Chemogenetic manipulation of the bed nucleus of the stria terminalis counteracts social behavioral deficits induced by early life stress in C57BL/6J mice.

Trauma during critical periods of development can induce long-lasting adverse effects. To study neural aberrations resulting from early life stress (ELS), many studies utilize rodent maternal separation, whereby pups are intermittently deprived of maternal care necessary for proper development. This can produce adulthood behavioral deficits related to anxiety, reward, and social behavior. The bed nucleus of the stria terminalis (BNST) encodes aspects of anxiety-like and social behaviors, and also undergoes developmental maturation during the early postnatal period, rendering it vulnerable to effects of ELS. Mice underwent maternal separation (separation 4 hr/day during postnatal day (PD)2-5 and 8 hr/day on PD6-16) with early weaning on PD17, which induced behavioral deficits in adulthood performance on two-part social interaction task designed to test social motivation (choice between a same-sex novel conspecific or an empty cup) and social novelty preference (choice between the original-novel conspecific vs. a new-novel conspecific). We used chemogenetics to non-selectively silence or activate neurons in the BNST to examine its role in social motivation and social novelty preference, in mice with or without the history of ELS. Manipulation of BNST produced differing social behavior effects in non-stressed versus ELS mice; social motivation was decreased in non-stressed mice following BNST activation, but unchanged following BNST silencing, while ELS mice showed no change in social behavior after BNST activation, but exhibited enhancement of social motivation-for which they were deficient prior-following BNST silencing. Findings emphasize the BNST as a potential therapeutic target for social anxiety disorders instigated by childhood trauma.

Sex-dependent and ontogenetic effects of low dose ethanol on social behavioral deficits induced by mouse maternal separation.

Early life stress can induce lifelong emotional and social behavioral deficits that may in some cases be alleviated by drugs or alcohol. A model for early life stress, rodent maternal separation, recapitulates these behavioral sequelae, which are not limited to potentiated anxiety-like behavior, attenuated social motivation, and altered reward-seeking. Here we employed mouse maternal separation with early weaning (MSEW), consisting of pup-dam separation lasting 4-8 hours on postnatal days (PD) 2-16, with early weaning on PD 17. Prior MSEW studies have limited subjects by age or sex, so we more comprehensively investigated MSEW effects in both sexes, during adolescence and adulthood. We found universal effects of MSEW to include lifelong enhancement of anxiety-like and despair behavior, as well as deficits in social motivation. We also observed some sex-dependent effects of MSEW, namely that female MSEW mice exhibited social habituation to a greater degree than their male counterparts. Low dose ethanol administration had no major effects on the social behavior of non-stressed mice. But interestingly, MSEW-induced social habituation was counteracted by low dose ethanol in adolescent female mice, and potentiated in adolescent male mice. These effects were absent in adult animals, suggesting that ethanol may exert differential effects on the developing brain in such a manner to produce age-, sex-, and stress-dependent effects upon social behavior. Together, results indicate that MSEW reliably produces long-lasting impairments in emotional and social behaviors in both sexes and across the lifespan, but may exert more salient social behavioral effects on female animals.