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.

项目摘要 过量饮酒导致约7%的人出现酒精使用障碍， 与许多健康状况有关，经济负担沉重，是第三大原因。 在美国可预防的死亡尽管酒精滥用是一个严重的健康和经济问题， 尽管酒精消费是全世界最令人关切的问题，但我们仍然不完全了解促成酒精消费的基本机制。 酒精的抗焦虑作用被认为是推动消费的一个主要因素。然而，特定的细胞 调节酒精抗焦虑作用的类型和网络尚不清楚。最近的研究表明， 基底外侧杏仁核（BLA）和内侧前额叶皮质（mPFC）之间的联系 焦虑的沟通。BLA和mPFC内的振荡以及这些区域之间的耦合是 被认为是由BLA中的小清蛋白（PV）中间神经元驱动的。BLA中的PV中间神经元表达 GABAAR δ亚基以高密度存在，这被认为是酒精的作用靶点。我们假设 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 在BLA和mPFC之间，从而介导抗焦虑作用。这一提议是第一次 试图研究酒精对焦虑网络通信的细胞类型特异性影响。的 本申请将探索BLA中酒精的细胞类型特异性靶点，并确定BLA中酒精的细胞类型特异性靶点是否与BLA中的细胞类型特异性靶点相关。 PV中间神经元GABAAR δ亚单位在低剂量酒精抗焦虑作用中的作用 （具体目标1）。本申请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）。此外，我们将确定是否驱动安全的网络通信重演 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）。这项提案将定义特定的细胞类型和相关的神经通路 以及这些神经回路如何协调对酒精的敏感性。此应用程序将 确定酒精的抗焦虑作用是否是由GABAAR δ亚单位介导的， 通过mPFC和BLA之间的活动协调，BLA中的PV中间神经元。