Operation of a homeostatic sleep switch

Abstract

Sleep disconnects animals from the external world, at considerable risks and costs that must be offset by a vital benefit. Insight into this mysterious benefit will come from understanding sleep homeostasis: to monitor sleep need, an internal bookkeeper must track physiological changes that are linked to the core function of sleep1. In Drosophila, a crucial component of the machinery for sleep homeostasis is a cluster of neurons innervating the dorsal fan-shaped body (dFB) of the central complex2,3. Artificial activation of these cells induces sleep2, whereas reductions in excitability cause insomnia3,4. dFB neurons in sleep-deprived flies tend to be electrically active, with high input resistances and long membrane time constants, while neurons in rested flies tend to be electrically silent3. Correlative evidence thus supports the simple view that homeostatic sleep control works by switching sleep-promoting neurons between active and quiescent states3. Here we demonstrate state switching by dFB neurons, identify dopamine as a neuromodulator that operates the switch, and delineate the switching mechanism. Arousing dopamine4–8 caused transient hyperpolarization of dFB neurons within tens of milliseconds and lasting excitability suppression within minutes. Both effects were transduced by Dop1R2 receptors and mediated by potassium conductances. The switch to electrical silence involved the downregulation of voltage-gated A-type currents carried by Shaker and Shab and the upregulation of voltage-independent leak currents through a two-pore domain potassium channel we term Sandman. Sandman is encoded by the CG8713 gene and translocates to the plasma membrane in response to dopamine. dFB-restricted interference with the expression of Shaker or Sandman decreased or increased sleep, respectively, by slowing the repetitive discharge of dFB neurons in the ON state or blocking their entry into the OFF state. Biophysical changes in a small population of neurons are thus linked to the control of sleep-wake state.

Molecular Mechanisms of Sleep Homeostasis in Flies and Mammals

“…The effects of sleep loss depend on the RhoGTPase-activating protein, CROSS-VEINLESS-C (CV-C) whose function also strongly affects baseline sleep (Donlea et al 2014). dFB neurons are inhibited by key arousal promoting dopaminergic neurons via activation of the potassium "leak" current carried by Sandman, a two-pore potassium channel, and the suppression of voltage-gated A-type potassium current likely encoded in part by Sh (Pimentel et al 2016). Although these studies reveal the mechanistic basis for dopaminergic arousal, it remains unclear whether these dopamine-dependent changes are important for homeostatic responses to sleep deprivation.…”

Do Quiescence and Wasp Venom-Induced Lethargy Share Common Neuronal Mechanisms in Cockroaches?

“…Regarding the CX, Guo and Ritzmann (2013) have shown that most CX units show an increase in their firing rate prior to the initiation of locomotion, indicating that the CX promotes walking. In addition, monoamines have been found to have an impact on the CX thereby affecting various aspects of sleep regulation in drosophila [34,35]. Finally, injection of the monoamine octopamine in the CX partially restores walking in hypokinetic cockroaches stung by the wasp [36].…”

Big Lessons from Tiny Flies:<em> Drosophila Melanogaster </em>as a Model to Explore Dysfunction of Dopaminergic and Serotonergic Neurotransmitter Systems

“…It was originally proposed that the dopamine engaged Dop1R1 and a Gs/cAMP-dependent pathway [81,83]. More recently, a (noncanonical, pertussis-toxin-sensitive) Gi/Go-mediated signaling via Dop1R2 was shown to elicit two distinct effects on the postsynaptic neurons of the fan-shaped body, which operate on different time scales: an instant -but transient -hyperpolarization, which was due to stimulation of one or several voltage-activated K+-channels, and an off-state, which relies on the exocytosis of an internal, vesicular store of a two-pore-domain K + -channel; this K2P-channel was termed Sandman [80]. Insertion of Sandman produces a large leak current, which silences the fan-shaped body neurons and thus produces a long-lasting state of wakefulness [80].…”

“…(ii) Sleep regulation in flies relies on the fan-shaped body [62,[80][81][82][83]. Dopamine promotes arousal; the neurons involved are somewhat controversial as are the postsynaptic receptors and signaling mechanisms: a single pair of dopaminergic neurons from PPL1 [81] and/or PPM3 [83] suffices to drive the arousal reaction.…”