Behavioral appraisal by implementing a short sequence of stress resolves adaptively changed stress gains

Abstract Chronic stress produces adaptive changes in the brain via the cumulative action of glucocorticoids, which causes psychiatric illnesses such as depression. Here we show that a behavioral method implementing weak stress does not strengthen but resolves existing stress gains. Chronic stress produces persistent depressive behaviors in mice, and repeated daily treatment with 5-min restraint produces antidepressive effects. Repeated treatment with low-dose glucocorticoids mimics the anti-depressive effects of weak stress. Repeated weak stress or low-dose glucocorticoid treatment distinctively activates the prelimbic cortex (PL), and reverses the stress-induced altered gene expression profiles. Chemogenetic inhibition of PL outputs projecting to the nucleus accumbens, basolateral amygdala, or bed nucleus of the stria terminalis (BNST) dissipates antidepressive effects of weak stress, but only the PL-to-BNST circuit produces changes in dysregulated glucocorticoid release. Our results suggest that behavioral appraisal by implementing weak stress can resolve adaptively altered stress gains and rectify stress-induced depressive behaviors.