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Genetic and neural regulation of sleep and arousal
Third-party funded project
Project title Genetic and neural regulation of sleep and arousal
Principal Investigator(s) Schier, Alexander
Organisation / Research unit Departement Biozentrum / Cell and Developmental Biology (Schier)
Project start 01.01.2021
Probable end 31.12.2024
Status Active
Abstract
Stimuli that elicit responses in awake animals fail to do so during sleep. This increased
arousal threshold and locomotor quiescence are hallmarks of sleep behavior, but the
genetic and neural mechanisms that control arousal remain poorly understood.
Inappropriate regulation of arousal contributes to insomnia or nonrestorative sleep,
which affect up to a third of the population. Revealing how the brain regulates arousal
states is thus of significant biomedical importance.
Genetic studies have provided entry points to define genes and neural circuits
regulating arousal. For example, studies of specific G-protein coupled receptors
(GPCRs) have revealed sleep regulatory mechanisms in Drosophila, zebrafish, mouse
and humans, while family linkage and genome-wide association studies have identified
candidate genes involved in human sleep behavior and sleep disorders. Our proposed
research extends these studies by analyzing the cellular roles of genes involved in
human insomnia and Restless Legs Syndrome (Aim 1), and by revealing novel
functions of G-protein coupled receptors in sleep and arousal (Aim 2). We use zebrafish
as a model system because powerful imaging, genetic, genomics, and behavioral
approaches can be combined to investigate vertebrate sleep and arousal.
In preliminary studies, we disrupted genes associated with human insomnia and
Restless Leg Syndrome (RLS) and profiled their effects on behavior. We discovered that
mutations in the transcriptional regulators meis1b and skor1a/b lead to overlapping
arousal phenotypes and perturbed cerebellum function. These results suggest that
meis1b and skor1a/b regulate cerebellar development and function, and implicate the
cerebellum in the regulation of sleep and arousal (Aim 1). In a complementary
approach to identify novel sleep and arousal regulators, we disrupted 93
brain-expressed G-protein coupled receptor genes. In our initial screening efforts, we
discovered several mutants with abnormal brain activity or behavior. In particular,
galr2a/b and gpr101 mutants exhibit daytime hyperactivity and hypoactivity,
respectively (Aim 2). We will extend these studies as follows:
Aim 1: Dissect how the transcriptional regulators meis1b and skor1a/b regulate
cerebellum circuitry and arousal. We hypothesize that disruption of specific subsets of
cerebellar neurons generates aberrant locomotor drive and heightened sensory
responsiveness in meis1b and skor1a/b mutants. To test this idea, we will use
imaging, genomic, and neuronal manipulation approaches to define, phenocopy, and
rescue cerebellum defects in meis1b and skor1a/b mutants. These studies will reveal
previously unknown functions for Restless Legs Syndrome genes, as well as novel roles
for cerebellum circuitry in arousal regulation.
Aim 2: Identify G-protein coupled receptors that modulate sleep and arousal. We will
complete our genetic screen to identify GPCRs that regulate arousal and identify
common signaling pathways by intersecting phenotypes with previous pharmacological
and overexpression screens. To prioritize hits for follow-up studies, we will characterize
candidates from the primary screen with a battery of secondary behavioral tests,
characterize GPCR expression vis-à-vis whole brain activity signatures, and determine
relevant ligand/receptor relationships. These studies will help identify novel GPCRs
and signaling pathways regulating sleep and arousal.
These studies will enrich our genetic and circuit-level understanding of how the brain
controls sleep and arousal, and inform potential diagnostic or therapeutic approaches
to human sleep disorders.
Financed by Swiss National Science Foundation (SNSF)
   

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