The Drosophila circuitry of sleep-wake regulation

Abstract

Sleep is a deeply conserved, yet fundamentally mysterious behavioral state. Knowledge of the circuitry of sleep-wake regulation is an essential step in understanding the physiology of the sleeping brain. Recent efforts in Drosophila have revealed new populations which impact sleep, as well as provided unprecedented mechanistic and electrophysiological detail of established sleep-regulating neurons. Multiple, distributed centers of sleep-wake circuitry exist in the fly, including the mushroom bodies, central complex and the circadian clock cells. Intriguingly, certain populations have been implicated in specific roles in homeostatic rebound sleep, occurring after sleep loss. In short, our knowledge of fly sleep circuitry advances towards a greater view of brain-wide connectivity and integration of the signals and correlates of the state of sleep.

Figure 1. The mushroom body exhibits complicated influence on sleep and wake.

Mushroom body α′/β′ and γm KCs are wake-promoting, while γd promote sleep. All of these KCs synapse at MBONs within the MB lobes, and the signal is integrated by glutamatergic wake-promoting MBONs (γ5,β′2,γ4) or sleep-promoting GABAergic (γ3,β′1) or cholinergic (α′ γ2) MBONS. DANs project to MBONs, and are wake-promoting through dopamine. DPMs are sleep promoting, and signal through GABA and serotonin. DPMs project to all lobes and are thought to be inhibitory. Blue fills indicate a sleep-promoting population. Red fills indicate a wake-promoting population. DA = dopamine. 5HT = serotonin. GLUT = glutamate. ACH = acetylcholine. Mushroom body and DAN depiction based on representations in Aso et?al. [11] and Sitaraman et?al. [21].

Figure 2. The central complex promotes sleep: dorsal fan-shaped body and ellipsoid body.

ExFl2 neurons of the dFSB and R2 neurons of the ellipsoid body are sleep-promoting. dFSB neurons are inhibited by dopaminergic neurons of the PPL1 and PPM3 cluster. The sleep-promoting effect of R2 depends on dFSB activity; the connectivity is unknown, but not monosynaptic. Blue fills indicate a sleep-promoting population. Red fills indicate a wake-promoting population. DA = dopamine.

Figure 3. The circadian clock network influences both sleep and wake.

The LNVs have been found to promote wake, at least in part through release of wake-promoting PDF. lLNvs are inhibited by GABA, although the source is unknown. DN1s are both wake-promoting through DH31+ neurons, as well as sleep-promoting through inhibition of sLNvs by glutamate. Whether these populations are distinct is unknown. Blue fills indicate a sleep-promoting population. Red fills indicate a wake-promoting population. Purple fills indicate populations which may promote sleep and wake. Diamonds are neuropeptides, with red fill indicating wake-promotion. GLUT = glutamate.

Figure 4. The PI is a diverse neurosecretory center which can promote sleep and wake.

IPCs of the PI are wake-promoting and are depolarized by the wake-promoting neuromodulator, octopamine. Other neurons within or adjacent to the PI are sleep promoting, through EGF and/or SIFamide signaling. A PL population is wake promoting, although not linked to currently known circuitry. Blue fills indicate a sleep-promoting population. Red fills indicate a wake-promoting population. Diamonds are neurotransmitters/peptides. OA = octopamine.