Circadian gene Bmal1 in the lateral habenula regulates alcohol drinking behavior in a sex specific manner

The circadian clock regulates most aspects of mammalian physiology and behaviour, including alcohol drinking behaviour. Disrupted circadian clock function via deletion of clock genes along the mesolimbic dopamine (DA) pathway has been linked to altered patterns of alcohol drinking behaviour. The lateral habenula (LHb), an epithalamic structure that house a semi-autonomous circadian clock, is a negative regulator of the mesolimbic DA system and of alcohol consumption. To study the role of the LHb circadian clock in alcohol consumption, we knocked out the core clock gene, Bmal1 specifically in the LHb and examined the impact on various alcohol drinking paradigms and affective behaviours in male and female mice. Our findings demonstrate that Bmal1 deletion in the LHb leads to sex-specific alterations in alcohol consumption. Male knockout mice exhibited increased voluntary alcohol intake, enhanced consumption of a bitter alcohol solution, and elevated alcohol binge drinking compared to controls. Conversely, female knockouts showed a marginal decrease in voluntary intake, significantly reduced consumption of an aversive alcohol solution, and lower post abstinence, relapse-like drinking. These results indicate that Bmal1 in the LHb exerts a repressive effect on alcohol intake in males, while it facilitates intake under certain aversive conditions in females. Interestingly, Bmal1 deletion did not significantly affect anxiety-like or depressive-like behaviours, suggesting that the habenular clocks role in alcohol consumption is independent of affective state. These findings mark Bmal1 in the LHb as a novel sexually dimorphic regulator of alcohol consumption in mice. Potential mechanisms involving the circadian modulation of DA and serotonin signaling pathways by the LHb clock is discussed.