A hypothalamic VMPO-supraoptic vasopressin circuit mediates procalcitonin-induced fluid imbalance.

Sepsis is a life-threatening condition characterized by infection-induced organ dysfunction, with fluid imbalance and cardiovascular instability as cardinal features. Although circulating procalcitonin (PCT) is widely used as a diagnostic and prognostic marker in sepsis, its pathophysiological role remains poorly understood. Here, we identify a central neural circuit through which PCT directly disrupts fluid homeostasis: systemic PCT crosses the blood-brain barrier, activates calcitonin receptors, and depolarizes the Oprk1-expressing neurons in the ventromedial preoptic nucleus of the hypothalamus (VMPOOprk1). In vivo, PCT administration induces polydipsia and polyuria-phenotypes recapitulated by chemogenetic stimulation of VMPOOprk1 neurons. We demonstrate that VMPOOprk1 neurons project to and activate arginine vasopressin (AVP)-expressing neurons in the supraoptic nucleus (SONAVP), leading to increased blood pressure. Together, our findings define a PCT-sensitive VMPOOprk1→SONAVP neural circuit that integrates fluid balance and cardiovascular regulation. Our data highlight critical role of the brain in coordinating organ pathophysiology during infection.