The Drosophila circuitry of sleep–wake regulation
Introduction
The use of Drosophila as a model for sleep research has grown for more than 15 years [1, 2] to become a vital component of our efforts to understand the molecular and cellular mechanisms and functions of this enigmatic behavioral state. The ease and power of genetic manipulation in this model has enabled targeted examination of neurotransmitter/neuromodulator systems [3, 4, 5] and neuropeptides [6] for a role in sleep–wake states, and led the way in forward-genetic screens to identify novel genes that regulate sleep [7, 8, 9].
The focus of this review will be on the circuitry of sleep–wake states, which has also been comprehensively studied in Drosophila. Advances in our understanding of fly brain anatomy, coupled with technology to manipulate activity of specific neurons, have facilitated the identification of neural populations required for daily baseline sleep and arousal as well as those that function in sleep homeostasis. The latter is typically assayed by depriving flies of sleep and monitoring the increased sleep (rebound) that follows. Interestingly, as discussed below, baseline and homeostatic sleep may be controlled by distinct neurons.
Section snippets
Sleep and wake-promoting circuits in the mushroom bodies
Located in the protocerebrum of the Drosophila brain, the mushroom body (MB) is a structure which has classically been established as an essential associative center for olfactory learning and memory, although more recently, this network has begun to be appreciated for much broader roles in behavior [10, 11]. The mushroom bodies are comprised of Kenyon cells (KCs) whose axons project together to form the three MB lobes – α/β, α′/β′, and γ – which can be further divided into 2–3 types, depending
Fan-shaped body
The central complex in Drosophila refers to a group of central brain neuropils, including the fan-shaped and ellipsoid body which, collectively, are implicated in processes such as sensory integration and locomotion, memory, and most recently, sleep [27]. Neuronal activation revealed ExFl2 cells of the dorsal fan-shaped body (dFSB) to be profoundly sleep-promoting [28]. Acute activation by TrpA1 demonstrated that sleep could be driven in defined windows [28, 29], with flies showing increased
Circadian clock cells
The clock neurons, which possess the molecular components of the circadian clock, are a diffuse network of groups, comprised of the PDF-positive small and large ventral lateral neurons (sLNVs and lLNVs), the dorsal neurons (DN1s, DN2s, and DN3s) and the dorsal lateral neurons (LNds) (for detailed review see Refs. [36, 37]).
Constitutive hyperpolarization of PDF-positive cells increases total sleep, while activating the same population results in sleep loss [38, 39]. A much subtler loss of sleep,
The pars intercerebralis and other sleep–wake regulating populations
One other region of well-described sleep–wake circuitry lies in the pars intercerebralis (PI), a diverse, neuropeptidergic population which has been compared to the mammalian hypothalamus [48].
The insulin-producing cells (IPCs) in the PI are wake-promoting [49]. This population is depolarized by octopamine, a wake-promoting neuromodulator, which produces an increase in cAMP, and affects the Slowpoke potassium current. Thereby, the model posits that octopamine-mediated excitation of the IPCs
Conclusion
In conclusion, multiple circuits of sleep–wake regulating neurons are found throughout the Drosophila brain. A clear, outstanding question is whether and how these disparate loci connect to control states, particularly given that any number of populations can mediate profound sleep–wake alteration. In fact, few studies [18] have attempted to link the currently known centers of sleep–wake circuitry.
Another major interest regards the interplay between baseline and homeostatic sleep regulation. A
Conflict of Interest Statement
The authors declare no conflict of interest.
Acknowledgements
Research in the lab is supported by the Ellison Medical Foundation and the Glenn Foundation. AS is an investigator with the Howard Hughes Medical Institute. GA is also supported by an NIH T32 training grant (5T32HL007953-17).
References (57)
- et al.
Rest in Drosophila is a sleep-like state
Neuron
(2000) Neuromodulatory control of sleep in Drosophila melanogaster: integration of competing and complementary behaviors
Curr Opin Neurobiol
(2013)- et al.
Genetics of sleep and sleep disorders
Cell
(2011) - et al.
Insomniac and Cullin-3 regulate sleep and wakefulness in Drosophila
Neuron
(2011) - et al.
Refined spatial manipulation of neuronal function by combinatorial restriction of transgene expression
Neuron
(2006) - et al.
Propagation of homeostatic sleep signals by segregated synaptic microcircuits of the Drosophila mushroom body
Curr Biol
(2015) - et al.
Neuroarchitecture and neuroanatomy of the Drosophila central complex: a GAL4-based dissection of protocerebral bridge neurons and circuits
J Comp Neurol
(2015) - et al.
Inducing sleep by remote control facilitates memory consolidation in Drosophila
Science
(2011) - et al.
Operation of a homeostatic sleep switch
Nature
(2016) - et al.
Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development
Trends Neurosci
(2001)
Circadian organization of behavior and physiology in Drosophila
Annu Rev Physiol
The GABA A receptor RDL acts in peptidergic PDF neurons to promote sleep in Drosophila
Curr Biol
WIDE AWAKE mediates the circadian timing of sleep onset
Neuron
Circadian neuron feedback controls the Drosophila sleep-activity profile
Nature
Allatostatin a signalling in Drosophila regulates feeding and sleep and is modulated by PDF
PLoS Genet
Reorganization of sleep by temperature in Drosophila requires light, the homeostat, and the circadian clock
Curr Biol
Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila
Nat Neurosci
Identification of a circadian output circuit for rest: activity rhythms in Drosophila
Cell
Regulation of sleep plasticity by a thermo-sensitive circuit in Drosophila
Sci Rep
Notch signaling modulates sleep homeostasis and learning after sleep deprivation in Drosophila
Curr Biol
A neuron-glia interaction involving GABA transaminase contributes to sleep loss in sleepless mutants
Mol Psychiatry
Sleep state switching
Neuron
Correlates of sleep and waking in Drosophila melanogaster
Science
Genetic analysis of sleep
Genes Dev
Monoamines and sleep in Drosophila
Behav Neurosci
Identification of sleepless, a sleep-promoting factor
Science
Identification of Redeye: a new sleep-regulating protein whose expression is modulated by sleep amount
Elife
The neuronal architecture of the mushroom body provides a logic for associative learning
Elife
Cited by (73)
Planning sleep-related animal and translational research
2023, Encyclopedia of Sleep and Circadian Rhythms: Volume 1-6, Second EditionThe role of Drosophila melanogaster in neurotoxicology studies: Responses to different harmful substances
2023, Advances in NeurotoxicologyIntrinsic maturation of sleep output neurons regulates sleep ontogeny in Drosophila
2022, Current BiologyMeasuring metabolic rate in single flies during sleep and waking states via indirect calorimetry
2022, Journal of Neuroscience MethodsOptogenetic activation of SIFamide (SIFa) neurons induces a complex sleep-promoting effect in the fruit fly Drosophila melanogaster
2021, Physiology and BehaviorCitation Excerpt :However, Tukey post-hoc tests did not find any bin at which experimental males significantly differed from both control groups. Neurons targeted by the SIFa-GAL4 driver [47] have been shown to be located in the PI, a brain region that utilizes several neurotransmitters to regulate downstream functions [3, 29]. In light of that, SIFa-GAL4 neurons, when being activated, might release other sleep-promoting neurotransmitters.