Sex differences in resilience at puberty depend upon divergent effects of a stress steroid at α4βδ GABAA receptors

Resilience is a critical skill that lessens the adverse effects of stress which are increasingly reported in adolescents, where sex differences are noted. It is not known how this process develops in adolescence when unique changes in neuronal properties occur. For this study, pubertal mice were tested for their coping ability following 2-week restraint. We show here that this predictable stress produced resilience in pubertal female mice where time immobile in the forced swim test (FST) decreased by ∼50 % (P < 0.0001), an effect that extended into adulthood, and increased escape behavior 8-fold (P = 0.01). This effect was not seen in pubertal male or adult female mice. This process required the stress steroid 3α-OH,5α-pregnan-20-one (THP, allopregnanolone) and its primary target, α4βδ GABA_A receptors (GABARs). These receptors emerge at puberty in prelimbic prefrontal cortex (PL PFC) and basolateral amygdala (BLA), which play a pivotal role in resilient behavior. Stress-induced release of THP decreased anxiety-like behavior (increasing open arm time in the elevated plus maze) and enhanced PFC-dependent learning (temporal order recognition) after 1d restraint in pubertal female, but not male, mice while differentially altering α4βδ expression in PL and BLA. This divergent THP-induced effect ultimately increased and decreased mushroom spine density in PL and BLA, respectively, to produce a circuit optimized for resilient behavior in the pubertal females. These findings demonstrate a novel mechanism for the development of resilience unique to the pubertal period. The results from the present study may suggest therapeutic strategies for adolescent stress which would impact mental health in adulthood.