<b>SEX-DEPENDENT EFFECTS OF INTERMITTENT ALCOHOL ON REVERSAL LEARNING IN AGED CROSSED HIGH ALCOHOL PREFERRING MICE</b>

<p dir="ltr">Cognitive flexibility declines with age and is further impaired by heavy alcohol use. However, how alcohol affects age-related cognitive decline, particularly in females, remains poorly understood. This study examined the effects of intermittent alcohol exposure on compulsive-like behaviors, reversal learning, and alpha-synuclein (α-syn) expression in aged crossed high alcohol-preferring (cHAP) mice. Twelve-month-old male and female cHAPs were exposed to a 3-week intermittent access two-bottle choice (IA2BC) procedure with 20% alcohol or water. Compulsive-like behaviors were assessed using marble burying and nestlet shredding. Cognitive flexibility was assessed using a touchscreen-based visual discrimination and reversal learning (VDR) task. A subset of brains was collected either before (Pre-VDR) or after VDR testing (Post-VDR) to assess α-syn expression in the orbitofrontal cortex (OFC) and dorsomedial striatum (DMS), as α-syn is implicated in both aging-related cognitive decline and alcohol-related reward processing. </p><p dir="ltr">Female cHAPs showed significantly greater alcohol intake and preference than males. Alcohol exposure did not affect compulsive-like behaviors. During discrimination learning, alcohol-exposed females made fewer correction trials than water controls, suggesting more efficient acquisition. However, alcohol impaired reversal learning in females, as indicated by lower accuracy and greater perseveration. In contrast, alcohol-exposed males showed higher reversal accuracy than water controls in a subset of fast learners. Linear mixed-effects models revealed that the rate of reduction in perseveration was faster in alcohol-exposed females and water control males, despite their higher average perseveration. α-syn levels did not differ by alcohol exposure or sex but were overall lower in Post-VDR brains than in Pre-VDR brains. Higher OFC α-syn was correlated with slower discrimination learning, while higher DMS α-syn was correlated with fewer completed trials and longer reward collection latencies during reversal.</p><p dir="ltr">These findings demonstrate that alcohol exposure has sex- and stage-specific effects on cognitive flexibility in aged mice with a genetic susceptibility for excessive alcohol consumption. Consistent with prior literature in spatial reversal learning paradigms, female mice were more vulnerable to alcohol-induced impairments in reversal learning. These results underscore the importance of considering both sexes in aging- and alcohol-related cognitive decline and may inform future interventions aimed at protecting executive function in older adults susceptible to excessive alcohol use.</p>