Cognitive Flexibility and Cortical Transcriptomic Correlates of Individual Differences in Mice Following Prolonged...

Prolonged alcohol consumption is associated with cognitive dysfunction, but behavioral outcomes vary across individuals. We combined prolonged voluntary alcohol drinking, a cross-modal rule-switching task, and cortical RNA sequencing in male C57BL/6J mice to examine behavioral and molecular heterogeneity. Alcohol-drinking mice showed heterogeneous learning outcomes: most reached criterion with performance broadly comparable to controls, whereas a subset failed, without a clear association with drinking level. Within the alcohol-drinking group, transcriptome-wide analyses revealed cortical expression differences between learner and nonlearner pools. Associations with overall trial burden largely paralleled these differences, while learner-only analyses identified additional associations with learning performance. We also examined eight prespecified inhibitory-signaling candidate genes across frontal, parietal, and temporal cortex. Of 264 gene-behavior associations, 22 reached nominal permutation significance in the full cohort and 11 in learner-only pools; none survived multiple-testing correction. Excluding nonlearners altered the pattern of nominal associations, with some retaining their direction, others reversing, and additional associations emerging among learners. Nominal associations predominantly involved SST/SST-receptor- and VIP/VIPr-related genes. These findings highlight heterogeneous learning outcomes during prolonged voluntary alcohol drinking, accompanied by cortical transcriptomic variation associated with learning performance, and identify exploratory molecular associations warranting further investigation.