Abstract
<jats:title>Abstract</jats:title> <jats:sec> <jats:title>Background</jats:title> <jats:p> Circadian disruption is strongly associated with alcohol use disorder (AUD), but insight into the underlying brain-region and sex-specific mechanisms is limited. The function of the circadian clock gene <jats:italic>Bmal1</jats:italic> within the striatum has been linked to alcohol drinking, yet its role within functionally distinct striatal subregions has not been systematically examined. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods</jats:title> <jats:p> We deleted <jats:italic>Bmal1</jats:italic> in medium spiny neurons of the dorsomedial striatum (DMS) or dorsolateral striatum (DLS). Male and female mice were tested for anxiety-like behavior, depressive-like behavior, and motor coordination. Voluntary alcohol intake was measured with an intermittent two-bottle choice paradigm, followed by sucrose preference and quinine-adulterated alcohol tests. To assess hormonal contributions, a subset of female mice underwent ovariectomy before behavioral testing. </jats:p> </jats:sec> <jats:sec> <jats:title>Results</jats:title> <jats:p> Deletion of <jats:italic>Bmal1</jats:italic> in the DLS did not alter alcohol intake, alcohol preference, or quinine-adulterated alcohol intake in either sex. In contrast, DMS <jats:italic>Bmal1</jats:italic> deletion significantly reduced alcohol consumption and alcohol preference in female mice, with no effect in males. These effects were not accompanied by changes in depressive-like behavior or motor coordination and were not explained by generalized reward changes, as sucrose preference was unaffected. Ovariectomy eliminated the effect of DMS <jats:italic>Bmal1</jats:italic> deletion on alcohol intake, indicating dependence on ovarian hormones. </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions</jats:title> <jats:p> The DMS is a critical site at which <jats:italic>Bmal1</jats:italic> regulates alcohol consumption in a sex-specific manner. These findings support an interaction between local circadian mechanisms and ovarian hormones in controlling alcohol drinking and highlight a potential target for sex-specific therapeutics in AUD. </jats:p> </jats:sec>