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Role of afferents to the rostromedial tegmental nucleus in symptoms of withdrawal from chronic ethanol exposure

Award Number: F31AA031178
ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/16/2023
PERIOD OF PERFORMANCE END DATE: 06/15/2025

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Role of afferents to the rostromedial tegmental nucleus in symptoms of withdrawal from chronic ethanol exposure - ABSTRACT A significant number of individuals with alcohol use disorder struggle to maintain sobriety as a result of withdrawal symptoms that emerge during early abstinence. Despite this, the neural mechanisms underlying symptoms of withdrawal are not well understood. The rostromedial tegmental nucleus (RMTg) is a GABAergic region that plays a critical role in avoidance behavior, aversive signaling, pain, and importantly, alcohol-related behaviors. Recent work from our lab provides evidence of RMTg hyperactivity during acute withdrawal from chronic intermittent ethanol (CIE) exposure. In addition, we showed that pharmacological inhibition of the RMTg attenuates withdrawal-induced anxiety-like behavior. The afferents that drive RMTg-mediated withdrawal symptoms are currently unknown. However, previously published studies have implicated the lateral habenula (LHb) – a region that provides dense input to the RMTg – in withdrawal-induced negative affect similar to our work in the RMTg. In addition, our preliminary data revealed significant cFos induction in RMTg-projecting LHb neurons during acute withdrawal in CIE-exposed rats compared to AIR controls. Interestingly, the LHb is heavily enriched in mu-opioid receptors (MORs), which are known to regulate both pain and affect. Oprm1, the gene that encodes MOR, is hypermethylated in individuals with AUD suggestive of a potential mechanism by which chronic ethanol exposure drives decreases in Oprm1 expression. However, the effect of withdrawal on MORs in the LHb is unclear. Together, these data lead us to hypothesize that LHb afferents to the RMTg are mechanistically involved in withdrawal from chronic ethanol and that epigenetic dysregulation of the Oprm1 gene may contribute to this mechanism. Three specific aims will be used to test this hypothesis. In Aim 1, in vivo chemogenetics will be used to determine whether selective inhibition of RMTg-projecting LHb neurons reverses symptoms of withdrawal. Oprm1 expression and methylation levels will be assessed in RMTg-projecting LHb neurons in Aim 2 using fluorescent in situ hybridization and MethylMiner. Tract tracing will be combined with ex vivo whole-cell patch-clamp slice electrophysiology in Aim 3 to investigate withdrawal-induced changes in epigenetic regulation of MOR receptor-mediated firing in RMTg-projecting LHb neurons. These studies will provide the applicant with new training in cutting-edge neuroscience techniques while also providing new insight into the role of the LHb-RMTg circuit in ethanol withdrawal.


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: 2024 ( Subtotal = $45,972 )
2024	2024	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Alcohol Research Programs	000	2	5/10/2024	NON-COMPETING CONTINUATION	$45,972
														Subtotal = $45,972

Issue Date FY: 2023 ( Subtotal = $44,692 )
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Alcohol Research Programs	000	1	5/12/2023	NEW	$44,692
2023	2023	UNIVERSITY OF ILLINOIS	809 S MARSHFIELD AVE M/C 551	CHICAGO	IL	60612	COOK	USA	Alcohol Research Programs	001	1	5/12/2023	NEW	$0
														Subtotal = $44,692

Grand Total All Awards = $90,664

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Role of afferents to the rostromedial tegmental nucleus in symptoms of withdrawal from chronic ethanol exposure

Award Number: F31AA031178

ORGANIZATION: NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/16/2023

PERIOD OF PERFORMANCE END DATE: 06/15/2025

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