Sleep is a fundamental physiological function and regulates many complex physiological aspects, such as mental health, metabolism, cognition and memory. Despite numerous efforts to understand the function of sleep, we still do not know why we spend a third of our life asleep. One way to tackle this mystery is the investigation of processes regulating sleep time and need, such as sleep homeostasis. Synaptic plasticity has been proposed as a mechanism capable of explaining sleep homeostasis, as synapse structure could change with fluctuations in sleep pressure. To understand whether plasticity mechanisms regulate sleep patterns, I deleted from lateral preoptic (LPO) hypothalamic neurons, key sleep regulators, the NR1 gene encoding a NMDA receptor subunit, fundamental for synaptic potentiation. Using floxed-NR1 animals and injections of Cre recombinase, I deleted the NMDAr from LPO neurons and observed sleep behaviours. ΔNR1-LPO animals were constantly hyperactive and showed dramatic sleep fragmentation and continuous sleep loss. Although sleepy, these animals were incapable of recuperating lost sleep after sleep deprivation, despite showing a delta power rebound- an indicator of sleep homeostasis. This phenotype was not present when the NR1 gene was deleted from other hypothalamic nuclei, suggesting that the NMDAr in LPO is a specific mechanism capable of coupling phenotypic sleep rebound to cortical delta power activity.
To better understand LPO functions during behavioural states, I analysed the in vivo calcium activity of subsets of LPO neurons and successfully dissected sleep and wake active circuits, to find that most of LPO neurons are REM sleep active but fire under Dexmedetomidine sedation.
Additionally, I studied Grm2 expressing neurons of the lateral habenula. Using a Grm2-cre mouse line, I performed in vivo calcium imaging and optogenetic stimulation showing how these neurons might be a connecting hub for the regulation of both NREM sleep and propofol-induced sedation.