Parasubthalamic Glutamatergic Neurons Coordinate Cardiovascular Homeostasis and Locomotion in Mice

Abstract Cardiovascular homeostasis and locomotion are vital for animal survival and the maintenance of essential physiological functions. The parasubthalamic nucleus (PSTN) has recently emerged as a novel interoceptive center in the central nervous system, yet its role in coordinating cardiovascular homeostasis and locomotor behavior remains poorly understood. Here, we demonstrate that PSTN ^Vglut2 neurons serve as a novel baroreflex center, exhibiting heightened activity during acute hypertension. Through their glutamatergic monosynaptic descending projections to the nucleus of the solitary tract (NTS), these neurons mediate parasympathetic output to regulate cardiovascular homeostasis while coordinately modulating locomotor activity. Chemogenetic activation of NTS‐projecting PSTN ^Vglut2 neurons rapidly reduces heart rate, attenuates hypertensive responses, and accelerates blood pressure recovery. Conversely, their inhibition exacerbates blood pressure elevations, delays recovery to baseline, and impairs locomotor performance. Correlation analyses reveal a significant negative relationship between blood pressure fluctuations and locomotor metrics, such as total running distance and high‐speed locomotion duration, underscoring the interdependence of cardiovascular stability and motor function. These findings position the PSTN as a critical central command hub, offering novel insights into the neural circuits governing cardiovascular homeostasis and locomotion, with potential implications for targeted neuromodulatory interventions in hypertension.