Homeostatic scaling ensures behavioural stability during corticosterone negative feedback

Maintaining appropriate behavioral and physiological responses in the face of challenge is essential for survival. The persistent increase in corticosteroids (CORT) during chronic stress blunts the endocrine response to any subsequent stressors. But the impact of prolonged CORT on behaviors that promote survival in the face of an acute stress is not well understood. Here we used an aerial predator threat model combined with in vivo calcium imaging, whole-cell electrophysiology, chemogenetics and computational modeling to evaluate the effects of short and long-term CORT. We show that in the short term, the activity of the corticotropin releasing hormone neurons of the paraventricular nucleus of the hypothalamus (CRH^PVN) and innate defensive behaviors that rely on these cells, are sensitive to the negative feedback effects of CORT. In response to long-term increases in CORT, however, behaviors recover, even though intrinsic CRH^PVN activity remains low. This escape from negative feedback requires local, homeostatic scaling of glutamate synapses that overcomes the inhibitory effects of CORT. This scaling is sufficient to maintain the output of this system in vivo and preserves innate defensive responses to threat. We propose that homeostatic synaptic scaling functions as a local adaptive mechanism to preserve the reliability of essential survival circuits during times of chronic stress.