| Crynodeb: | Sleep is conserved across the animal kingdom, and it is essential for cognitive and physical wellbeing. Therefore, understanding the biological basis underlying sleep homeostasis is of critical importance. In Drosophila melanogaster, a small number of neurons with projections to the dorsal fan-shaped body (dFB) in the brain function as a homeostatic switch that controls sleep according to sleep need. During wake, these neurons are in an electrically silent (OFF) state and, as sleep pressure builds up, they switch to an electrically excitable (ON) state, promoting sleep. Dopamine signalling into the dFB neurons controls the switch from the ON to the OFF state, waking flies up. However, the relevant dopaminergic neurons that convey the arousal-promoting signals to the dFB are unknown, and so are the mechanisms and rules that govern their activity. In this study, I have identified and gained genetic access to a restricted subset of wake-promoting dopaminergic neurons with projections to the dFB. The accumulation of mitochondrial reactive oxygen species (ROS) increases the excitability of the dFB neurons and promotes sleep through the modulation of the plasma membrane Shaker channel β-subunit, Hyperkinetic. Here, I hypothesised that lipid peroxidation by-products link mitochondrial ROS to the modulation of Hyperkinetic. Accordingly, supplementing Drosophila’s diet with lipid peroxidation- resistant D-PUFAs resulted in a decrease in sleep. In addition, I evaluated the influence of ROS in tissues other than the dFB neurons in promoting sleep. Using an innovative inducible ROS-generating chemogenetic system based on the D-amino acid oxidase enzyme, I observed that inducing ROS in gut enterocytes (MyO1A-GAL4 cells) increases sleep. Interestingly, I also found that dietary composition significantly altered sleep amount, further highlighting the gut as a potential target where diet, ROS, and sleep may intersect.
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