Sexually dimorphic influence of the circadian clock gene Bmal1 in the striatum on alcohol intake

The gene Bmal1 (brain and muscle Arnt-like 1) plays an obligatory role in the generation of circadian rhythms in the suprachiasmatic nucleus (SCN), the master circadian clock in mammals [1-5]. Notably, Bmal1 is widely expressed in mammalian brain [6], and perturbations in Bmal1 expression in select forebrain regions cause behavioral disturbances that are independent of the SCN, such as disturbances in sleep architecture, and in cognitive and affective behaviors [1, 7-15]. Interestingly, gene association studies in humans and in animals suggest that Bmal1 may influence the propensity to consume alcohol, and that polymorphisms in Bmal1 may confer risk for alcohol dependence and related disorders [16-20]. However, research has not yet provided evidence of a causal role of Bmal1 in the control of alcohol intake. We investigated voluntary alcohol consumption in conditional knockout mice that lack Bmal1 exclusively in the striatum, which is an important structure in the control of alcohol intake and preference [21-26]. Experiments were carried out in both male and female mice in order to account for the known sex differences in alcohol consumption [27-31] and in striatal functioning [32-36], as well as in the expression of clock genes and in the impact of circadian clocks on behavior [37-44]. We found that, in both males and females, selective deletion of Bmal1 from principal medium spiny neurons (MSNs) of the striatum significantly altered voluntary alcohol intake and preference. Strikingly, the effect of Bmal1 deletion was sexually dimorphic. Whereas in males, deletion of Bmal1 augmented alcohol intake and preference, in females, the same deletion suppressed alcohol intake and preference. Interestingly, striatal deletion of the clock gene Per2, which interacts with Bmal1 in the generation of circadian rhythms [4], and which has been shown to affect alcohol consumption in male mice [45], mimicked the effect of Bmal1 deletion, albeit only in males. These results show that Bmal1 in MSNs of the striatum exerts a sexually dimorphic influence on alcohol intake in mice, moderating intake in males, possibly via Per2, and promoting heightened intake in females, independently of Per2. We propose that a sexually dimorphic mechanism in the function of Bmal1 in the striatum contributes to sex differences in the propensity to consume alcohol in mice. Whether such mechanism contributes to sex differences in other striatum-dependent appetitive and consummatory behaviors remains to be investigated.