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Neural Mechanisms Underlying Cataplexy Control by MCH Neurons

Award Number: R01NS119223
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: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 04/30/2027

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Neural Mechanisms Underlying Cataplexy Control by MCH Neurons - PROJECT SUMMARY Understanding the neural mechanisms underlying narcolepsy with cataplexy (NC) is crucial, considering the debilitating and life-threatening nature of this sleep disorder and its high prevalence. Previous studies have established that the loss of orexins is the fundamental cause of NC in humans and animals. However, the role of melanin-concentrating hormone (MCH) neurons, which are reciprocally connected with orexin neurons and play a complementary role in sleep-wake regulation, in the pathophysiology of NC remains unclear. The proposed work is aimed to address this question and to define the neural circuitry through which MCH neurons may influence cataplexy. To understand if MCH neurons are active during cataplexy, in Aim1, we will image activity dynamics of MCH neurons in a mouse model of NC during spontaneous cataplexy as well as in the presence of positive emotional stimuli that enhance cataplexy. To demonstrate a causal role of MCH neurons in cataplexy, in Aim 2, we will selectively activate and silence the MCH neurons using chemogenetic methods and study the changes in spontaneous cataplexy and positive-emotion-triggered cataplexy (PES-cataplexy). As MCH neurons heavily project to the midbrain locomotor region (MLR; involved in facilitating muscle tone and locomotor activity), whose lesions in rats produced cataplexy, we then hypothesized that the MCH neurons might target the MLR to modulate cataplexy. We will test this hypothesis, in Aim 3, by studying the changes in cataplexy a) following in vivo optogenetic stimulation of the MCH terminals in the MLR with concurrent chemogenetic inhibition of MCH soma and b) following optogenetic inhibition of the MCH terminals in the MLR with concurrent chemogenetic activation of MCH soma. Finally, in Aim 4, to identify the neurochemically distinct subset(s) of MLR neurons involved in MCH control of cataplexy, we will chemogenetically activate or inhibit the glutamatergic and GABAergic neurons in the MLR in mice with or without orexins and study cataplexy behavior. Collectively, these experiments will identify the specific mechanisms and pathways by which MCH neurons influence cataplexy and thereby will improve our understanding of the neural basis of NC.


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 = $0 )
2026	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	2/5/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $437,500 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	5/1/2025	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2024 ( Subtotal = $424,375 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	4/29/2024	NON-COMPETING CONTINUATION	$424,375
														Subtotal = $424,375

Issue Date FY: 2023 ( Subtotal = $437,500 )
2023	2023	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	4/18/2023	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2022 ( Subtotal = $437,500 )
2022	2022	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	4/8/2022	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2021 ( Subtotal = $437,500 )
2021	2021	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	4/26/2021	NEW	$437,500
														Subtotal = $437,500

Grand Total All Awards = $2,174,375

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Neural Mechanisms Underlying Cataplexy Control by MCH Neurons

Award Number: R01NS119223

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: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 04/30/2027

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