Sexually dimorphic effects of a modified adolescent social isolation paradigm on behavioral risk factors of alcohol use disorder in Long Evans Rats.

Early life stress (ELS) is a major risk factor for alcohol use disorder (AUD) and comorbid neuropsychiatric conditions. We previously demonstrated that an adolescent social isolation (aSI) model of ELS significantly increased behavioral risk factors for these disorders (e.g. anxiety-like behaviors, alcohol drinking) in male, but not female rats. Since many neurodevelopmental milestones are accelerated in females, we investigated whether an earlier/shorter isolation window (PND 21-38) would yield comparable phenotypes in both sexes. In two experiments, Long Evans rats were socially isolated (SI) or group-housed (GH) on postnatal day (PND) 21 and locomotion was assessed in the open field test (OFT; PND 30). Experiment 1 also assessed behavior on the elevated plus-maze (EPM) (PND 32). In Experiment 2, all rats were single housed on PND 38 to assess home cage alcohol drinking. Experiment 1 revealed that SI females had increased locomotor activity in the OFT but did not differ from GH subjects on the EPM. The OFT results were replicated in both sexes in Experiment 2 and both male and female SI rats had significantly greater ethanol consumption during an eight day continuous access paradigm. In contrast, during subsequent intermittent two-bottle choice drinking, only SI females displayed greater ethanol intake and preference and increased consumption of a quinine-adulterated alcohol solution. These findings demonstrate that early life social isolation can promote AUD vulnerability-related phenotypes in female rats but that there are profound sex differences in the vulnerability window to this early life stressor. Uncovering the neural mechanisms responsible for these sexually dimorphic differences in sensitivity to ELS may shed light on the biological substrates associated with vulnerability to AUD and comorbid disorders of negative emotion in men and women.

Chronic stress from adolescence to adulthood increases adiposity and anxiety in rats with decreased expression of Krtcap3.

We previously identified Keratinocyte-associated protein 3, Krtcap3, as a novel adiposity gene, but subsequently found that its impact on adiposity may depend on environmental stress. To more thoroughly understand the connection between Krtcap3, adiposity, and stress, we exposed wild-type (WT) and Krtcap3 knock-out (KO) rats to chronic stress then measured adiposity and behavioral outcomes. We found that KO rats displayed lower basal stress than WT rats under control conditions and exhibited metabolic and behavioral responses to chronic stress exposure. Specifically, stress-exposed KO rats gained more weight, consumed more food when socially isolated, and displayed more anxiety-like behaviors relative to control KO rats. Meanwhile, there were minimal differences between control and stressed WT rats. At study conclusion stress-exposed KO rats had increased corticosterone (CORT) relative to control KO rats with no differences between WT rats. In addition, KO rats, independent of prior stress exposure, had an increased CORT response to removal of their cage-mate (psychosocial stress), which was only seen in WT rats when exposed to chronic stress. Finally, we found differences in expression of the glucocorticoid receptor, Nr3c1, in the pituitary and colon between control and stress-exposed KO rats that were not present in WT rats. These data support that Krtcap3 expression affects stress response, potentially via interactions with Nr3c1, with downstream effects on adiposity and behavior. Future work is necessary to more thoroughly understand the role of Krtcap3 in the stress response.