Biology subjects

Goldfarb, C.

Publications and source records attributed to Goldfarb, C..

3 recordsLinked to original sources

bioRxiv2024

Circadian clock in the lateral habenula affects motor function in mice through the regulation of daily rhythms in the nigrostriatal pathway

Alterations to the dopaminergic system can have several consequences on behaviour such as the development of disorders like addiction, schizophrenia, and Parkinsons. The lateral habenula (LHb) is uniquely positioned to act on a large group of dopaminergic (DA) neurons, sending inhibitory signals both directly and indirectly to the ventral tegmental area (VTA) and the substantia nigra (SN). Additionally, the LHb houses a circadian clock that appears to function independently from the central circadian pacemaker. We investigated the role of the LHb as a pacemaker for the production and release of DA along the nigrostriatal pathway. Using male and female Bmal1 floxed mice, we injected AAV-2/9 Cre-eGFP virus into the LHb to selectively knockout Bmal1, a clock gene essential for clock functioning. We found a significant impact on motor functioning in both male and female knockout mice. Analysis of daily rhythms of expression of circadian clock genes and genes involved in DA synthesis, and liquid chromatography coupled mass spectrometry for striatal DA measurements revealed blunting of rhythms in the dorsal striatum (DS) and (SN) of knockout animals, that may contribute to the observed behavioural phenotype. As proper functioning of the striatum is likely maintained by a mutual interaction of the circadian clock and DAergic system, these findings support that disrupting the LHb clock can impact functioning of the nigrostriatal DA pathway.

neuroscience↗

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↗

bioRxiv2023

Circadian clock genes Bmal1 and Per2 in the nucleus accumbens are negative regulators of alcohol-drinking behavior in mice.

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 animals 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.

neuroscience↗