Amplified microglial dysfunction and brain lesions in mouse models for comorbidity of chronic stress and cerebral hypoperfusion.

Both clinical and preclinical evidence demonstrates a robust association between mood disorders and cerebrovascular diseases, but the underlying mechanism remains elusive. In this study, to model the comorbidity of depression and cerebral hypoperfusion, we combined two different types of chronic stress paradigms, chronic unpredictable mild stress (CUMS) and social defeat (SD), with bilateral carotid artery stenosis (BCAS). Mice in the comorbidity group exhibited additive impairments in cognitive behaviors, surpassing the effects observed in the sham, stress-only, or BCAS-only groups. Notably, the most prominent change was massive microglial activation in the comorbidity group extending into critical gray matter areas, accompanied by severe brain lesion including blood-brain barrier (BBB) damage, demyelination, localized neuronal disruption, and abnormal vessel formation. Importantly, microglia emerged as central players in all observed cellular events, displayed stage-specific roles mediated by distinct subpopulations, driving neuroinflammation in response to BCAS and promoting angiogenesis under comorbid condition. Our findings suggest chronic stress impairs microglial function, increasing vulnerability to cerebral hypoperfusion. This study highlights chronic stress as a key risk factor for cerebrovascular events and underscores the importance of stress management in patients with this comorbidity.