Amplified Microglial Dysfunction and Brain Lesions in Mouse Models for Comorbidity of Chronic Stress and Intracerebral Hypoperfusion

Abstract Both clinical and preclinical evidence demonstrates a robust association between mood disorders and cerebrovascular diseases, with the dysfunction of the neurovascular unit (NVU) recognized as a crucial factor. Despite existing research illustrating that chronic stress can induce mood-related behavioral deficits by disrupting the NVU, the underlying mechanisms remain elusive. In this study, we uncovered notable transcriptomic alterations within the NVU following chronic stress, with up-regulated genes highly enriched in microglia. Additionally, an increased interaction between microglia and cerebral microvessels was observed in the stressed brain. However, no notable evidence of blood-brain barrier (BBB) compromise was found in response to chronic stress alone. To mimic the comorbidity of depression and intracranial hypoperfusion, we combined chronic stress with bilateral common carotid artery stenosis (BCAS). Strikingly, the comorbidity model exhibited severe brain lesions across multiple regions, surpassing the effects observed in the control, stress-only, or BCAS-only groups. These lesions included pronounced microglial activation, disrupted neuronal formation, demyelination, BBB compromise, and neovascularization. Importantly, microglia emerged as central players in all observed cellular events. Our findings strongly suggest that chronic stress may compromise microglial functions, thereby increasing vulnerability to adverse cerebrovascular events. This study provides valuable insights into the intricate relationship between chronic stress and cerebrovascular diseases, underscoring the significance of considering mood management for patients with this complex comorbidity.