Differential impact of adolescent or adult stress on behavior and cortical parvalbumin interneurons and perineuronal nets in male and female mice

Background Stress has become a prevalent public health concern, contributing to the rising prevalence of psychiatric disorders. Understanding stress impact considering critical variables, such as age, sex, and individual differences, is of utmost importance for developing effective intervention strategies. Methods Stress effects (daily footshocks for ten days) during adolescence (postnatal day, PND31–40) and adulthood (PND65–74) were investigated on behavioral outcomes and parvalbumin (PV)-expressing GABAergic interneurons and their associated perineuronal nets (PNNs) in the prefrontal cortex (PFC) of male and female mice five weeks post-stress. Results In adulthood, adolescent stress induced behavioral alterations in male mice, including anxiety-like behaviors, social deficits, cognitive impairments, and altered dopamine system responsivity. Applying integrated behavioral z-score analysis, we identified sex-specific differences in response to adolescent stress, with males displaying greater vulnerability than females. Furthermore, adolescent-stressed male mice showed a decrease PV+ and PNN+ cell numbers and PV+/PNN+ colocalization, while in females, adolescent stress reduced prefrontal PV+/PNN+ colocalization in the PFC. Further analysis identified distinct behavioral clusters, with certain females demonstrating resilience to adolescent stress-induced deficits in sociability and PV+ cell number. Adult stress in male and female mice did not cause long-lasting changes in behavior and PV+ and PNN+ cell number. Conclusion Our findings indicate that the timing of stress, sex and individual variabilities seem to be determinants for the development of behavioral changes associated with psychiatric disorders, particularly in male mice during adolescence.