Sexual differentiation of neural mechanisms of stress sensitivity during puberty

Abstract

Adolescence is an important developmental period during which anxiety-related behaviors differentiate in males and females. In humans anxiety prevalence increases to a greater degree in women than men after puberty, but the mechanism is unknown. We used social defeat stress to model anxiety behaviors in California mouse, a species in which aggressive females allow for comparison of social anxiety behaviors across sex. Adult female California mice show reduced social approach and increased social vigilance after exposure to stress, while these changes are weaker in males. Here we show that in juveniles, social defeat reduces social approach and increases social vigilance in both males and females. Next, we show that prepubertal castration sensitizes adult males to social defeat. However, when pubertal castration was paired with either testosterone or dihydrostesterone replacement, effects of defeat on social approach and vigilance were blunted in adult males. We also showed that effects of defeat on social behavior in juveniles were oxytocin receptor dependent, as has been described for adult females. This work highlights the importance of pubertal testosterone to the development of sex differences in anxiety behavior, and provides evidence that androgen receptors play an important role in the development of neural circuits of anxiety.

Neuroendocrine mechanisms of aggression in rodents.

“…These studies indicate that higher neonatal testosterone may influence the rewarding nongoal oriented behavior of play but not the goal-directed aggression of adults. In male California mice, prepubertal castration made adult males more likely to show social defeat after an aggressive encounter, but adult replacement of testosterone or dihydrotestosterone (DHT) reversed these effects (Wright et al, 2020). This suggests that testosterone during adolescence is also important for adult resilience to aggression.…”