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Inhibitory Cell Types and Circuits in the Lateral Hypothalamus

Award Number: R01MH112739
ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/20/2017
PERIOD OF PERFORMANCE END DATE: 06/30/2027

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Inhibitory Cell Types and Circuits in the Lateral Hypothalamus - PROJECT SUMMARY/ABSTRACT The goal of this proposal is to define the cellular diversity, connectivity and function of inhibitory neurons in the lateral hypothalamic area (LHA). The LHA is a linchpin in the orchestration of fundamental aspects of behavior owing to its unique position at the intersection of multiple neural and humoral systems. LHA GABAergic neurons in particular have emerged as potent actuators of arousal, goal-directed behavior as well as both negative and positive valence behavior. Within this broad class of inhibitory LHA neurons lie poorly resolved but functionally important subpopulations, which may differentially determine behavioral output. Important among these is a population of putative inhibitory neurons that express the neuropeptide melanin-concentrating hormone (MCH). LHA MCH-expressing neurons (LHAMCH) display remarkable functional diversity, sending extensive projections throughout the brain and coordinating a broad range of physiological functions and behaviors, including the modulation of sleep-wake states, feeding, motivated behavior, stress and memory. However, experimental manipulations of LHAMCH neurons are largely interpreted in the context of LHAMCH neurons being a monolithic, neuromodulatory projection system, creating a profound knowledge gap as to the source of their functional diversity. There is, therefore, a critical need to delineate the unique cellular, circuit-level and behavioral impact of LHAMCH diversity. In the previous grant cycle, we made significant progress towards our long-term goal of defining the population structure of LHA GABAergic neurons, including the generation of the most comprehensive cellular taxonomy to date of molecularly distinct LHA cell types in the mouse. Here, we will build upon that progress through our investigation of: 1) two transcriptomically-distinct LHAMCH subpopulations that differentially express the neurokinin 3 receptor (NK3R), the receptor for neurokinin B (NKB); 2) and a novel projection from NKB neurons in the central extended amygdala to the LHA. In Aim 1, we will determine whether distinct LHAMCH subpopulations give rise to functional sub-circuits that project to different targets in the brain and release different neurochemicals using a precise intersectional viral strategy based on the enrichment of NK3R in one LHAMCH subpopulation over the other. In Aim 2, we will explore whether differential engagement of LHAMCH subpopulations elicits distinct behavioral repertoires using two parallel intersectional strategies for optogenetically targeting LHAMCH subpopulations and then subjecting animals to a suite of behavioral assessments. In Aim 3, we will investigate the biological mechanisms underlying NKB/NK3R signaling in the central extended amygdala–LHA circuit through a detailed electrophysiological investigation of NKB/GABA co- transmission onto LHAMCH neurons, and by studying the behavioral impact of these projections. Together, the proposed experiments will address outstanding questions concerning the cellular and circuit-level functions of LHAMCH neuron diversity, which is necessary both for a mechanistic understanding of LHA circuit function, and as a critical precursor for identifying therapeutic targets for neuropsychiatric, sleep and metabolic 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: 2025 ( Subtotal = $528,771 )
2025	2025	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	9	6/25/2025	NON-COMPETING CONTINUATION	$528,771
														Subtotal = $528,771

Issue Date FY: 2024 ( Subtotal = $491,843 )
2024	2024	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	004	8	6/19/2024	NON-COMPETING CONTINUATION	$491,843
2024	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	7	10/16/2023	NON-COMPETING CONTINUATION	$0
2024	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	003	7	1/15/2024	NON-COMPETING CONTINUATION	$0
2024	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	002	6	11/28/2023	COMPETING CONTINUATION	$402,150
2024	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	001	5	11/28/2023	SUPPLEMENT FOR EXPANSION	-$402,150
														Subtotal = $491,843

Issue Date FY: 2023 ( Subtotal = $557,325 )
2023	2023	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	001	7	7/14/2023	NON-COMPETING CONTINUATION	$557,325
2023	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	5	1/5/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $557,325

Issue Date FY: 2022 ( Subtotal = $585,300 )
2022	2022	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	001	6	9/8/2022	COMPETING CONTINUATION	$585,300
2022	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	5	9/2/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $585,300

Issue Date FY: 2021 ( Subtotal = $816,411 )
2021	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	001	5	7/21/2021	SUPPLEMENT FOR EXPANSION	$420,634
2021	2021	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	5	3/23/2021	NON-COMPETING CONTINUATION	$395,777
														Subtotal = $816,411

Issue Date FY: 2020 ( Subtotal = $396,157 )
2020	2020	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	4	3/19/2020	NON-COMPETING CONTINUATION	$396,157
														Subtotal = $396,157

Issue Date FY: 2019 ( Subtotal = $395,616 )
2019	2019	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	3	3/12/2019	NON-COMPETING CONTINUATION	$395,616
														Subtotal = $395,616

Issue Date FY: 2018 ( Subtotal = $393,244 )
2018	2018	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	001	2	6/4/2018	NON-COMPETING CONTINUATION	$39,325
2018	2018	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	2	3/19/2018	NON-COMPETING CONTINUATION	$353,919
														Subtotal = $393,244

Issue Date FY: 2017 ( Subtotal = $393,556 )
2017	2017	UNIVERSITY OF CONNECTICUT	438 WHITNEY RD EXTENSION UNIT 1133	STORRS	CT	06269	CAPITOL	USA	Mental Health Research Grants	000	1	4/20/2017	NEW	$393,556
														Subtotal = $393,556

Grand Total All Awards = $4,558,223

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Inhibitory Cell Types and Circuits in the Lateral Hypothalamus

Award Number: R01MH112739

ORGANIZATION: NATIONAL INSTITUTE OF MENTAL HEALTH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/20/2017

PERIOD OF PERFORMANCE END DATE: 06/30/2027

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