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Role of RMTg afferents in mechanisms of withdrawal from chronic ethanol exposure

Award Number: R01AA031003
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: 08/15/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Role of RMTg afferents in mechanisms of withdrawal from chronic ethanol exposure - PROJECT SUMMARY A significant number of individuals struggle to maintain sobriety as a result of withdrawal symptoms that emerge during early abstinence from alcohol. Despite this, pharmacotherapeutics for the treatment of withdrawal are lacking, at least in part, due to poor understanding of the mechanisms underlying symptoms of withdrawal. The rostromedial tegmental nucleus (RMTg) is a GABAergic region that exerts inhibitory control over midbrain bioaminergic and cholinergic nuclei. Recently, work from our lab revealed significantly enhanced cFos expression, a marker of recent neuronal activity, in the RMTg of chronic intermittent ethanol (CIE) exposed rats 12 hours into acute withdrawal. In addition, we showed that pharmacological inhibition of the RMTg attenuates withdrawal-induced anxiety-like behavior. However, the precise neural circuits that drive this putative RMTg hyperactivity is unknown. The lateral habenula (LHb) provides dense glutamatergic input to the RMTg and exhibits significant functional overlap with the RMTg. In addition, our preliminary data reveals a significant increase in cFos expression in RMTg-projecting lateral habenula (LHb) neurons during acute withdrawal. Together, these data lead us to hypothesize that LHb inputs to the RMTg play a mechanistic role in regulating symptoms of withdrawal from chronic ethanol exposure. Experiments in the current proposal are designed to test this hypothesis by using in vivo chemogenetics to bidirectionally and selectively manipulate LHb-RMTg activity during behavioral tests of withdrawal symptoms including anxiety-like behavior, mechanical pain sensitivity, and impulsive choice. Additional work will use ex vivo slice electrophysiology to explore the physiological neuroadaptations that occur in this circuitry during withdrawal from chronic ethanol exposure. Findings from these experiments will shed new light onto the role of this neural circuit in regulating symptoms of withdrawal and by extension have the potential to uncover new neurobiological targets for the treatment of alcohol use 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: 2025 ( Subtotal = $432,262 )
2025	2025	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Alcohol Research Programs	000	3	5/16/2025	NON-COMPETING CONTINUATION	$432,262
														Subtotal = $432,262

Issue Date FY: 2024 ( Subtotal = $432,262 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Alcohol Research Programs	000	2	5/9/2024	NON-COMPETING CONTINUATION	$432,262
														Subtotal = $432,262

Issue Date FY: 2023 ( Subtotal = $448,347 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Alcohol Research Programs	000	1	8/15/2023	NEW	$448,347
														Subtotal = $448,347

Grand Total All Awards = $1,312,871

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Role of RMTg afferents in mechanisms of withdrawal from chronic ethanol exposure

Award Number: R01AA031003

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: 08/15/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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