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CHRONIC ETHANOL EXPOSURE POTENTIATES NUCLEUS BASALIS CHOLINERGIC PROJECTIONS AND PROMOTES NICOTINIC ACETYLCHOLINE RECEPTOR-DEPENDENT NEUROMODULATION IN THE BASOLATERAL AMYGDALA

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title
CHRONIC ETHANOL EXPOSURE POTENTIATES NUCLEUS BASALIS CHOLINERGIC PROJECTIONS AND PROMOTES NICOTINIC ACETYLCHOLINE RECEPTOR-DEPENDENT NEUROMODULATION IN THE BASOLATERAL AMYGDALA
author
Sizer, Sarah Elizabeth
abstract
Alcohol use disorder (AUD) is a chronic brain disease characterized by uncontrollable drinking despite adverse consequences. Heavy alcohol use causes neuroadaptations in the brain that promote the cycles of drinking, abstinence, and relapse that are associated with AUD. The onset of acute and protracted withdrawal (WD) symptoms during abstinence promote maladaptive behaviors and significantly increases the likelihood of relapse. One brain region that regulates emotional behaviors and is involved in the pathophysiology of AUD is the basolateral amygdala (BLA). The BLA functions as a central hub that coordinates appetitive and aversive behavioral responses to environmental cues. Our laboratory has shown that chronic intermittent ethanol (CIE) exposure, a paradigm that produces neurophysiological and behavioral changes that closely model AUD symptomology, causes input-specific alterations in GABAergic and glutamatergic signaling in the BLA and increases anxiety-like behavior during withdrawal. Although the impact of CIE exposure and withdrawal on GABAergic and glutamatergic neurotransmission is well-understood, it remains unclear whether alterations in nucleus basalis magnocellularis (NBM) cholinergic signaling mediate these effects. Therefore, the overall goal of this project is to understand whether acetylcholine shifts the excitatory and inhibitory balance in the BLA during ethanol withdrawal. Therefore, this project uses ex vivo whole-cell patch clamp electrophysiology to understand whether CIE exposure and withdrawal upregulate cholinergic signaling in the BLA and mediate alterations at distinct GABAergic and glutamatergic circuits. Since nicotinic acetylcholine receptors (nAChRs) in the BLA serve as critical regulators of anxiety- and depressive-like behaviors, in Chapter 2, we measured nAChR-dependent alterations in GABA and glutamate release during ethanol withdrawal. We report that CIE exposure and withdrawal robustly increase the acetylcholine concentration in the BLA and cause tonic activation of presynaptic nAChRs at stria terminalis glutamatergic and local GABAergic synapses onto BLA pyramidal neurons. Notably, these findings illustrate that nAChR-dependent modulation of neurotransmitter release can serve as a proxy for circuit-level dysregulation of NBM-BLA cholinergic projections during ethanol withdrawal. Therefore, Chapter 3 used optogenetics and electrophysiology to show that CIE exposure and withdrawal increase NBM cholinergic neuron excitability and acetylcholine release in the BLA. Our results provide a novel characterization of the NBM-BLA circuit and illustrate that CIE-dependent modifications to NBM afferents may promote enhancements in BLA pyramidal neuron activity during ethanol withdrawal. These findings provide the foundation for future investigations to study the effects of CIE exposure and withdrawal on cholinergic signaling in the BLA.
subject
acetylcholine
basolateral amygdala
chronic intermittent ethanol exposure
nucleus basalis magnocellularis
contributor
McCool, Brian A. (committee chair)
Martin, Thomas J. (committee member)
Chen, Rong (committee member)
Czoty, Paul W. (committee member)
Ferris, Mark J. (committee member)
date
2022-09-17T08:35:37Z (accessioned)
2023-09-16T08:30:06Z (available)
2022 (issued)
degree
Physiology and Pharmacology (discipline)
embargo
2023-09-16 (terms)
identifier
http://hdl.handle.net/10339/101246 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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