Hypothalamic recurrent inhibition regulates functional states of stress effector neurons

Corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) are essential for homeostasis and stress responses, bidirectionally shifting from low- to high-activity state. However, the circuit mechanisms governing these state transitions remain unclear. Here, we develop spiking network models of CRH_PVN neurons using microendoscopic calcium imaging and single-unit electrophysiology datasets, and both approaches converge on a CRH-GABA recurrent inhibition motif, regulating bidirectional state transitions. Guided by model predictions, we show experimentally that PVN-projecting GABAergic neurons (GABA^→PVN) maintain CRH_PVN neurons in a low-activity state through feedback inhibition, and that their suppression enables transitions into a high-activity state. CRH_PVN→GABA^→PVN synapses are primarily mediated by glutamatergic transmission with minimal contributions from CRHergic transmission, providing further refinements to the model. Together, our results identify recurrent inhibition as a fundamental circuit motif controlling CRH_PVN functional states and demonstrate the value of iterative experiment-model integration for understanding hypothalamic circuit dynamics.