Mitochondrial control of sleep by galaninergic neurons of the preoptic hypothalamus

Thesis

Sleep is an evolutionarily conserved, reversible state whose functions remain incompletely understood. Leading theories implicate synaptic renormalisation, metabolic restoration and enhanced interstitial clearance as complementary processes underlying sleep. Here we show that mitochondrial redox state and morphology in galanin-expressing neurons of the ventrolateral preoptic nucleus (VLPO), a sleep-promoting centre, encode sleep pressure and causally regulate non-rapid eye movement (NREM) sleep. Using AAV-mediated, cell-type specific expression of the mitochondrial hydrogen peroxide sensor mito-ro-GFP2-Orp1 in galanin-cre mice, we show that acute sleep deprivation increases mitochondrial oxidation and fragmentation in VLPO neurons. Manipulating mitochondrial dynamics and mitochondrial nicotinamide adenine dinucleotide (phosphate) (NAD(P)H) balance in these neurons bidirectionally alters NREM sleep. Ex vivo patch clamp and calcium recordings link these mitochondrial changes to shifts in the proportion of spontaneously active VLPO neurons. Together our results identify VLPO mitochondria as both sensors and effectors of sleep pressure. The findings parallel earlier results in Drosophila and provide a framework linking cellular redox biology, mitochondrial dynamics and sleep regulation.

Authors: Britton, Z

• DOI: 10.5287/ora-dabvyynvd
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English