Ethanol abuse produces marked changes in behavior and neurobiological function. Among the behavioral manifestations critical for continued abuse are the profound increases in anxiety-like and reward-seeking behaviors. These outcomes are intimately related and together drive subsequent ethanol abuse. The lateral/basolateral amygdala plays a critical role in the regulation of both anxiety and reward-seeking. Recent work with conditioned behaviors in drug nave animals suggests that segregated but intermingled populations basolateral amygdala principal neurons independently participate within `reward'- and `aversion'-related circuits. Importantly, this segregation is also reflected at the synaptic level with reward or aversion influencing glutamatergic synapses onto these populations in a circuit-specific and mutually exclusive manner. Yet, in spite of this functional segregation in the nave condition, reward-seeking and `aversion' are typically are co- expressed in drug-experienced animals. And, we have shown that dependence-like ethanol exposure robustly alters BLA synaptic function in what appears to be a non-segregated fashion. The juxtaposition of reward-/ affective-circuit control within the BLA, and the effects of chronic ethanol across neurons participating in these circuits, suggests possible cellular mechanisms driving coincidental reward-seeking and negative affect following alcohol dependence. This leads to the CENTRAL HYPOTHESIS of the current application that cooperative synaptic plasticity at distinct BLA inputs controls the interaction between reward-seeking and negative affective states that follow chronic ethanol exposure. To test this hypothesis, we propose three specific aims.
Aim 1 will test the working hypothesis that chronic ethanol, unlike naturally conditioned behaviors, facilitates BLA synaptic function at principal neurons independent of their projection target. We will integrate retrograde tracing and electrophysiological approaches to measure both synaptic function and intrinsic properties of differentially `valenced' BLA neurons participating within distinct `reward' and `aversion' circuits.
Aim 2 will test the working hypothesis that presynaptic facilitation by chronic ethanol is necessary and sufficient for the development of postsynaptic plasticity at distinct synapses. We this `ethanol-induced heterosynaptic cooperation' by integrating optogenetics, chemogentics, and in vitro electrophysiology to 1) assay functional coupling between defined inputs (prelimbic and agranular insular cortex) and 2) disrupt their functional interaction. Finally, for Aim 3, we will test the working hypothesis that ethanol dysregulation of BLA-PrL synapses governs both negative affect and reward seeking following chronic ethanol by integrating chemogenetics with dependence-related ethanol drinking and anxiety-like behavior. The proposed work is both technically innovative and significant because it utilizes state-of-the-art circuit-based approaches to directly define neurobiological mechanisms regulating both ethanol-dependent negative affect and reward- seeking which characterize alcohol abuse and addiction.

Public Health Relevance

The focus of this research project is to understand the impact of chronic ethanol exposure and withdrawal on neurophysiological processes that regulate emotions like anxiety and reward-seeking. Once the project is completed, we will better understand how chronic ethanol exposure and withdrawal alter the brain; and the research could provide specific neurophysiological targets for therapeutics development.

National Institute of Health (NIH)
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Research Project (R01)
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Neurotoxicology and Alcohol Study Section (NAL)
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Liu, Qi-Ying
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Wake Forest University Health Sciences
Schools of Medicine
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Morales, Melissa; McGinnis, Molly M; Robinson, Stacey L et al. (2018) Chronic Intermittent Ethanol Exposure Modulation of Glutamatergic Neurotransmission in Rat Lateral/Basolateral Amygdala is Duration-, Input-, and Sex-Dependent. Neuroscience 371:277-287
Alexander, Nancy J; Rau, Andrew R; Jimenez, Vanessa A et al. (2018) SNARE Complex-Associated Proteins in the Lateral Amygdala of Macaca mulatta Following Long-Term Ethanol Drinking. Alcohol Clin Exp Res 42:1661-1673
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Gioia, Dominic A; McCool, Brian (2017) Strain-Dependent Effects of Acute Alcohol on Synaptic Vesicle Recycling and Post-Tetanic Potentiation in Medial Glutamate Inputs to the Mouse Basolateral Amygdala. Alcohol Clin Exp Res 41:735-746
Robinson, Stacey L; Alexander, Nancy J; Bluett, Rebecca J et al. (2016) Acute and chronic ethanol exposure differentially regulate CB1 receptor function at glutamatergic synapses in the rat basolateral amygdala. Neuropharmacology 108:474-84
Luessen, Deborah J; Hinshaw, Tyler P; Sun, Haiguo et al. (2016) RGS2 modulates the activity and internalization of dopamine D2 receptors in neuroblastoma N2A cells. Neuropharmacology 110:297-307
Rose, Jamie H; Karkhanis, Anushree N; Chen, Rong et al. (2016) Supersensitive Kappa Opioid Receptors Promotes Ethanol Withdrawal-Related Behaviors and Reduce Dopamine Signaling in the Nucleus Accumbens. Int J Neuropsychopharmacol 19:
Gioia, Dominic A; Alexander, Nancy J; McCool, Brian A (2016) Differential Expression of Munc13-2 Produces Unique Synaptic Phenotypes in the Basolateral Amygdala of C57BL/6J and DBA/2J Mice. J Neurosci 36:10964-10977
Karkhanis, Anushree N; Alexander, Nancy J; McCool, Brian A et al. (2015) Chronic social isolation during adolescence augments catecholamine response to acute ethanol in the basolateral amygdala. Synapse 69:385-95
Morales, Melissa; McGinnis, Molly M; McCool, Brian A (2015) Chronic ethanol exposure increases voluntary home cage intake in adult male, but not female, Long-Evans rats. Pharmacol Biochem Behav 139:67-76

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