Adaptive synaptic plasticity maintains CRH neuron output during chronic glucocorticoid exposure

An increase in circulating glucocorticoids (CORT) is an essential part of the response to stress. Sustained elevations of CORT, however, have dramatic consequences on behavior, endocrine systems and peripheral organs. Critically, they dampen the endocrine response to acute challenges and decrease intrinsic excitability of corticotropin-releasing hormone neurons in the paraventricular nucleus (CRH), suggesting key circuits may be less responsive to stress. Here, we make the surprising discovery that CRH neurons harness a form of adaptive synaptic scaling to escape the persistent negative feedback pressure from CORT and maintain stable output . Specifically, there is an increase in glutamatergic drive to these cells that is mediated by a postsynaptic, multiplicative increase in synaptic strength. These findings suggest that dysfunctions associated with chronic stress may not be due to the primary actions of CORT, but instead reflect the emergence of synaptic adaptations as networks seek to re-establish intrinsic activity setpoints.