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Alcohol-induced neuromodulation of sleep-wake circuits: Insights from Drosophila

Award Number: R16AA033393
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2030

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Alcohol-induced neuromodulation of sleep-wake circuits: Insights from Drosophila - Project Summary/Abstract Accumulating evidence in both humans and animal models suggests that alcohol use contributes to a wide range of sleep disturbances, many of which have severe repercussions on health. In recovering alcoholics, this is especially problematic as these changes can last for prolonged periods of time, even after years of abstinence. Moreover, the sustained effects on sleep processes can lead to relapse, as many individuals mistakenly turn to alcohol to induce sleep. Sustained sleep problems have thus become a significant obstacle in the recovery from alcohol use disorder. Unfortunately, the underlying mechanisms of the alcohol-sleep interactions remain unclear. This proposal leverages the use of Drosophila melanogaster as a biological model to elucidate the molecular underpinnings of alcohol's effects on the neuronal substrates that regulate sleep. In Drosophila, acute alcohol exposure causes disturbances in sleep patterns that resemble those described in mammals. Because both alcohol dependence and sleep modulation are under homeostatic regulation, these processes may share common mechanisms. The central hypothesis of this proposal is that alcohol influences sleep by modulating the release of the neuropeptide PDF from the ventrolateral neuron (LNv), a specific neural circuit known to control sleep/wake cycles in Drosophila. We propose that two distinct subsets of neurons within these circuits control circadian timing and arousal state independently through synaptic and paracrine neuropeptide release, respectively. The overall goal of this application is to investigate the role of these neuronal subsets in alcohol-induced behaviors and identify the mechanisms by which these neural substrates are involved. To achieve this goal, the proposal will (1) define the contributions of the small and large ventrolateral neurons (LNv) to alcohol tolerance and sleep phenotypes distinguishing between somatic and synaptic release, (2) determine how alcohol alters the morphology and compartment-specific release of neuropeptide from LNv neurons using structural assays and live imaging reporters of dense-core vesicle fusion, and (3) identify the downstream neuronal targets that express the PDF receptor that are required for alcohol tolerance and sleep regulation. Together, these aims will help elucidate the effect of alcohol exposure on processes critical for sleep regulation and shed new light on how individual neural circuits respond to alcohol. The integrated approach across aims will produce a cohesive mechanistic model in which somatic and synaptic PDF release from distinct LNv populations differentially regulates alcohol tolerance, sleep disruption, and circadian function through specific PDFR-positive targets. The expected outcomes will also establish technical frameworks applicable to other systems and offer translational insights into mammalian VIP/VPAC pathways that parallel PDF/PDFR. Ultimately, this research will generate mechanistic principles linking circadian and locomotor circuits to alcohol neuroadaptations, with implications for developing strategies to stabilize sleep and reduce relapse risk in AUD.


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 = $145,254 )
2026	2026	UNIVERSITY OF PUERTO RICO	39 PONCE DE LEON AVE	SAN JUAN	PR	00931	SAN JUAN	USA	Alcohol Research Programs	000	1	9/11/2026	NEW	$145,254
														Subtotal = $145,254

Grand Total All Awards = $145,254

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Alcohol-induced neuromodulation of sleep-wake circuits: Insights from Drosophila

Award Number: R16AA033393

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2030

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