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

剖析大细胞基底核回路在基底外侧杏仁核生理学中的作用以及慢性乙醇暴露和戒断后焦虑的调节

• 批准号: 10454798
• 负责人: Sarah Elizabeth Sizer
• 金额: $ 2.59万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2022-06-17
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454798
• 关键词: Abstinence; Acute; Address; Affect; Affective; Alcohol abuse; Alcohol dependence; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Anatomy; Anti-Anxiety Agents; Anxiety; Attenuated; Behavior; Behavioral; Biological Assay; Brain region; Cell Nucleus; Cells; Characteristics; Chronic; Clinical; Cognitive; Data; Depressed mood; Electrophysiology (science); Emotional; Equilibrium; Ethanol; Excitotoxic lesion; Exhibits; Fellowship; Fright; Functional Magnetic Resonance Imaging; Generations; Glutamates; Goals; Heavy Drinking; Human; Interneurons; Laboratories; Lateral; Lead; Learning; Lesion; Literature; Measures; Mediating; Memory; Methods; Modeling; Molecular; Muscarinic Acetylcholine Receptor; National Research Service Awards; Neurons; Nucleus Basalis Magnocellularis; Outcome; Patients; Persons; Physiology; Population; Process; Psychological reinforcement; Publishing; Regulation; Relapse; Research; Rewards; Rodent; Role; Sensory; Symptoms; Synapses; Synaptic plasticity; System; Technical Expertise; Technology; Testing; Therapeutic; United States; Up-Regulation; Withdrawal; Withdrawal Symptom; alcohol exposure; alcohol use disorder; anxiety-like behavior; attenuation; career; cholinergic; conditioned fear; depressive symptoms; effective therapy; emotional behavior; experience; experimental study; field study; gamma-Aminobutyric Acid; hippocampal pyramidal neuron; innovation; neuroadaptation; neuronal excitability; neurophysiology; neuroregulation; neurotransmission; neurotransmitter release; novel; optogenetics; patch clamp; pre-clinical; presynaptic; psychologic; stria terminalis; transmission process; vapor; withdrawal-induced anxiety

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.

项目摘要 戒酒期间的焦虑会导致高复发率，并且仍然是饮酒的障碍 障碍（AUD）治疗。基底外侧杏仁核（BLA）是参与参与的大脑区域 酒精依赖有助于寻求奖励和情感行为，例如焦虑。我们的实验室有 表明在慢性后发生谷氨酸/GABA神经传递的特异性变化 乙醇/退出。例如，Stria terminalis（ST）谷氨酸能传入表现出突触前的促进作用 在退出期间。 Bla Gabaergic系统的外侧副偏细胞（LPC）和局部神经元 对慢性乙醇表达不同的结果：LPC显示出GABA释放的衰减，而本地 中间神经元没有显着变化。加在一起的GABA能/谷氨酸能传入中的这些变化 在戒酒期间，在BLA锥体神经元中产生过度可见的状态。但是，还不清楚 乙醇如何改变上游调节系统的神经生理学，或者这些预测是否是 影响类似焦虑的行为的产生。 BLA从 底核核细胞（NBM）调节神经元兴奋性和神经释放性通过 作用于GABA能中间神经元，谷氨酸能末端和BLA锥体神经元。这些与众不同 神经元室包含烟碱和毒蕈碱乙酰胆碱受体的不同组合 （N/MACHR）共同起作用以调节厌恶记忆的形成。慢性的影响 NBM突触生理学的乙醇及其在介导戒断引起的焦虑行为中的作用 BLA是未知的。我们的初步数据导致了一个中心假设，即慢性乙醇失调 BLA传入的胆碱能调节并增强戒断的神经生理症状。我们 将通过两个具体目标解决这一假设。在AIM 1中，我们将主要采用光遗传学和 兴奋性病变研究以操纵NBM末端的活性并测量GABA/谷氨酸 神经生理学，全细胞贴片夹电生理学。我们假设那个慢性 乙醇/戒断会上调NBM胆碱能输入并增强谷氨酸能和GABA能 突触前可塑性。在AIM 2中，我们将使用化学遗传学和病变实验来操纵 胆碱能输入和使用高架迷宫，浅色/深色盒子等测定法测量焦虑般的行为 和开放式测试。我们假设胆碱能回路的破坏将改善 焦虑般的行为。了解NBM-BLA电路可能会导致潜在的新目标 在临床环境中，有效治疗酒精戒断引起的焦虑。