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Abstract
Alcohol consumption has been strongly associated with circadian clock gene expression in mammals. Analysis of clock genes revealed a potential role of Bmal1 in the control of alcohol drinking behavior. However, a causal role of Bmal1 and neural pathways through which it may influence alcohol intake have not yet been established. Here we show that selective ablation of Bmal1 (Cre/loxP system) from medium spiny neurons of the striatum induces sexual dimorphic alterations in alcohol consumption in mice, resulting in augmentation of voluntary alcohol intake in males and repression of intake in females. Per2mRNA expression, quantified by qPCR, decreases in the striatum after the deletion of Bmal1. To address the possibility that the effect of striatal Bmal1 deletion on alcohol intake and preference involves changes in the local expression of Per2, voluntary alcohol intake (two-bottle, free-choice paradigm) was studied in mice with a selective ablation of Per2 from medium spiny neurons of the striatum. Striatal ablation of Per2 increases voluntary alcohol intake in males but has no effect in females. Striatal Bmal1 and Per2 expression thus may contribute to the propensity to consume alcohol in a sex -specific manner in mice.
Highlights
Alcohol consumption has been strongly associated with circadian clock gene expression in mammals
To determine if the deletion of Bmal[1] disrupted the striatal circadian clock, we studied the expression of the clock gene Per[2] and the canonical clock-controlled gene Dbp
The influence of Bmal[1] is sexually dimorphic, associated with repression of alcohol consumption in male mice, potentially mediated by Per[2], and enhancement of alcohol consumption in females via a mechanism independent of Per[2]. Both clock genes are associated with the regulation of alcohol intake in humans or animal models, but the exact mechanism of Brain and muscle ARNT-like protein 1 (Bmal1)- and Per2-dependent changes in alcohol consumption remains elusive
Summary
Alcohol consumption has been strongly associated with circadian clock gene expression in mammals. Our experiments reveal that Bmal[1] in MSNs exerts a sexually dimorphic influence on alcohol drinking behavior – repressing preference and intake in males and promoting high preference and intake in females – which may contribute to sex differences in the propensity to consume alcohol in mice. This mechanism seems to be mediated by Per[2] in male mice, whereas is appears to be independent of Per[2] in females
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