Abstract

Dopamine (DA) plays a crucial role in regulating a variety of behaviours, including motor function and reward. While the presence of DA is essential, its rhythmic release into regions such as the striatum is equally critical for maintaining normal physiological functions. This thesis investigates the hypothesis that the lateral habenula (LHb) serves as a pacemaker for rhythmic DA release, independently of the suprachiasmatic nucleus (SCN). The habenula's circadian pacemaker properties and its projections to the substantia nigra (SN) and ventral tegmental area (VTA) suggest it could regulate DA rhythms.
To test this hypothesis, we performed a targeted knockout of Bmal1 in the LHb of male and female mice and assessed the impact on motor and alcohol consumption behaviours. Our findings indicate significant disruptions in motor function, DA levels, and gene expression in the SN and dorsal striatum (DS) following LHb Bmal1 knockout. Specifically, we observed altered rhythms in clock genes and DA-related genes, supporting the LHb's role in regulating DA rhythms.
We further explored therapeutic strategies to mitigate the observed motor deficits using pharmacological (quinpirole) and non-pharmacological (running wheels) interventions. Both interventions improved motor performance, with notable sex-specific responses, highlighting the complexity of motor regulation by circadian mechanisms. However, neither intervention fully restored normal DA levels, suggesting involvement of additional pathways, such as the serotonergic system.
Additionally, we found sexually dimorphic effects on alcohol consumption behaviours following LHb Bmal1 knockout. Male mice showed increased voluntary alcohol intake and binge drinking, while female mice displayed reduced consumption under specific conditions. These results underscore the interaction between the LHb, DA, and serotonin systems in regulating alcohol-related behaviours.
In conclusion, this thesis demonstrates that the LHb acts as a pacemaker for rhythmic dopamine release, influencing both motor and reward behaviours. The findings provide new insights into the complex interplay between circadian rhythms and the dopaminergic system, with potential implications for the LHb as a novel site for therapeutic interventions targeting both systems. Understanding the role of the LHb in setting DA's rhythms offers a novel perspective on neuronal functioning and circadian biology.