Identification of Neurons with a Privileged Role in Sleep Homeostasis in Drosophila melanogaster

Abstract

Summary Sleep is thought to be controlled by two main processes: a circadian clock that primarily regulates sleep timing and a homeostatic mechanism that detects and responds to sleep need. While abundant experimental evidence suggests that sleep need increases with time spent awake, the contributions of different brain arousal systems have not been assessed independently of each other to determine if certain neural circuits, rather than waking per se, selectively contribute to sleep homeostasis. Using the fruit fly, Drosophila melanogaster, we found that sustained thermogenetic activation of three independent neurotransmitter systems promoted nighttime wakefulness. However, only sleep deprivation resulting from activation of cholinergic neurons was sufficient to elicit subsequent homeostatic recovery sleep, as assessed by multiple behavioral criteria. In contrast, sleep deprivation resulting from activation of octopaminergic neurons suppressed homeostatic recovery sleep, indicating that wakefulness can be dissociated from accrual of sleep need. Neurons that promote sleep homeostasis were found to innervate the central brain and motor control regions of the thoracic ganglion. Blocking activity of these neurons suppressed recovery sleep but did not alter baseline sleep, further differentiating between neural control of sleep homeostasis and daily fluctuations in the sleep/wake cycle. Importantly, selective activation of wake-promoting neurons without engaging the sleep homeostat impaired subsequent short-term memory, thus providing evidence that neural circuits that regulate sleep homeostasis are important for behavioral plasticity. Together, our data suggest a neural circuit model involving distinct populations of wake-promoting neurons, some of which are involved in homeostatic control of sleep and cognition.

Hypocretin (orexin) is critical in sustaining theta/gamma-rich waking behaviors that drive sleep need

“…Spontaneous wake thus drastically differs from "gentle handling"-enforced wake in Hcrt dependence, presumed arousal circuits, and homeostatic impact. This is reminiscent of studies in Drosophila suggesting that distinct arousal neuromodulators impart distinct processing modes in target circuits, with distinct homeostatic costs (14). Likewise, Hcrt involvement in arousal appears to be driven by context-dependent determinants and drive system-wide processes, such as θ and fast-γ network rhythms.…”

“…Distinct wake-enhancing modulators promote distinct aspects of behavioral and cognitive arousal (11)(12)(13), but whether different wake-active cells or neuromodulator/receptor pairs differentially regulate waking electrocortical signatures or differently impact the sleep homeostat is poorly understood. In flies, striking differences are seen between wake induced by acetylcholine, dopamine, or octopamine cell activation on subsequent sleep (14). Among mammalian wakeenhancing neuromodulators, only Hcrt loss leads to a defined clinical condition, narcolepsy with cataplexy, characterized by sleep attacks, unstable nocturnal sleep, PS emergence into wake, and cataplexy.…”

Molecular Mechanisms of Sleep Homeostasis in Flies and Mammals

“…Several sleep parameters are similarly affected by sleep loss in flies and mammals, and are used to define sleep homeostasis in Drosophila. Thus, sleep deprivation in flies is followed by longer and more consolidated sleep, characterized by reduced number of brief awakenings, longer sleep episodes, and higher arousal thresholds (Hendricks et al 2000;Shaw et al 2000;Huber et al 2004b;van Alphen et al 2013;Seidner et al 2015). These parameters serve as markers of sleep homeostasis in lieu of SWA, which requires electrophysiological measurements that are possible but technically challenging in flies.…”

“…Activation of cholinergic neurons is sufficient to induce wakefulness and subsequent sleep rebound (Seidner et al 2015). Sleep homeostasis defects in the short sleeping mutant insomniac (inc) could be rescued by inc expression in cholinergic neurons (Pfeiffenberger and Allada 2012).…”

Pleiotropic Effects of Loss of the Dα1 Subunit in Drosophila melanogaster: Implications for Insecticide Resistance

“…While activation of all cholinergic neurons inhibits sleep in flies (Seidner et al 2015), different neuronal groups can be wake-promoting (Yi et al 2013) or sleep-promoting (Wu et al 2014). Individual nAChR subunits also appear to have different roles in sleep regulation (Yi et al 2013;Shi et al 2014;Wu et al 2014).…”