Circadian clock genesBmal1andPer2in the nucleus accumbens are negative regulators of alcohol-drinking behavior in mice

Abstract

Voluntary alcohol consumption is influenced by a variety of environmental and genetic factors, including circadian clock genes. Even though their sex-specific role in alcohol drinking was identified through selective ablation of Bmal1 and Per2 from neurons of the mouse striatum, the contribution of specific striatal subregions to the observed drinking behavior remains unclear. Thus, alcohol intake and preference was investigated in male and female mice with a conditional knockout of Bmal1 and Per2 from cells in the nucleus accumbens (Nac). Mood- and anxiety-related behaviors were assessed prior to alcohol drinking to exclude potential confounding effects of the animal's behavioral state on alcohol consumption. Alcohol consumption and preference were increased in male and female mice with a conditional knockout of Bmal1, whereas the same effect was only found in males with a deletion of Per2. Because affective behaviors were only mildly influenced by the conditional gene knockouts, observed alcohol-drinking phenotypes can be directly associated with the Nac-specific clock gene deletion. The results thus suggest an inhibitory role of Bmal1 and Per2 in the Nac on alcohol consumption in male mice. In females, the inhibitory effect of Bmal1 is strictly localized to the Nac, because striatal-wide deletion of Bmal1 caused a suppression of alcohol consumption. This sex-dependent stimulatory effect of Bmal1 on alcohol drinking is probably mediated through other striatal subregions such as the dorsal striatum.

Effects of chronodisruption and alcohol consumption on gene expression in reward-related brain areas in female rats

“…Moreover, the selective deletion of Per2 in either the entire striatum or the NAc did not affect alcohol consumption in female mice (de Zavalia et al, 2021; Herrera et al, 2023). The results suggest that clock genes may have inhibitory or stimulatory effects on alcohol consumption in females, depending on the specific clock gene and brain region, highlighting the intricate regulation of alcohol consumption by these genes.…”

“…The expression of Bmal1 appeared to be dysregulated in the striatum and prefrontal cortex in animals exposed to aberrant light conditions but their drinking remained unchanged compared to control animals. This suggests that, in females, the sole abundance of Bmal1 in the striatum rather than its oscillation plays a role in the regulation of alcohol consumption as demonstrated by experiments in mice with ablation of Bmal1 from neurons of the entire striatum or just the NAc (de Zavalia et al, 2021; Herrera et al, 2023).…”

“…Mutations of Per1, Per2, and Clock in mice have been shown to enhance alcohol consumption, likely through their impact on brain reward processes (Gamsby et al, 2013;Ozburn et al, 2013;Rizk et al, 2022;Spanagel, Pendyala, et al, 2005), whereas Cry1/2-deficient mice exhibited decreased alcohol preference (Hühne et al, 2022). Notably, a targeted knockout of Bmal1 in medium spiny neurons (MSNs) of the striatum decreased alcohol consumption in female mice (de Zavalia et al, 2021), while Bmal1 ablation in the NAc resulted in higher alcohol consumption (Herrera et al, 2023). Moreover, the selective deletion of Per2 in either the entire striatum or the NAc did not affect alcohol consumption in female mice (de Zavalia et al, 2021;Herrera et al, 2023).…”

“…Notably, a targeted knockout of Bmal1 in medium spiny neurons (MSNs) of the striatum decreased alcohol consumption in female mice (de Zavalia et al, 2021), while Bmal1 ablation in the NAc resulted in higher alcohol consumption (Herrera et al, 2023). Moreover, the selective deletion of Per2 in either the entire striatum or the NAc did not affect alcohol consumption in female mice (de Zavalia et al, 2021;Herrera et al, 2023). The results suggest that clock genes may have inhibitory or stimulatory effects on alcohol consumption in females, depending on the specific clock gene and brain region, highlighting the intricate regulation of alcohol consumption by these genes.…”

“…Previous studies have associated Per2 expression with alcohol consumption in rodents, but recent findings in mice suggest that these effects are sex-dependent. For example, a global or striatum-specific knockout of Per2 increased alcohol consumption in male mice (de Zavalia et al, 2021;Herrera et al, 2023;Spanagel, Pendyala, et al, 2005). In contrast, female mice with striatum-specific Per2 knockout display no change in alcohol consumption, indicating that other sex-specific factors must be considered in the regulation of alcohol-drinking behavior in females.…”