EFFECTS OF EARLY LIFE STRESS AND ALCOHOL EXPOSURE ON COGNITIVE, EMOTIONAL AND ADULT HIPPOCAMPAL NEUROGENESIS ALTERATIONS IN MALE AND FEMALE MICE

Early life stress is a major risk factor for neuropsychiatric disorders including anxiety, depression and substance use. Animal models such as maternal separation and early weaning (MSEW) allow investigation of long-term behavioral and brain consequences of adverse early environments. Moreover, early alcohol exposure persistently impairs cognitive and emotional functions, with vulnerability potentially modulated by early stress and sex. The hippocampus, a key region for emotional regulation and memory, remains highly plastic throughout life via adult hippocampal neurogenesis (AHN) and is sensitive to early life experiences.
We investigated how MSEW modulates alcohol-induced behavioral and hippocampal changes in adult male and female CD1 mice. Mice underwent MSEW or standard nesting, and received ethanol (16 doses; 1.25g/kg injected intraperitoneally) or vehicle from postnatal day (PD) 29-43.
Locomotion, anxiety- and depressive-like behaviors and hippocampal-dependent memory were assessed from PD52-65 using behavioral tests. Animals were euthanized to obtain hippocampal samples (PD65) and AHN markers [doublecortin (DCX) and proliferating cell nuclear antigen (PCNA)] were assessed by immunohistochemistry.
Ethanol reduced locomotion and impaired long-term object recognition memory, with sex-dependent effects: males showed greater reductions in locomotion and exploration, whereas females exhibited increased anxiety, particularly after MSEW. MSEW and ethanol each increased PCNA expression, indicating enhanced cell proliferation in both sexes, and DCX-positive neurons with immature-like morphology were elevated only in males exposed to both MSEW and ethanol.
These results reveal that MSEW and alcohol interact in a sex-dependent manner to shape adult behavior and hippocampal plasticity, highlighting mechanisms of sex-specific vulnerability relevant to alcohol-related neuropsychiatric disorders.