Impact of adverse postnatal environment on emotional regulation and neuroimmune function in adolescent rats prenatally exposed to alcohol

Individuals with prenatal alcohol exposure (PAE) are at increased risk for experiencing early-life adversity (ELA), which may contribute to their heightened vulnerability to mental health problems. Using rat models, we examined the independent and interactive effects of PAE (liquid ethanol diet) and ELA (limited bedding) on emotional regulation, specifically anxiety- and depressive-like behaviors, and assessed neuroimmune alterations in the amygdala and hypothalamus during early and late adolescence as a potential underlying mechanism. Our results indicate that PAE induced anxiety-like behaviors across multiple tasks. PAE females exhibited anxiety-like behavior in the open field during both stages, whereas PAE males and females showed anxiety-like behavior in the light-dark test during early adolescence. In the forced swim test, depressive-like behavior was reduced in PAE females but increased in PAE males during late adolescence. ELA also produced sex- and age-dependent effects, increasing anxiety-like behavior in females during both stages and in males during early adolescence, and enhancing depressive-like behavior in both sexes during late adolescence. Importantly, ELA did not exacerbate PAE-related behavioral alterations. Neuroimmune analyses revealed age-, sex-, and region-specific cytokine changes: PAE induced a strong proinflammatory bias in the amygdala of females and altered both anti- and proinflammatory cytokines in the hypothalamus of males and females. In contrast, ELA effects were milder, with both the amygdala and hypothalamus similarly affected across sexes. Together, these findings indicate that PAE and ELA independently disrupt neuroimmune signaling and emotional regulation, supporting the hypothesis that cytokine dysregulation contributes to long-term vulnerability to emotional dysregulation.