Exploring sexual dimorphism in behavioral and neuropathological outcomes in mice after bilateral common carotid...

Cerebral ischemia (CI) is a leading cause of mortality and morbidity worldwide. Despite its high incidence and the severe consequences it entails, effective prevention and treatment strategies to mitigate CI complications remain elusive. Consequently, the use of suitable animal models is crucial for understanding CI pathophysiology and for evaluating potential therapeutic approaches. Incorporation of external validity criteria in preclinical studies, including the use of diverse animal strains and species, both sexes, and relevant comorbidities, is crucial. To adhere to these recommended standards and enhance the translational value of preclinical research, this study aimed to investigate the effects of bilateral common carotid artery occlusion (BCCAO) in both male and female C57BL/6 J mice. Functional assessments were conducted through a series of behavioral tests over 21 days post-BCCAO. Additionally, the study examined the impact of BCCAO on hippocampal neurodegeneration, blood-brain barrier (BBB) integrity, and white matter (WM) integrity. Our findings revealed significant sex differences in the functional and neurohistological outcomes of BCCAO in C57BL/6 J mice. In male mice, 20 min of BCCAO resulted in spatial memory deficits, depression-like behaviors, hippocampal neurodegeneration, WM injury, and BBB disruption. Although female mice also exhibited BBB disruption, they did not display significant behavioral alterations, hippocampal neurodegeneration, or white matter injury after BCCAO, in contrast to the effects observed in males subjected to the same procedure. These results highlight the importance of sex differences in BCCAO outcomes and underscore the need for the inclusion of female subjects in CI therapy research.