Biology subjects

Schottner, K.

Publications and source records attributed to Schottner, K..

3 recordsLinked to original sources

bioRxiv2024

Circadian gene Bmal1 in the lateral habenula regulates alcohol drinking behavior in a sex specific manner

The circadian clock regulates most aspects of mammalian physiology and behaviour, including alcohol drinking behaviour. Disrupted circadian clock function via deletion of clock genes along the mesolimbic dopamine (DA) pathway has been linked to altered patterns of alcohol drinking behaviour. The lateral habenula (LHb), an epithalamic structure that house a semi-autonomous circadian clock, is a negative regulator of the mesolimbic DA system and of alcohol consumption. To study the role of the LHb circadian clock in alcohol consumption, we knocked out the core clock gene, Bmal1 specifically in the LHb and examined the impact on various alcohol drinking paradigms and affective behaviours in male and female mice. Our findings demonstrate that Bmal1 deletion in the LHb leads to sex-specific alterations in alcohol consumption. Male knockout mice exhibited increased voluntary alcohol intake, enhanced consumption of a bitter alcohol solution, and elevated alcohol binge drinking compared to controls. Conversely, female knockouts showed a marginal decrease in voluntary intake, significantly reduced consumption of an aversive alcohol solution, and lower post abstinence, relapse-like drinking. These results indicate that Bmal1 in the LHb exerts a repressive effect on alcohol intake in males, while it facilitates intake under certain aversive conditions in females. Interestingly, Bmal1 deletion did not significantly affect anxiety-like or depressive-like behaviours, suggesting that the habenular clocks role in alcohol consumption is independent of affective state. These findings mark Bmal1 in the LHb as a novel sexually dimorphic regulator of alcohol consumption in mice. Potential mechanisms involving the circadian modulation of DA and serotonin signaling pathways by the LHb clock is discussed.

neuroscience↗

bioRxiv2024

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

Circadian dysfunction caused by exposure to aberrant light-dark conditions is associated with abnormal alcohol consumption in humans and animal models. Changes in drinking behavior have been linked to alterations in clock gene expression in reward-related brain areas, which could be attributed to either the effect of chronodisruption or alcohol. To date, however, the combinatory effect of circadian disruption and alcohol on brain functions is less understood. Moreover, despite known sex differences in alcohol drinking behavior, most research has been carried out on male subjects only, and therefore implications for females remain unclear. To address this gap, adult female rats housed under an 11h/11h light-dark cycle (LD22) or standard light conditions (LD24, 12h/ 12h light-dark) were given access to an intermittent alcohol drinking protocol (IA20%) to assess the impact on gene expression in brain areas implicated in alcohol consumption and reward: the prefrontal cortex (PFC), nucleus accumbens (NAc), and dorsal striatum (DS). mRNA expression of core clock genes (Bmal1, Clock, Per2), sex hormone receptors (ER{beta}, PR), glutamate receptors (mGluR5, GluN2B), a calcium-activated channel (Kcnn2), and an inflammatory cytokine (TNF-) were measured at two-time points relative to the locomotor activity cycle. Housing under LD22 did not affect alcohol intake but significantly disrupted circadian activity rhythms and reduced locomotion. Significant changes in the expression of Bmal1, ER{beta}, and TNF- were primarily related to the aberrant light conditions, whereas changes in Per2 and PR expression were associated with the effect of alcohol. Collectively, these results indicate that disruption of circadian rhythms and/or intermittent alcohol exposure have distinct effects on gene expression in the female brain, which may have implications for the regulation of alcohol drinking, addiction, and, ultimately, brain health.

neuroscience↗

bioRxiv2020

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.

neuroscience↗