Neuronal mechanisms of sleep alterations in Parkinson's Disease: A circuit based investigation

2018 Fiscal Year Annual Research Report

• Project/Area Number: 18F18073
• Research Institution: University of Tsukuba
• Principal Investigator: ラザルス ミハエル 筑波大学, 国際統合睡眠医科学研究機構, 准教授 (80469650)
• Co-Investigator(Kenkyū-buntansha): FIFEL KARIM 筑波大学, 国際統合睡眠医科学研究機構, 外国人特別研究員
• Project Period (FY): 2018-04-25 – 2020-03-31
• Keywords: Parkinson's disease

Outline of Annual Research Achievements

Current understanding of the neuronal mechanisms and populations that regulate sleep/wake behavior is incomplete. The Lazarus lab recently found that ventral tegmental area dopaminergic neurons strongly induce and consolidate wakefulness (Oishi et al., Brain Struct. Funct., 2017), but the overall role of this midbrain area in sleep/wake regulation remains unclear. We have further advanced significantly in the project that aims to elucidate the role of dopamine in the modulation of processes of sleep regulation. Models of sleep regulation have emphasized two distinct processes for the regulation of the timing of sleep; a homeostatically regulated sleep process and a circadian oscillatory process. The circadian oscillator gates consolidated bouts of sleep and wakefulness during specific times of the day while the homeostatic process is responsible for monitoring and adjusting the duration and intensity of sleep depending on prior amounts of sleep and wakefulness. Surprising however, by using chemogenetic inhibition of dopamine neurons, our results suggest that dysfunctional dopamine signaling precipitates quantitative and qualitative sleep impairment without affecting circadian and homeostatic processes of sleep regulation.

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

A major portion of our project is to investigate the role of basal ganglia in sleep regulation by investigating the impact of DA loss in a mouse model of PD ‘Mitopark mice’. During our first year, we have built the colony of Mitopark animals which will be now used to test our scientific hypothesis.
A significant amount of time was dedicated to set up the appropriate electrophysiological equipments that will be used for in vivo electrophysiology recordings.

Strategy for Future Research Activity

Impairment of the balance between D1 and D2 pathways underlie behavioral alterations in several neurological and psychiatric disorders. Using a well validated mouse model of PD (i.e., ‘Mitopark mice’), we aim to optogenetically restore normal transmission by targeting D1 and/or D2 pathways in selected brain areas and evaluate the impact of these manipulations on behavior. Our aim will be to identify the aberrant neuronal networks, the manipulation of which will restore normal sleep/wake behavior.