Interneurons tune the neural circuits mediating the anxiolytic effects of alcohol

项目摘要 在大约7%的人中，过度饮酒会导致酒精使用障碍 与许多健康状况、巨大的经济负担有关，是导致 在美国，可预防的死亡。尽管酗酒是一种严重的健康和经济问题 尽管全世界都在关注这一问题，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 调节酒精抗焦虑作用的类型和网络尚不清楚。最近的研究阐明了 杏仁基底外侧核(BLA)和内侧前额叶皮质(MPFC)在网络中的联系 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中的小白蛋白(PV)中间神经元驱动的。BLA中的PV中间神经元表达 高密度的伽巴δ亚基，被认为是酒精的作用靶标。我们假设 酒精优先作用于BLA中的PV中间神经元，调制局部振荡和频率耦合 BLA和mPFC之间的相互作用，从而介导抗焦虑作用。这项提议是第一个 试图考察酒精对焦虑的网络交流的特定细胞类型的影响。这个 目前的应用将探索BLA中酒精的细胞类型特定靶点，并确定是否 PV中间神经元GABA受体δ亚基在小剂量酒精抗焦虑中的作用 (具体目标1)。这项应用将确定酒精的抗焦虑作用是否涉及调节 BLA和mPFC中的局域振荡以及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的安全是否概括 酒精的抗焦虑作用以及支持安全的沟通中断是否减少了抗焦虑 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 它们对酒精最敏感，以及这些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由GABA受体δ亚基介导 通过mPFC和BLA之间的活动协调，在BLA内存在PV中间神经元。

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.