Active coping mitigates the effects of stress on glucocorticoid levels in the prefrontal cortex

Exposure to stressors elevates glucocorticoid (GC) levels in the periphery and brain, directly impacting neurogenesis, neuronal morphology and function, as well as neuroinflammatory processes. The ability to exert behavioral control over an adverse event prevents many of the sequelae of stressor exposure; however, extensive evidence indicates that this protection occurs without concomitant reductions in hypothalamic–pituitary–adrenal (HPA) axis activity. Given that brain GC levels can be regulated independently of changes in HPA output, we investigated whether controllability might alter corticosterone (CORT) levels and CORT-sensitive gene expression in rat brain, even though it does not modulate peripheral CORT. We found that behavioral control (escapable shock, ES) selectively attenuated stress-induced CORT and modulated CORT-sensitive genes (Nr3c1, Ilb, Nlrp3, and Cd200r1), as well as IL-1β protein in the medial prefrontal cortex (PFC) relative to uncontrollable stress (inescapable shock, IS). Stress-induced expression of PFC 11β-hydroxysteroid dehydrogenase type 1, an enzyme that regulates local concentrations of CORT, was increased (mRNA) and decreased (protein) in ES relative to IS. These controllability effects were absent in other brain structures previously implicated in the differential behavioral outcomes of ES and IS. Together, the findings provide initial evidence that active coping with a stressor is a key determinant for regulating GC action, potentially shaping cognitive and neuroimmune responses to adverse events at a local tissue level.