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.

项目概要 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) 是参与疾病进展的大脑区域 酒精依赖会促进寻求奖励和焦虑等情绪行为。我们实验室有 表明谷氨酸/GABA 神经传递的输入特异性改变发生在慢性 乙醇/戒断。例如，终纹 (ST) 谷氨酸传入神经表现出突触前促进作用 提款期间。 BLA GABA 能系统的外侧杯状细胞 (LPC) 和局部中间神经元 对慢性乙醇表现出不同的结果：LPC 显示 GABA 释放减弱，而局部 中间神经元没有表现出明显的变化。总之，GABA 能/谷氨酸传入的这些改变 在酒精戒断过程中，BLA 锥体神经元会产生过度兴奋状态。但目前尚不清楚 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 影响焦虑样行为的产生。 BLA 接收来自 大细胞基底核（NBM）通过调节神经元兴奋性和神经递质释放 作用于 GABA 能中间神经元、谷氨酸能末端和 BLA 锥体神经元。这些截然不同的 神经元区室包含烟碱和毒蕈碱乙酰胆碱受体的不同组合 (n/mAChR) 共同发挥调节厌恶记忆形成的作用。慢性病的影响 乙醇对 NBM 突触生理学的影响及其在介导戒断诱导的焦虑样行为中的作用 BLA 未知。我们的初步数据得出了一个中心假设：慢性乙醇失调 BLA 传入神经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来解决这一假设。在目标 1 中，我们将主要采用光遗传学和 兴奋性毒性损伤研究，以操纵 NBM 末端的活性并测量 GABA/谷氨酸 神经生理学与全细胞膜片钳电生理学。我们假设慢性 乙醇/戒断上调 NBM 胆碱能输入并增强谷氨酸能和 GABA 能 突触前可塑性。在目标 2 中，我们将使用化学遗传学和损伤实验来操纵 胆碱能输入并使用高架零迷宫、明/暗盒等测定法测量焦虑样行为， 和旷场测试。我们假设胆碱能回路的破坏将改善疾病的进展 类似焦虑的行为。了解 NBM-BLA 电路可能会带来更多潜在的新目标 在临床环境中有效治疗酒精戒断引起的焦虑。