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Lateral hypothalamic neurotensin neurons in the pathophysiology of narcolepsy

Award Number: R21NS146763
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: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Lateral hypothalamic neurotensin neurons in the pathophysiology of narcolepsy - Project Summary Understanding the neural mechanisms underlying narcolepsy with cataplexy (NT1) 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 (OX) is the fundamental cause of NT1 in humans and animals. However, the role of neurotensin (Nts)-expressing neurons in the lateral hypothalamus (LH), which are reciprocally connected with OX neurons and play an analogous role in sleep-wake regulation, in the NT1 pathophysiology remains unexplored. Based on our prior data on NtsLH neurons in sleep-wake and muscle tone control (Naganuma et al., 2019, 2025), I hypothesized that enhancing NtsLH neuron activity mitigates sleepiness and cataplexy that occurs with the loss of OX signaling. We will test this hypothesis in the proposed experiments and determine the specific contribution of NtsLH signaling in NT1 pathophysiology. To examine if the activity pattern of NtsLH neurons is altered by loss of OX signaling and to assess its causal association with NT1 symptoms, in Aim1, we will examine the activity dynamics of NtsLH neurons (both at cellular resolution and population level) across spontaneous sleep-wake cycles, with acute sleep-deprivation (to induce sleepiness), and in the presence of positive emotional stimuli that enhance cataplexy in normal mice and in a mouse model of narcolepsy (OXKO mice). To determine the causal role of NtsLH neurons in attenuating cataplexy and sleepiness, in Aim 2, we will selectively activate or inhibit the NtsLH neurons in OXKO mice using both optogenetic and chemogenetic methods and study the impact on sleep-wake behavior and cataplexy. These experiments will identify a novel population of LH neurons involved in alleviating the primary symptoms of NT1, thereby, revealing novel pharmacological targets for the management and/or treatment of this disorder.


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 = $475,475 )
2026	2026	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	9/1/2026	NEW	$475,475
														Subtotal = $475,475

Grand Total All Awards = $475,475

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Lateral hypothalamic neurotensin neurons in the pathophysiology of narcolepsy

Award Number: R21NS146763

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: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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