Network-Specific Synchronization of Electrical Slow-Wave Oscillations Regulates Sleep Drive in Drosophila

Abstract

Graphical Abstract Highlights d Drosophila R5 network exhibits sleep-regulating compound slow-wave oscillations d Activation of circadian pathways mediates R5 multi-unit synchronization d Synchronization and compound delta oscillations require NMDAR coincidence detection d Eliminating NMDAR coincidence detection in R5 disrupts sleep In Brief Raccuglia et al. discover sleep-regulatory compound delta oscillations within the Drosophila R5 network. NMDAR coincidence detection mediates singleunit synchronization, which is the mechanistic basis for generating compound delta oscillations. Eliminating NMDAR coincidence detection, and thus compound oscillations, disrupts sleep and facilitates wakening. SUMMARYSlow-wave rhythms characteristic of deep sleep oscillate in the delta band (0.5-4 Hz) and can be found across various brain regions in vertebrates. Across phyla, however, an understanding of the mechanisms underlying oscillations and how these link to behavior remains limited. Here, we discover compound delta oscillations in the sleep-regulating R5 network of Drosophila. We find that the power of these slowwave oscillations increases with sleep need and is subject to diurnal variation. Optical multi-unit voltage recordings reveal that single R5 neurons get synchronized by activating circadian input pathways. We show that this synchronization depends on NMDA receptor (NMDAR) coincidence detector function, and that an interplay of cholinergic and glutamatergic inputs regulates oscillatory frequency. Genetically targeting the coincidence detector function of NMDARs in R5, and thus the uncovered mechanism underlying synchronization, abolished network-specific compound slow-wave oscillations. It also disrupted sleep and facilitated light-induced wakening, establishing a role for slow-wave oscillations in regulating sleep and sensory gating. We therefore propose that the synchronization-based increase in oscillatory power likely represents an evolutionarily conserved, potentially ''optimal,'' strategy for constructing sleep-regulating sensory gates.

Hypothalamic NMDA receptors stabilize NREM sleep and are essential for REM sleep

“…As well as calcium permeability, NMDA receptors have a voltage-dependent magnesium block, and in contrast to AMPA-gated ionotropic glutamate receptors, with which they are often paired in synapses, stay open from around 100 msec to 1 s (Paoletti et al, 2013). Because of these properties NMDA receptors are famously studied for their role in synaptic plasticity, and this is the thinking behind why NMDA receptors would be involved in sleep homeostasis (Liu et al, 2016;Raccuglia et al, 2019). But these same properties also allow NMDA receptors to act as pacemakers, controlling rhythmic firing e.g.…”

“…CC-BY-NC 4.0 International license perpetuity. It is made available under a preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in The copyright holder for this this version posted October 20, 2020. ; https://doi.org/10.1101/2020.10.19.345728 doi: bioRxiv preprint 4 mechanism to changing synaptic strength that underlies memory formation (Liu et al, 2016;Raccuglia et al, 2019;Tatsuki et al, 2016). These studies provided our initial motivation for the experiments reported here.…”

Better Sleep at Night: How Light Influences Sleep in Drosophila

“…Sleep in flies is defined as at least 5 min of total inactivity (Shaw et al, 2000), meaning that during this time no infrared break is recorded by the system. Recordings of local field potential in the brain suggest that Drosophila sleep can be divided to specific phases of different intensities, similar to mammalian sleep (Nitz et al, 2002;van Alphen et al, 2013;Raccuglia et al, 2019). Sleep differs according to sex: males sleep more, with comparable resting time during the day and night, while mated females sleep mostly during the night, and they are more active during the day (Huber et al, 2004).…”

NOSA, an Analytical Toolbox for Multicellular Optical Electrophysiology

“…For a fully functional Mg 2+ plug, Drosophila NMDA receptors require 20 mM of Mg 2+ (Miyashita et al, 2012). To substitute for missing sensory input in the ex vivo preparation, we reduced external Mg 2+ to 5 mM which leads to spontaneous activity in R5 neurons (Raccuglia et al, 2019).…”

“…A power spectrum analysis revealed that single R5 neurons oscillate between 0.5 -1.5 Hz ( Figure 3B). We recently reported that R5 oscillations within this spectrum are linked to the fly's sleep quality because they facilitate consolidated sleep phases (Raccuglia et al, 2019). The cross-correlation function built into NOSA provides a simple way of visualizing the temporal relation between the electrical patterns of the different cells ( Figure 3C).…”