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Functional Heterogeneity of Hypocretin Neurons

Award Number: R01MH116470
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/08/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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Functional Heterogeneity of Hypocretin Neurons - Functional heterogeneity of Hcrt neurons Complex neuronal circuits regulate arousal, and deficiencies in these circuits are a highly prevalent cause for sleep disturbances and anxiety disorders. The multi-functional hypocretin/orexin (Hcrt) neurons regulate arousal-related behavioral states including sleep, wakefulness, feeding, emotions, stress and reward. However, how a presumably uniform Hcrt population regulates such diverse functions, and how alteration in these circuitries result in sleep and anxiety disorders is not clear. We hypothesize that Hcrt neurons are genetically, anatomically and functionally heterogenous, and that subpopulations of Hcrt neurons projecting to different brain regions regulate specific features of sleep and arousal. Here, we will use a combination of viral monosynaptic circuit tracing, two-photon live imaging of single synapse and neuronal activity, optogenetics, fiber photometry and behavioral experiments in zebrafish and mice to identify and elucidate the function of subpopulations of Hcrt neurons in regulating sleep. In aim 1, we will use retrogradely transported viral vectors and live imaging of single pre- and post-synaptic structure to characterize anatomically distinct subpopulations of Hcrt neurons, innervating the VTA, LC and TMN regions. The transparent zebrafish model enables anatomical and functional live visualization of the relatively simple, but conserved, Hcrt system (20-40 cells). In aim 2, fiber photometry recording in behaving mice and real-time two-photon imaging of neuronal activity in single cell resolution will be performed to elucidate the differential neuronal activity of subpopulations of Hcrt neurons in regulating sleep and arousal. In aim 3, optogenetic, synaptic silencing and genetically induced neuron ablation will be used to manipulate subpopulations of Hcrt neurons. We will monitor the effect on neuronal activity in post synaptic dopaminergic and histaminergic target neurons using genetically encoded calcium indicators. These neuronal activity recordings will be complemented with behavioral experiments in mice. The results are expected to challenge the generalized assumption that neurons that secrete a specific neuropeptide share similar identities and functions. The combined strength of the two vertebrate models will uncover the role of evolutionary conserved sub neuronal circuitries and may provide new therapeutic targets for the treatment of 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: 2024 ( Subtotal = $0 )
2024	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	5	4/12/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $466,427 )
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	5	11/8/2022	NON-COMPETING CONTINUATION	$419,784
2023	2023	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	5	1/23/2023	NON-COMPETING CONTINUATION	$46,643
														Subtotal = $466,427

Issue Date FY: 2022 ( Subtotal = $465,014 )
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	4	11/23/2021	NON-COMPETING CONTINUATION	$418,512
2022	2022	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	4	5/16/2022	NON-COMPETING CONTINUATION	$46,502
														Subtotal = $465,014

Issue Date FY: 2021 ( Subtotal = $462,855 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	3	4/13/2021	NON-COMPETING CONTINUATION	$46,285
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	3	12/3/2020	NON-COMPETING CONTINUATION	$416,570
														Subtotal = $462,855

Issue Date FY: 2020 ( Subtotal = $482,664 )
2020	2020	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	2	1/23/2020	NON-COMPETING CONTINUATION	$482,664
														Subtotal = $482,664

Issue Date FY: 2019 ( Subtotal = $496,789 )
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	000	1	2/8/2019	NEW	$496,789
2019	2019	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 SERRA MALL	STANFORD	CA	94305	SANTA CLARA	USA	Mental Health Research Grants	001	1	9/24/2019	NEW	$0
														Subtotal = $496,789

Grand Total All Awards = $2,373,749

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Functional Heterogeneity of Hypocretin Neurons

Award Number: R01MH116470

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/08/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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