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Title: Identification and characterisation of a novel aldo-keto reductase regulating sleep in Drosophila melanogaster
Author: Petzold, Anne
ISNI:       0000 0004 6422 9509
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2017
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Sleep is an important behaviour that has been observed in all animals studied so far, including Drosophila melanogaster. While a range of studies demonstrates that sleep is crucial to preserve an animal’s cognitive and physical health, relatively little is known about its regulation. Specifically, the molecular mechanisms that regulate sleep are still unclear, although a strong heritable component prevails. While the gene network governing sleep timing – the circadian system – is comparatively well described, the network calibrating the sleep homeostat is still vague. The study of sleep-regulatory mechanisms was greatly advanced by the adoption of the relatively simple model organism Drosophila melanogaster. Following seminal studies that demonstrated the suitability of Drosophila for the study of sleep, several sleep mutants were identified. Among those, hyperkinetic – a member of the aldo-keto reductase (AKR) family of enzymes – was one of the first Drosophila sleep mutants ever described. The abundance and importance of AKRs for human health and disease in combination with their conservation in Drosophila provides an excellent basis to examine whether AKRs systematically act as molecular regulators of sleep behaviour. Thus, we produced the first in silico study of potential Drosophila AKRs. We experimentally tested potential AKRs for neural sleep-regulatory roles through a nervous system-wide and Mushroom body-specific screen. We identified and further characterised the neural populations expressing particular candidates and the role these candidate AKRs fulfil to modulate sleep behaviour. We identified a novel AKR, CG10638, which specifically acts through a pair of wake-promoting peptidergic projection neurons termed “inferior contralateral interneurons” (ICLI) whose inhibition is necessary to relieve sleep pressure built up during the day, or specifically induced through dedicated sleep deprivation. We also demonstrate that ICLI neurons receive inputs from the major ‘clock’ neurons of the fly brain, and show that CG10638 negatively regulates ICLI neurons to acutely gauge the sleep homeostat and to integrate sleep pressure with the circadian network. We also identified a Mushroom body-specific sleep-regulatory AKR, CG3397, that may be close to Hyperkinetic in structure and function.
Supervisor: Gilestro, Giorgio Sponsor: Edmond Safra Foundation ; Biotechnology and Biological Sciences Research Council
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral