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Non-cell-autonomous circadian regulation of brain function

English title Non-cell-autonomous circadian regulation of brain function
Applicant Nagoshi Emi
Number 189169
Funding scheme Project funding (Div. I-III)
Research institution Département de Génétique et Evolution Faculté des Sciences Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.04.2020 - 31.03.2024
Approved amount 632'000.00
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All Disciplines (3)

Discipline
Neurophysiology and Brain Research
Molecular Biology
Genetics

Keywords (10)

brain function; circadian rhythms; Drosophila; Pka-c1; neural circuit; sleep; Neurofibromatosis type 1; gene expression regulation; mushroom body; Neurofibromin 1

Lay Summary (French)

Lead
Les mutations du gène neurofibromin1 (Nf1) chez l'homme provoquent la neurofibromatose de type 1 (NF-1), un trouble multisystémique caractérisé par la formation de tumeurs dans le système nerveux et la peau. Nous étudierons comment le gène Nf1 régule le cycle veille-sommeil.
Lay summary

De nombreux processus cognitifs, sensoriels, comportementaux et émotionnels présentent le rythme circadien chez la plupart des espèces animales, y compris les humains. Les fonctions cérébrales circadiens, en particulier le cycle veille-sommeil, sont fréquemment perturbées chez les patients souffrant de troubles neuropsychiatriques. Nous étudierons les mécanismes génétiques moléculaires des fonctions cérébrales rythmiques chez l'organisme modèle invertébré Drosophila melanogaster, car de nombreux gènes contrôlant le rythme circadien et diverses fonctions neurologiques sont conservés entre les mouches et les humains. Plus précisément, nous étudierons comment le gène neurofibromin 1 (Nf1) régule le cycle veille-sommeil. Les mutations du gène Nf1 chez l'homme provoquent la neurofibromatose de type 1 (NF-1), un trouble multisystémique caractérisé par la formation de tumeurs dans le système nerveux et la peau. Les troubles du sommeil sont fréquents chez les patients atteints de NF-1. Les résultats obtenus dans cette recherche fourniront des connaissances qui aident à mieux comprendre la physiopathologie de NF-1.

Direct link to Lay Summary Last update: 13.01.2020

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Abstract

Numerous cognitive, sensory, behavioral and emotional processes exhibit daily rhythms in most animal species. Although basic mechanisms of the circadian clocks and neurological underpinning of various brain functions have been extensively studied, how the former regulates the latter remains incompletely understood. Our objective is to answer this question using fruit fly Drosophila melanogaster, focusing on the circadian regulation of the mushroom body (MB), a center of information processing and sleep regulation. In the CNS neurons of the fly, molecular clocks are present only within the circadian pacemaker neurons, which signal time-of-day information to non-clock cells in different brain areas, thereby modulating their functional output. To explore the molecular basis of non-cell-autonomous circadian regulation, we have profiled gene expression in the MB and identified for the first time a large number of genes expressed rhythmically in the MB intrinsic neurons. A follow-up RNAi screen of the MB-cycling genes identified Neurofibromin 1 (Nf1) and cAMP-dependent protein kinase catalytic subunit 1 (Pka-c1) as regulators of sleep, specifically required for keeping adequate sleep-episode duration at night.This proposed research will investigate the circuitry, signaling mechanism and molecular underpinning of the rhythmic Nf1 and Pka-c1 gene expression in the MB and their roles in sleep regulation by pursuing three independent but complementary aims: (1) to identify the cellular function of Nf1 and Pka-c1 in the MB neuron subtypes responsible for sleep regulation; (2) to uncover molecular mechanisms controlling Nf1 and Pka-c1 gene expression rhythms in the MB; and (3) to map anatomical and functional connectivity between circadian pacemaker neurons and the MB neurons.Circadian brain functions, particularly the sleep-wake cycles, are frequently disrupted in patients with neuropsychiatric disorders (Logan & McClung, 2019). This research will provide new insights into understanding the mechanisms controlling the rhythmic brain function, which will help uncovering causal links between the circadian disturbance and these disorders. Nf1 gene mutations in humans cause neurofibromatosis type 1 (NF-1), a multisystem disorder characterized by the tumor formation in the nervous system and skin (Reviewed in (North, 2000)). Sleep disturbance is frequent in patients with NF-1 (Leschziner, Golding, & Ferner, 2013; Licis et al., 2013; Marana Perez et al., 2015). Since NF1 is highly conserved between flies and mammals, the results obtained in this research will likely yield knowledge that helps better understand the pathophysiology of NF-1.
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