Acute and persistent neuroendocrine and behavioral alterations after social fear conditioning in adolescent male mice.

Abstract

Adolescence is a critical developmental period with heightened stress susceptibility. Traumatic experiences during this phase are highly predictive of future affective disorders, such as social anxiety disorder (SAD), which may manifest during early adolescence. Social avoidance, a major symptom of SAD, can be robustly generated in adult male and female mice using the social fear conditioning (SFC) paradigm. Using the SFC paradigm in adolescent mice, we analyze behavioral and neuroendocrine responses after adolescent social trauma. Here, we demonstrate that social fear elicited by SFC in early adolescent (EA) male mice (SFC⁺EA/29d) persists until adulthood (SFC⁺EA/57d). We further compared neuroendocrine responses to a heterotypic (elevated platform) or homotypic (exposure to a conspecific) stressor after SFC performed either in EA (SFC⁺EA/29d, SFC⁺EA/57d) or adulthood (SFC⁺AD). While in non-conditioned SFC^-EA/29d mice plasma corticosterone concentrations remained unchanged after social exposure in adolescence, SFC⁺EA/29d resulted in a hyper-response of the HPA axis to the social, but not heterotypic stressor, with a negative correlation of plasma corticosterone concentrations and social investigation times. This effect of SFC⁺EA/29d on plasma corticosterone response was absent in SFC⁺EA/57d and SFC⁺AD mice indicating a higher sensitivity to social trauma in EA. We further revealed a rise in plasma oxytocin (OXT) levels in adult SFC^- mice in response to the social challenge, whereas the OXT system of SFC^-EA/29d mice still seems to be unresponsive to the social stimulus. Importantly, after SFC⁺ either in EA or AD, the OXT response to social exposure found in SFC^-AD controls was completely abolished, whereas in SFC^-EA/57d mice OXT levels positively correlated with social investigation times, indicating social trauma-induced acute and long-lasting dysfunctions of the OXT system. In summary, we show that exposure to social trauma (SFC⁺) in early adolescence exerts both short-term as well as long-term effects on social behavior. We further reveal that SFC⁺EA/29d prevents the corticosterone hypo-response to social stimuli characteristic for early adolescence. Moreover, SFC⁺/AD and SFC⁺EA/57d impair the plasma OXT response to a social, but not heterotypic, stressor.