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Decoding neural circuits controlling sleep drive and sedation

Periodic Reporting for period 1 - DNCSS (Decoding neural circuits controlling sleep drive and sedation)

Reporting period: 2018-09-01 to 2020-08-31

Sleep is a universal behaviour across the animal kingdom and humans spend on average one-third of their lives asleep. Surprisingly, the full picture of how sleep is regulated and why we need sleep is still yet to be completed. In mammals, sleep consists of two phases: rapid eye movement (REM) sleep and non-rapid eye movement (NREM) sleep. Both REM and NREM sleep are chronologically and homeostatically regulated by several brain regions. Previous studies have established the association between sleep disturbances and almost all the neurological disorders, including autism, Alzheimer’s disease and Parkinson’s disease. In addition, sleep has also been compared to sedation, a state sharing significant behavioural similarities with sleep, such as reduced movements, enhanced slow-wave activity and lowered body temperature. Whether sedatives work through a common mechanism of hijacking the sleep-regulating circuits still remains elusive.

This project aimed to identify novel neuronal circuits controlling sleep and sedation. Discoveries of this project would significantly advance our understanding of the fundamental mechanisms of sleep/sedation and provide novel insights into how sleep is linked with various neurological disorders. It would also offer potential therapeutic strategies and contribute to designing more efficient and safer medications.

The main scientific goal was broken down into the following three objectives:
- To evaluate alterations of excitatory/inhibitory input onto defined LPO neurons during prolonged wakefulness and sedation.
- To identify the origin of inputs onto the defined LPO neurons
- To determine the effects of altered connectivity involving active LPO neurons on sleep and sedation status in vivo.
Input and output brain regions of the LPO have been successfully mapped and several potential targets in the LPO circuits involved in sleep regulation have been identified. Two critical and novel regions were selected for further investigations during the course of the project. First, we have identified a novel REM-specific circuit wired from subcortical areas to the midbrain in the mammalian brain. The emotional stability was significantly compromised as a consequence of lacking REM sleep, providing novel evidence of why sleep is essential. Second, we captured sleep-pressure-responding neuronal ensembles located in the brainstem in vivo and further delineated their regulatory roles in NREM sleep and recovery sleep after sleep deprivation. In addition, our results revealed that sleep regulating neurons located in the midbrain contribute to mania-like behaviour. The findings of this project have been discussed in various scientific conferences/symposiums, departmental seminars, as well as college-organised events for engaging with the public.
The findings of this project will offer novel insights into the mechanisms of sleep/sedation at the circuitry level. We are expecting to conduct further studies on other novel connecting areas of LPO identified in this project and hoping to obtain a more complete picture of how sleep is regulated. By designing and managing the project, the fellow has achieved a degree of professional maturation. After publishing all the data acquired in this project, the fellow will further build a competitive scientific profile for the next career stage. The results obtained during the funded period will also set important and new research directions for the fellow. Apart from the scientific impact, we were actively involved in College-organised events to engage with the public. Our research has attracted lots of attentions from the public, especially from the students in the British schools. We hope that by presenting our work and showing them around the lab, we would inspire younger generations to pursue science and make bigger impact for the society.