Chronic intermittent alcohol yields sex-specific disruptions in cortical-striatal-limbic oscillations

Background While the neurobiology of alcohol use disorder (AUD) has been extensively researched, the vast majority of these studies included only male organisms. However, there are significant sex differences in both the causes and consequences of alcohol misuse and dependence, suggesting sex-specific neurobiological mechanisms. The current study used a rodent model to determine whether chronic alcohol exposure impacts sex-specific neural circuits, and whether these changes contribute to the development of alcohol misuse.

Male and female Sprague-Dawley rats were trained to self-administer 10% alcohol before implanting bilateral electrodes into the infralimbic medial prefrontal cortex (IL), nucleus accumbens shell (NAcSh), and central nucleus of the amygdala (CeA). Half of the rats were then exposed to four weeks of chronic intermittent alcohol (CIA) vapor (14 hours on/10 hours off). During acute withdrawal (6-8 after the vapor turns off), local field potentials (LFPs) were recorded from the IL, NAcSh, and CeA during 30-minute self-administration sessions. Using an unbiased machine learning approach, we built predictive models to determine whether/which LFP features could distinguish CIA-exposed from control rats in each sex, as well as if any of these LFP features correlated with rates of alcohol self-administration.

Female rats self-administered more alcohol in general compared to males, but only males exposed to CIA showed increased alcohol intake during acute withdrawal. LFPs predicted CIA exposure in both sexes better than chance estimates, but models built on IL and NAcSh oscillations performed the best in males, while models built on IL and CeA LFPs performed best in females. High γ LFPs recorded in the NAcSh correlated with rates of alcohol self-administration in males exposed to CIA, while only left-right NAcSh β coherence correlated with drinking in control females.

These data provide support for the hypothesis that the neural circuits driving alcohol dependence development are sex-specific, and that high frequency oscillations in the NAcSh may be related to the increased drinking observed in males exposed to CIA. Overall, these data add to our understanding of the neurobiological underpinnings behind the sex differences observed in AUD and offer promising biomarkers for future therapeutic research. Competing Interest Statement The authors have declared no competing interest. Footnotes The wrong table 2 was inserted in the original submission. We have now included the correct table 2 in this version.