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Genetic and neural regulation of sleep and arousal

Research Project
 | 
01.01.2021
 - 31.12.2024

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.

Funding

Genetic and neural regulation of sleep and arousal

SNF Projekt (GrantsTool), 01.2021-12.2024 (48)
PI : Schier, Alexander.

Members (1)

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Alexander Schier

Principal Investigator