Hypothalamic recurrent inhibition regulates functional states of stress effector neurons

ABSTRACT Stress triggers rapid and reversible shifts in vital physiological functions from homeostatic operation to emergency response. However, the neural mechanisms regulating such functional stress states remain poorly understood. Here we identify a novel recurrent inhibitory circuit governing functional states of key stress regulatory neurons: corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN). Microendoscopic calcium imaging in freely behaving mice revealed synchronized low-activity state at baselines and a reversible high-activity state during mild stress. Ensemble analysis indicated increased dimensionality of network dynamics during high-activity state. Computational modeling of calcium ensemble data, together with independent modeling of single-unit CRH PVN neurons spiking dynamics, converged to show that recurrent inhibition is a key circuit motif for stress-induced functional state transitions. Guided by model predictions, chemogenetic manipulations of PVN-projecting GABAergic neurons ( PVN→ GABA) revealed their roles in constraining CRH PVN neurons to low-activity state at baselines via a prolonged feedback inhibition. Unexpectedly, slow CRHergic excitation was dispensable for driving this prolonged feedback, whereas glutamatergic transmission predominated at CRH→ PVN→ GABA excitatory synapses. Incorporating these findings, we refined our computational model to include fast excitation and slow inhibition, yielding new predictions for circuit operation. Together, our results establish recurrent inhibition as a fundamental circuit motif controlling CRH PVN neurons functional states and highlight the value of iterative experiment–model integration in advancing understanding of neural circuits functions.