery from TBI. Male and female mice underwent BCAS using steel microcoils around the carotid arteries, a mild-moderate closed-head TBI, or a combination of BCAS followed by TBI 30 days post-implantation. Cerebral blood flow, spatial learning and memory, axonal damage, and gene expression profiles were assessed. BCAS led to a ∼10% reduction in CBF, while TBI caused a similar decrease. However, mice exposed to both BCAS and TBI exhibited more pronounced reductions in CBF, associated with marked spatial learning and memory deficits, particularly in males. Axonal damage in male mice was also exacerbated by the combination of BCAS and TBI compared to either injury alone. Females exhibited spatial memory deficits associated with BCAS, but this was not exacerbated by TBI. We performed single nuclei RNA sequencing on male brain tissue to investigate the mechanisms underlying poorer long term functional outcomes in in TBI-BCAS animals. TBI and BCAS independently altered gene expression profiles in neurons and glia but in most cases BCAS and TBI together produced markedly different transcriptional patterns than either challenge alone. Overall, our findings reveal that the presence of mild reductions in cerebrovascular blood flow as a proxy for preexisting cardiovascular disease significantly exacerbated TBI outcomes in male but not female mice, indicating that even relatively mild comorbidities could significantly alter TBI outcomes and increase the probability of secondary disease processes.