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 (VMPO^Oprk1). In vivo, PCT administration induces polydipsia and polyuria-phenotypes recapitulated by chemogenetic stimulation of VMPO^Oprk1 neurons. We demonstrate that VMPO^Oprk1 neurons project to and activate arginine vasopressin (AVP)-expressing neurons in the supraoptic nucleus (SON^AVP), leading to increased blood pressure. Together, our findings define a PCT-sensitive VMPO^Oprk1→SON^AVP neural circuit that integrates fluid balance and cardiovascular regulation. Our data highlight critical role of the brain in coordinating organ pathophysiology during infection.