Restless legs syndrome (RLS) is a common neurological disorder affecting up to 20% of the population. RLS sufferers describe unpleasant and painful sensations in the legs and the intense urge to move. As well, the vast majority of patients display involuntary limb movements during sleep. These symptoms occur almost exclusively at night leading to major sleep disturbances and daily fatigue. The underlying cause of RLS is unknown but the most effective medications are those that activate the dopamine D2 type receptors. Dopamine has been described as a key regulator of motor activity for some time. Indeed, loss of motor coordination from Parkinson's Disease is caused by a degeneration of midbrain dopamine cells. Interestingly, Parkinson's disease is often associated with severe sleep disturbances, suggesting a link between the circadian system and dopaminergic systems. It is known that dopamine levels in the brain have a daily (circadian) rhythm. Since RLS symptoms occur exclusively at night, it is possible that a disruption in rhythmic dopamine signaling is what leads to the development of RLS. Through better understanding of the regulation of rhythmic dopamine signaling, better treatment options for RLS and other motor and sleep-related disorders can be developed. Our preliminary data suggests that CLOCK, a central component in the circadian clock, is involved in regulating dopaminergic activity. In this study we will determine if dopamine cells have an intrinsic circadian rhythm in activity and if a mutation in the CLOCK gene disrupts this rhythm. Furthermore, we will determine if common medications used to treat RLS affect circadian dopaminergic activity or change the firing properties of dopamine cells in the CLOCK mutant mice. Next, we will determine if local CLOCK expression in the dopamine-rich ventral tegmental area (VTA) or substantia nigra (SN) is sufficient to rescue the dopaminergic and locomotor phenotypes observed in the CLOCK mutant mice. In turn, we will also determine if a selective disruption of CLOCK function in the VTA produces these phenotypes in wild- type mice. Finally, we will determine if CLOCK (a transcription factor) directly regulates the rhythmic expression of tyrosine hydroxylase, the rate limiting enzyme in dopamine synthesis. This could provide a mechanism for how CLOCK influences dopamine neuronal and locomotor activity. These studies will provide the very basis for our understanding of circadian dopaminergic signaling and the underlying pathogenesis of RLS. Restless legs syndrome (RLS) is a common neurological disorder affecting up to 20% of the population, characterized by unpleasant and painful sensations in the legs with the intense urge to move. These symptoms occur almost exclusively at night leading to major sleep disturbances and daily fatigue. The underlying cause of RLS is unknown, but studies suggest that it may involve a disruption in dopamine signaling in the brain. Through these proposed experiments, we will better understand the regulation of dopamine signaling throughout the light/dark cycle with the hope of someday developing better treatment options for those that suffer from RLS or other motor and sleep-related disorders ? ? ?
