Defining the cell-type specific control of alcohol drinking

定义饮酒的细胞类型特异性控制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要酒精使用障碍 (AUD) 的特点是有问题的饮酒，这种情况会随着时间的推移而演变。虽然最初的饮酒被认为是由其积极的强化作用驱动的，长期饮酒后，戒断期间会出现负面情绪状态。随着反复发作后对酒精的渴求、耐受性和消费水平的增加这导致了负强化成为主要动机的假设。驾驶——人们通过饮酒来缓解这些负面状态。然而，这是基于回路的。控制这种向负强化转变的机制尚不清楚。该提案的目标是：概述与酒精相关的线索如何招募控制慢性酒精前后负强化的回路我们的初步数据表明，D2 中型多棘神经元 (MSN) 是一个关键的负面因素。强化回路并控制动机驱动以避免环境中的厌恶刺激。该提案将检验以下假设：酒精相关线索会在体内招募 D2 MSN 激活并驱动通过结合光学方法进行双向记录。饮酒期间调节 NAc 中的 D2 MSN 我将准确定义其活动的时间和方式在目标 1 和 2 中，我将通过视觉方式抑制或控制饮酒行为。在出现酒精预测提示时激活 D2 MSN 活动，以确定其如何控制操作在慢性间歇性乙醇 (CIE) 暴露之前和之后饮酒在目标 3 中，我将确定是否存在动态变化。操作性饮酒期间的 D2 MSN 通过结合纤维来预测特定的饮酒模式我领导了 D2 MSN 的光度测定和操作行为分析。作为负强化信号——只有在经历了酒精相关的历史之后才会被招募 CIE 暴露，当饮酒是由负强化驱动时。总而言之，本提案中的实验将确定负强化电路在饮酒的后期阶段被招募，这些神经回路的动态是否可以预测饮酒表型该提案包括技术和理论培训：将提供解决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导致持续饮酒。研究结果最终可以帮助我们理解潜在的奖励和学习过程，并带来更多 AUD 的有效治疗干预措施。