Chemogenetic Pericyte Activation Reveals Broad Contractile Ability and Limbic Vulnerability to Capillary Flow Deficits

ABSTRACT Capillary pericytes contact most of the brain’s microvasculature. Yet, their influence on blood flow remains incompletely understood both locally in capillary networks and across brain regions. Here, we sparsely expressed the chemogenetic actuator Gq-DREADD in mouse brain pericytes to stochastically probe their contractility and influence on tissue perfusion and oxygenation. Chemogenetic stimulation induced robust contraction of pericytes over minutes, including those with thin processes on capillary segments proximal to venules, indicating control of vascular tone across the entire capillary bed. Pericyte contraction combined circumferential compression with longitudinal tension applied through thin processes, resulting in vasoconstriction and hypoperfusion. Histology revealed hypoxic microdomains induced by sparse pericyte contraction across the brain, and enriched hypoxia in limbic structures including the amygdala and hippocampus. These microscale perfusion deficits were undetectable by arterial spin labeling MRI. Our findings reveal the in vivo mechanics of pericyte contraction and identify limbic system vulnerability to capillary flow impairment.