Insomniac links the development and function of a sleep-regulatory circuit.

Qiuling Li,Nicholas Stavropoulos,Alexie Lessing,Kayla Y Lim,Hyunsoo Jang

doi:10.7554/elife.65437

Qiuling Li, Nicholas Stavropoulos + Show 3 more

Open Access

https://doi.org/10.7554/elife.65437

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Abstract

Although many genes are known to influence sleep, when and how they impact sleep-regulatory circuits remain ill-defined. Here, we show that insomniac (inc), a conserved adaptor for the autism-associated Cul3 ubiquitin ligase, acts in a restricted period of neuronal development to impact sleep in adult Drosophila. The loss of inc causes structural and functional alterations within the mushroom body (MB), a center for sensory integration, associative learning, and sleep regulation. In inc mutants, MB neurons are produced in excess, develop anatomical defects that impede circuit assembly, and are unable to promote sleep when activated in adulthood. Our findings link neurogenesis and postmitotic development of sleep-regulatory neurons to their adult function and suggest that developmental perturbations of circuits that couple sensory inputs and sleep may underlie sleep dysfunction in neurodevelopmental disorders.

Highlights

A central goal of sleep research has been elucidating the mechanisms by which genes shape normal sleep patterns and cause sleep disorders
While numerous genes that strongly impact sleep have been identified in humans and in animals ranging from mammals to invertebrates (Chemelli et al, 1999; Chiu et al, 2016; Cirelli et al, 2005; Funato et al, 2016; He et al, 2009; Lin et al, 1999; Raizen et al, 2008), when these genes act to influence sleep is in many cases unresolved
Pan-neuronal depletion of inc causes short sleep, while restoring inc solely to neurons is largely sufficient to rescue the sleep deficits of inc mutants, indicating that inc impacts sleep through neurons (Pfeiffenberger and Allada, 2012; Stavropoulos and Young, 2011). inc is expressed in the larval, pupal, and adult brain (Pfeiffenberger and Allada, 2012; Stavropoulos and Young, 2011), but when inc acts to influence sleep remains uncertain (Li and Stavropoulos, 2016; Pfeiffenberger and Allada, 2012). inc encodes an adaptor for the Cul3 ubiquitin ligase (Li et al, 2019), which, like inc, is required in neurons for normal sleep (Pfeiffenberger and Allada, 2012; Stavropoulos and Young, 2011)

Summary

Introduction

A central goal of sleep research has been elucidating the mechanisms by which genes shape normal sleep patterns and cause sleep disorders. Activation of sleep-inhibiting populations that include Helicon (Donlea et al, 2018), l-LNv (Sheeba et al, 2008), or pars intercerebralis and dopaminergic PPM3 neurons (PI, PPM3) (Dubowy et al, 2016) strongly decreased sleep in wild-type and inc animals (Figure 5A,B; Figure 5—figure supplement 1) The functions of these populations appear to be intact in inc mutants, suggesting that the loss of inc impairs the sleepregulatory functions of MB neurons. Axons and dendrites of other sleep-regulatory circuits, including those of the dorsal fan-shaped body, CRZ+ neurons, and PDF+ circadian pacemaker neurons, exhibited no obvious changes in inc mutants (Figure 7I; Figure 7—figure supplement 2), suggesting that alterations of neuronal anatomy in inc mutants are specific to the MB These findings indicate that increases in the numbers of late-born MB neurons in inc mutants are associated with changes in postmitotic development expected to perturb circuit assembly and function. The altered axons of multiple MB neuron subtypes are unlikely to form normal circuits with their targets that influence sleep, including dopaminergic neurons, mushroom body output neurons, and recurrent connections to the MB (Aso et al, 2014b; Sitaraman et al, 2015a; 2015b)

Discussion

Findings

Materials and methods