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Genetic and Neuronal Mechanisms that Regulate Zebrafish Sleep

Award Number: R35NS122172
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Genetic and Neuronal Mechanisms that Regulate Zebrafish Sleep - ABSTRACT Sleep disorders are pervasive, contribute to morbidity in several psychiatric disorders, and cause an annual economic burden of $100 billion. However, despite its importance for health, the mechanisms that regulate sleep are poorly understood. We are taking a new approach to this problem by exploiting useful features of zebrafish to answer an important and basic question: What genetic and neuronal mechanisms regulate sleep? Sleep is regulated by a homeostatic process that reflects internal cues of sleep need and a circadian process that is entrained by environmental cues and restricts sleep to the appropriate time. Sleep is also directly and rapidly regulated by a phenomenon known as masking, in which light induces wake and dark induces sleep in diurnal animals. Factors that regulate the homeostatic process have been identified, including our recent finding that the serotonergic raphe promote sleep homeostasis in zebrafish and mice. We also showed that melatonin is essential for circadian regulation of sleep in zebrafish, and identified a pathway in the brain that regulates masking. Here we build upon these discoveries to elucidate mechanisms that underlie homeostatic, circadian, and light-dependent regulation of sleep. We will investigate these mechanisms using zebrafish, a diurnal vertebrate with several advantages that complement rodent models, using a combination of genetic, optogenetic, and chemogenetic perturbations coupled with high-throughput behavioral assays and whole-brain neuronal activity monitoring with single cell resolution. In Project 1, we will identify raphe subsystems that promote sleep homeostasis, and identify genetic and neuronal circuits that act upstream and downstream of these subsystems in sleep control. In Project 2, we will identify melatonin receptors that mediate the sleep-promoting function of melatonin, and also perform a screen to identify neurons through which melatonin implements circadian regulation of sleep. Project 3 builds on our recent discovery that the hypothalamic neuropeptide prokineticin 2 suppresses both light- and dark-induced masking behavior. Similar to Project 1, we will identify genetic and neuronal circuits that act upstream and downstream of prokineticin 2 to regulate masking. In Project 4, we will validate a large number of human sleep disorder candidate genes that were identified by genome-wide association studies. We will do so by leveraging zebrafish to efficiently and inexpensively generate and test many mutant lines for sleep phenotypes. We will determine the mechanisms through which validated candidate genes regulate sleep, and integrate these genes into the pathways identified in Projects 1-3. The homeostatic (Project 1), circadian (Project 2) and light-dependent (Project 3) mechanisms that regulate sleep, as well as the sleep disorder genes identified in humans and validated in zebrafish (Project 4), are likely to be integrated at multiple levels to produce either sleep or wakefulness. This research program provides a unified platform to explore interactions between genes and neurons identified in each project. This will allow us to derive a comprehensive understanding of mechanisms that regulate sleep, and will set the stage for novel therapies for sleep disorders.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,366,280 )
2026	2026	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	007	5	9/11/2026	SUPPLEMENT FOR EXPANSION	$110,030
2026	2026	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	006	5	8/19/2026	NON-COMPETING CONTINUATION	$1,256,250
2026	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	005	4	8/13/2026	SUPPLEMENT FOR EXPANSION	$0
2026	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	004	4	8/12/2026	NON-COMPETING CONTINUATION	$0
2026	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	003	4	4/6/2026	NON-COMPETING CONTINUATION	$0
2026	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	3	4/3/2026	NON-COMPETING CONTINUATION	$0
2026	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	4/2/2026	NON-COMPETING CONTINUATION	$0
2026	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/1/2026	NEW	$0
														Subtotal = $1,366,280

Issue Date FY: 2024 ( Subtotal = $1,299,975 )
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/25/2024	NON-COMPETING CONTINUATION	$1,218,563
2024	2024	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	4	7/8/2024	SUPPLEMENT FOR EXPANSION	$81,412
														Subtotal = $1,299,975

Issue Date FY: 2023 ( Subtotal = $1,256,250 )
2023	2023	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/2/2023	NON-COMPETING CONTINUATION	$1,256,250
														Subtotal = $1,256,250

Issue Date FY: 2022 ( Subtotal = $1,256,250 )
2022	2022	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/19/2022	NON-COMPETING CONTINUATION	$1,256,250
														Subtotal = $1,256,250

Issue Date FY: 2021 ( Subtotal = $888,594 )
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/19/2021	NEW	$883,289
2021	2021	CALIFORNIA INSTITUTE OF TECHNOLOGY	1200 E CALIFORNIA BLVD	PASADENA	CA	91125	LOS ANGELES	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	5/20/2021	NEW	$5,305
														Subtotal = $888,594

Grand Total All Awards = $6,067,349

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Genetic and Neuronal Mechanisms that Regulate Zebrafish Sleep

Award Number: R35NS122172

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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