Defining the cell-type specific control of alcohol drinking

定义饮酒的细胞类型特异性控制

• 批准号: 10679197
• 负责人: Hye Jean Yoon
• 金额: $ 4.77万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10679197
• 关键词: Abstinence; Address; Affect; Affective; Air; Alcohol abuse; Alcohol consumption; Alcohol withdrawal syndrome; Alcohols; Amygdaloid structure; Animals; Aversive Stimulus; Behavior; Brain; Brain region; Cells; Chronic; Consumption; Cues; Data; Dopamine D2 Receptor; Environment; Ethanol; Exposure to; Fiber; Genetic; Goals; Individual; Individual Differences; Inhalation; Learning; Link; Measures; Mediating; Modeling; Motivation; Mus; Negative Reinforcements; Neurons; Nucleus Accumbens; Operant Conditioning; Optics; Pattern; Pharmaceutical Preparations; Phase; Phenotype; Photometry; Play; Population; Positioning Attribute; Process; Recording of previous events; Research; Rewards; Role; Self Administration; Signal Transduction; Stimulus; Testing; Thinking; Time; Training; Withdrawal; alcohol behavior; alcohol exposure; alcohol intervention; alcohol response; alcohol seeking behavior; alcohol use disorder; behavioral response; cell type; drinking; drinking behavior; efficacious treatment; experimental study; in vivo; individual variation; negative affect; neural circuit; neuronal circuitry; optogenetics; receptor expression; recruit; response; reward processing; tool; vapor

PROJECT SUMMARY/ABSTRACT Alcohol use disorder (AUD) is characterized by problematic alcohol consumption that evolves over an individual’s drinking history. While initial alcohol use is thought to be driven by its positive reinforcing effects, following long-term drinking, negative affective states emerge during withdrawal. These states are associated with increases in alcohol seeking, tolerance, and levels of consumption that follow repeated bouts of abstinence. This has led to the hypothesis that negative reinforcement becomes the primary motivational drive – where individuals consume alcohol to alleviate these negative states. However, the circuit-based mechanisms that control this switch to negative reinforcement are unclear. The goal of this proposal is to outline how alcohol-associated cues recruit circuits that control negative reinforcement before and after chronic alcohol exposure. Our preliminary data show that D2 medium spiny neurons (MSNs) are a critical a negative reinforcement circuit and control the motivational drive to avoid aversive stimuli in an environment. This proposal will test the hypothesis, that alcohol-associated cues recruit D2 MSNs activation in vivo and drive drinking after chronic exposure to alcohol. By combining optical approaches to record from and bidirectionally modulate D2 MSNs in the NAc during alcohol drinking I will define exactly when and how their activity is recruited over a history of drinking and how it controls drinking behavior. In Aim 1& 2, I will optically inhibit or activate D2 MSN activity at the time of an alcohol-predictive cue to determine how this controls operant drinking before and after chronic intermittent ethanol (CIE) exposure. In Aim 3, I will determine if the dynamics of D2 MSNs during operant alcohol drinking are predictive of specific drinking patterns by combining fiber photometry with operant behavior and doing deep-phenotyping analysis. I hypothesize that D2 MSNs – which function as a negative reinforcement signal – are recruited by alcohol associated cues only after a history of CIE exposure, when alcohol use is driven by negative reinforcement. Taken together, the experiments in this proposal will determine the negative reinforcement circuits that are recruited in the later phases of alcohol drinking and whether the dynamics of these neuronal circuits could be predictive of alcohol drinking phenotypes. This proposal encompasses technical and theoretical training that will provide the foundational expertise and conceptual thinking needed to address larger questions regarding how long-term exposure of alcohol changes the brain and drives continued alcohol use. Additionally, these findings can ultimately inform our understanding of underlying reward and learning process and lead to more efficacious treatment interventions for AUD.

项目总结/摘要 酒精使用障碍（AUD）的特征是有问题的酒精消费， 个人的饮酒史虽然最初的酒精使用被认为是由其积极的强化作用驱动的， 长期饮酒后，在戒断过程中会出现消极的情感状态。这些国家与 随着酒精寻求、耐受性和消费水平的增加， 禁欲这导致了负强化成为主要动机的假设 驱力--个体通过饮酒来缓解这些消极状态。然而，基于电路的 控制这种向负强化转变的机制尚不清楚。本提案的目的是 概述酒精相关的线索如何招募控制负强化的电路之前和之后的慢性 酒精暴露我们的初步数据表明，D2中型多刺神经元（MSN）是一个关键的阴性 强化电路和控制动机驱动器，以避免在环境中的厌恶刺激。这 该提案将测试这一假设，即酒精相关的线索在体内招募D2 MSN激活并驱动D2 MSN。 在长期接触酒精后饮酒。通过结合光学方法从和双向记录 在饮酒期间调节NAc中的D2 MSN，我将确切地定义何时以及如何调节它们的活性。 以及它如何控制饮酒行为。在目标1和2中，我将光学抑制或 激活D2 MSN活动时，酒精预测线索，以确定这是如何控制操作性 在慢性间歇性乙醇暴露（CIE）之前和之后饮酒。在目标3中，我将确定 的D2 MSNs在操作性饮酒期间通过结合纤维 光度法与操作行为和做深表型分析。我假设D2 MSN- 作为一个负强化信号-被招募的酒精相关的线索，只有在历史后， CIE曝光，当酒精使用是由负强化驱动。 总之，本提案中的实验将确定负强化回路， 在饮酒的后期阶段被招募，以及这些神经元回路的动力学是否可以 可以预测饮酒的表型。这项建议包括技术和理论培训， 将提供解决以下更大问题所需的基础专业知识和概念思维 长期接触酒精如何改变大脑并驱使持续饮酒。此外，这些 这些发现最终可以帮助我们理解潜在的奖励和学习过程，并导致更多的 有效的AUD治疗干预。