Abstract
<title>Abstract</title> <p>Perinatal alcohol exposure increases the risk of lifelong physical, cognitive, and behavioral impairments, collectively termed Fetal Alcohol Spectrum Disorders (FASD). While deficits in memory and executive function are largely documented, alterations in emotional learning and reward processing remain less understood. Using a binge-like drinking-in-the-dark paradigm in C57BL/6 dams, we assessed sex-dependent behavioral outcomes and transcriptional adaptations in offspring from adolescence to adulthood. Perinatal and lactational alcohol exposure (PLAE) induced sex-specific fear learning impairments during adolescence: males exhibited deficits in fear acquisition, whereas females showed impaired extinction and elevated contextual fear. PLAE also increased alcohol preference in both sexes, without inducing anhedonia, or anxiety-like behaviors in open field or elevated plus maze paradigms. In adulthood, fear-related alterations normalized; however, females displayed reduced anxiety-like behavior, whereas males exhibited persistent increases in voluntary alcohol intake and sucrose preference. In addition, continuous home-cage monitoring revealed reduced circadian locomotor activity in both sexes, suggesting altered basal arousal and motivational states. Transcriptomic profiling revealed region- and sex-specific alterations in glutamatergic, dopaminergic, endocannabinoid, and stress-related genes across hippocampal, amygdalar, and midbrain structures, providing a molecular substrate for adolescent emotional and reward vulnerabilities. Collectively, these findings identify biased emotional processing following early-life alcohol exposure and uncover persistent male-specific reward sensitivity. By revealing sex-dependent molecular signatures associated with these behavioral outcomes, our study provides a foundation for the development of precision interventions aimed at reducing long-term neuropsychiatric vulnerability in FASD.</p>