Interneurons tune the neural circuits mediating the anxiolytic effects of alcohol

中间神经元调节神经回路介导酒精的抗焦虑作用

• 批准号: 10456879
• 负责人: Jamie Lynn Maguire
• 金额: $ 37.02万
• 依托单位: TUFTS UNIVERSITY BOSTON
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10456879
• 关键词: Acute; Age; Alcohol consumption; Alcohols; Amygdaloid structure; Animals; Anti-Anxiety Agents; Anxiety; Automobile Driving; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Communication; Consumption; Coupling; Data; Disease; Dose; Economic Burden; Ethanol; Frequencies; Fright; Health; Heavy Drinking; Hippocampus (Brain); Individual; Injury; Interneurons; Measures; Medial; Mediating; Modeling; Monitor; Mus; Neural Pathways; Neurons; Parvalbumins; Persons; Phase; Play; Prefrontal Cortex; Reporting; Role; Safety; Testing; United States; Wild Type Mouse; alcohol effect; alcohol involvement; alcohol misuse; alcohol sensitivity; alcohol use disorder; anxiety-like behavior; cell type; density; drinking; health economics; neural circuit; optogenetics; patch clamp; prevent; preventable death; receptor

Project Summary Excessive alcohol consumption leads to alcohol use disorders in approximately 7% of individuals and is associated with numerous health conditions, substantial economic burden, and is the third leading cause of preventable deaths in the United States. Despite the fact that alcohol misuse is a serious health and economic concern worldwide, we still do not fully understand the basic mechanisms contributing to alcohol consumption. One primary factor thought to drive consumption is the anxiolytic effects of alcohol. However, the specific cell types and networks mediating the anxiolytic effects of alcohol are unknown. Recent studies have elucidated connections between the basolateral amygdala (BLA) and the medial prefrontal cortex (mPFC) in the network communication of anxiety. Oscillations within the BLA and mPFC and the coupling between these regions is thought to be driven by parvalbumin (PV) interneurons in the BLA. PV interneurons in the BLA express the GABAAR δ subunit at a high density, which is thought to be a target of action for alcohol. We hypothesize that alcohol acts preferentially on PV interneurons in the BLA, modulating local oscillations and frequency coupling between the BLA and mPFC, thereby mediating the anxiolytic effects. This proposal represents the first attempt to examine the cell type-specific effects of alcohol on the network communication of anxiety. The current application will explore the cell type-specific targets of alcohol in the BLA and determine whether the GABAAR δ subunit on PV interneurons plays a role in mediating the anxiolytic effects of low dose alcohol (Specific Aim 1). This application will determine whether the anxiolytic effects of alcohol involve modulation of the local oscillations in the BLA and mPFC as well as the frequency coupling between the mPFC and BLA (Specific Aim 2). Further, we will determine whether driving the network communication of safety recapitulates the anxiolytic effects of alcohol and whether disruption of the pro-safety communication reduces the anxiolytic effects of alcohol (Specific Aim 3). This proposal will define specific cell types and associated neural pathways that are most sensitive to alcohol and how these circuits orchestrate sensitivity to alcohol. This application will determine whether the anxiolytic effects of alcohol are mediated by GABAAR δ subunit containing receptors on PV interneurons in the BLA through the coordination of activity between the mPFC and BLA.

项目概要 过量饮酒会导致大约 7% 的人出现酒精使用障碍，并且 与许多健康状况、沉重的经济负担有关，是导致健康问题的第三大原因。 尽管酗酒对健康和经济造成严重影响，但在美国仍有可预防的死亡。 尽管全世界都在关注，但我们仍然不完全了解导致饮酒的基本机制。 人们认为推动消费的一个主要因素是酒精的抗焦虑作用，然而，特定的细胞。 最近的研究已经阐明了调节酒精抗焦虑作用的类型和网络。 网络中基底外侧杏仁核（BLA）和内侧前额皮质（mPFC）之间的连接 BLA 和 mPFC 内的振荡以及这些区域之间的耦合是焦虑的交流。 被认为是由 BLA 中的小清蛋白 (PV) 中间神经元驱动 BLA 中的 PV 中间神经元表达了 高密度的 GABAAR δ 亚基被认为是酒精的作用目标。 酒精优先作用于 BLA 中的 PV 中间神经元，调节局部振荡和频率耦合 BLA 和 mPFC 之间的相互作用，从而调节抗焦虑作用。该提案代表了第一个提案。 尝试检查酒精对焦虑网络交流的细胞类型特异性影响。 目前的应用将探索 BLA 中酒精的细胞类型特异性目标，并确定是否 PV 中间神经元上的 GABAAR δ 亚基在介导低剂量酒精的抗焦虑作用中发挥作用 （具体目标 1）。该应用将确定酒精的抗焦虑作用是否涉及调节。 BLA 和 mPFC 中的本地振荡以及 mPFC 和 BLA 之间的频率耦合 （具体目标2）进一步，我们将确定驱动网络通信是否安全概括。 酒精的抗焦虑作用以及破坏支持安全的沟通是否会降低抗焦虑作用 酒精的影响（具体目标 3）。该提案将定义特定的细胞类型和相关的神经通路。 对酒精最敏感的电路以及这些电路如何协调对酒精的敏感性。 确定酒精的抗焦虑作用是否由含有 GABAAR δ 亚基的受体介导 BLA 中的 PV 中间神经元通过 mPFC 和 BLA 之间的活动协调。