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Dissecting the Role of Nucleus Basalis Magnocellularis Circuitry in Basolateral Amygdala Physiology and Regulation of Anxiety Following Chronic Ethanol Exposure and Withdrawal

Award Number: F31AA028722
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: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 06/17/2022

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Dissecting the Role of Nucleus Basalis Magnocellularis Circuitry in Basolateral Amygdala Physiology and Regulation of Anxiety Following Chronic Ethanol Exposure and Withdrawal - PROJECT SUMMARY Anxiety during alcohol withdrawal contributes to high relapse rates and remains an obstacle for alcohol use disorder (AUD) treatment. The basolateral amygdala (BLA) is a brain region involved in the progression of alcohol dependence that facilitates reward-seeking and emotional behaviors like anxiety. Our laboratory has shown that input-specific alterations in glutamate/GABA neurotransmission occur following chronic ethanol/withdrawal. For example, stria terminalis (ST) glutamatergic afferents exhibit presynaptic facilitation during withdrawal. Lateral paracupsular cells (LPCs) and local interneurons of the BLA GABAergic system express different outcomes to chronic ethanol: LPCs show an attenuation of GABA release, while local interneurons show no significant change. Together, these alterations in GABAergic/glutamatergic afferents yield a hyperexcitable state in BLA pyramidal neurons during alcohol withdrawal. However, it remains unclear how ethanol alters the neurophysiology of upstream modulatory systems, or whether these projections influence the generation of anxiety-like behaviors. The BLA receives dense cholinergic projections from the nucleus basalis magnocellularis (NBM) to modulate neuronal excitability and neurotransmitt er release by acting on GABAergic interneurons, glutamatergic terminals, and BLA pyramidal neurons. These distinct neuronal compartments contain different combinations of nicotinic and muscarinic acetylcholine receptors (n/mAChRs) that collectively function to regulate the formation of aversive memories. The effects of chronic ethanol on NBM synaptic physiology and their roles in mediating withdrawal-induced anxiety-like behavior in the BLA is unknown. Our preliminary data leads to the central hypothesis that chronic ethanol dysregulates cholinergic modulation of BLA afferents and potentiates the neurophysiological symptoms of withdrawal. We will address this hypothesis through two Specific Aims. In Aim 1, we will primarily employ optogenetic and excitotoxic lesion studies to manipulate the activity of NBM terminals and measure GABA/glutamate neurophysiology with whole-cell patch clamp electrophysiology. We hypothesize that chronic ethanol/withdrawal upregulates NBM cholinergic input and enhances glutamatergic and GABAergic presynaptic plasticity. In Aim 2, we will use chemogenetics and lesion experiments to manipulate the cholinergic inputs and measure anxiety-like behavior using assays like the elevated zero maze, light/dark box, and open field test. We hypothesize that disruption of the cholinergic circuit will ameliorate the progression of anxiety-like behaviors. Understanding the NBM-BLA circuit might lead to potential novel targets for more effective treatments of alcohol withdrawal-induced anxiety in the clinical setting.


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: 2023 ( Subtotal = -$21,228 )
2023	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	2	5/15/2023	NON-COMPETING CONTINUATION	-$21,228
														Subtotal = -$21,228

Issue Date FY: 2022 ( Subtotal = $25,871 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	002	2	7/21/2022	NON-COMPETING CONTINUATION	-$20,881
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	2	5/24/2022	NON-COMPETING CONTINUATION	$716
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	2	2/3/2022	NON-COMPETING CONTINUATION	$46,036
														Subtotal = $25,871

Issue Date FY: 2021 ( Subtotal = $46,036 )
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	000	1	3/1/2021	NEW	$46,036
2021	2021	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Alcohol Research Programs	001	1	3/1/2021	NEW	$0
														Subtotal = $46,036

Grand Total All Awards = $50,679

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Dissecting the Role of Nucleus Basalis Magnocellularis Circuitry in Basolateral Amygdala Physiology and Regulation of Anxiety Following Chronic Ethanol Exposure and Withdrawal

Award Number: F31AA028722

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: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 06/17/2022

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