Bmal1 in the striatum influences alcohol intake in a sexually dimorphic manner

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.

Characterization of Affective Behaviors and Motor Functions in Mice With a Striatal-Specific Deletion of Bmal1 and Per2

“…Besides the impact of striatal Bmal1 and Per2 deletion on affective behaviors, pronounced effects on motor functioning were found. Despite previous work demonstrates that locomotor activity levels and circadian functioning were not affected by the conditional knockout of Bmal1 and Per2 when locomotor activity rhythms were assessed using running wheels ( de Zavalia et al, 2021 ), cKO mice of both strains displayed increased levels of locomotor activity compared to CTRL animals in the open field test. Although studies suggest a role of circadian clock genes in the adaptation to novel environments ( Kondratova et al, 2010 ), novelty-induced hyperactivity in the OFT was likely not caused by a striatal loss-of-function of the respective clock genes in our study.…”

“…Our unpublished results in C57BL/6 mice confirm this view. However, a sucrose-preference test conducted in mice of the Bmal1 and Per2 lines revealed no difference in sucrose preference between the genotypes ( de Zavalia et al, 2021 ).…”

“…The conditional ablation of Bmal1 and Per2 in striatal MSNs was achieved as described before ( de Zavalia et al, 2021 ). In brief, mice carrying homozygous floxed alleles of the Bmal1 ( Bmal1 fl/fl ; B6.129S4(Cg)-Arntl tm1Weit /J; stock #: 7668, The Jackson Laboratory) ( Storch et al, 2007 ) or Per2 locus ( Per2 fl/fl ; B6.129-Per2 tm1.2Ual /Biat, strain ID: EM10599, European Mouse Mutant Archive) ( Chavan et al, 2016 ) were crossed with mice expressing Cre recombinase and enhanced green fluorescence protein (EGFP) under control of the Gpr88 promoter ( Gpr88 cre/+; B6.129S4-Gpr88 tm1.1(cre/GFP)Rpa /J; stock #: 22,510, The Jackson Laboratory) ( Beutler et al, 2011 ).…”

DataSheet1.DOCX

“…Besides the impact of striatal Bmal1 and Per2 deletion on affective behaviors, pronounced effects on motor functioning were found. Despite previous work demonstrates that locomotor activity levels and circadian functioning were not affected by the conditional knockout of Bmal1 and Per2 when locomotor activity rhythms were assessed using running wheels (de Zavalia et al, 2021), cKO mice of both strains displayed increased levels of locomotor activity compared to CTRL animals in the open field test. Although studies suggest a role of circadian clock genes in the adaptation to novel environments (Kondratova et al, 2010), novelty-induced hyperactivity in the OFT was likely not caused by a striatal loss-of-function of the respective clock genes in our study.…”

Haploinsufficiency of a Circadian Clock Gene Bmal1 (Arntl or Mop3) Causes Brain-Wide mTOR Hyperactivation and Autism-like Behavioral Phenotypes in Mice

“…The discrepancies between Bmal1 +/− and Bmal1 KO mice in these tests could be due to different compensatory mechanisms that are activated after differential disruption of the Bmal1 function. For example, although the Bmal1 protein levels are markedly reduced in Bmal1 +/− mice, the circadian rhythms of these mice are intact [ 23 ]. Bmal1 KO mice exhibit neurodegeneration, early aging, and age-related pathologies, but these phenotypes are never reported in Bmal1 +/− mice [ 24 , 25 , 26 , 27 ].…”