PVT inhibition mitigates neuropathology and cognitive deficits in chronic cerebral hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is a key pathophysiological substrate of vascular cognitive impairment, and the reorganization of neuronal activity across disease progression underlies network dysfunction and intervention strategy. Using immediate-early gene imaging with whole-brain mapping, we characterized spatiotemporal activation patterns in a bilateral common carotid artery stenosis mouse model at early (day 7) and chronic (day 40) stages across 225 brain regions. Weighted gene co-expression network analysis identified the paraventricular thalamus (PVT) as a persistently hyperactive and central region, with early thalamic-hypothalamic hyperactivation giving way to delayed cortical deactivation at chronic stages. Chemogenetic inhibition of PVT during the early post-ischemic phase attenuated neuronal damage in medial prefrontal cortex, hippocampus, and white matter, and improved cognitive performance and sleep continuity. These findings implicate PVT hyperactivation as a disease-associated node contributing to network-wide pathology in CCH, and suggest that early suppression of a central hub may help limit distributed injury.