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

Abstract

Background: There are significant sex differences in the causes and consequences of alcohol misuse, suggesting that sex-specific neurobiological mechanisms might drive drinking. The current study used a rodent model to determine whether chronic intermittent alcohol exposure impacts cortical, striatal, and limbic neural circuits in a sex-specific manner.

Methods: Female and male Sprague-Dawley rats were trained to self-administer 10% alcohol before implanting bilateral electrodes into the infralimbic cortex (IL), nucleus accumbens shell (NAcSh), and central nucleus of the amygdala (CeA). Half of the rats were then exposed to 4 weeks of chronic intermittent alcohol (CIA) vapor. During acute withdrawal, local field potentials (LFPs) were recorded in the IL, NAcSh, and CeA. 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. Real and permuted model performance is reported as average area under the receiver operating curve (AUC).

Results: Acute withdrawal was associated with increased alcohol self-administration in males (p < 0.05), but not in females (p > 0.05). Models built from all LFP data performed significantly better than chance in each sex (females AUC: 0.88; males AUC: 0.63). However, when models were restricted, those built on IL and CeA LFPs performed best in females (females AUC: 0.83; males AUC: 0.65), while those built on IL and NAcSh LFPs performed the best in males (males AUC: 0.78; females AUC: 0.57). Individual LFP features that best predicted CIA exposure were also sex-specific, with CeA features predicting CIA exposure in females and corticostriatal features predicting CIA exposure in males.

Conclusions: These data support the hypothesis that the neural circuits impacted by chronic alcohol exposure are sex-specific, and significantly add to our understanding of the neurobiological underpinnings behind the sex differences observed in alcohol misuse, offering promising biomarkers for future therapeutic research.