Neuropeptide Y: Role in Ethanol Intake and Sensitivity

项目摘要 酒精（乙醇）依赖和戒酒者的复发是整个世界的主要健康问题。 目前正在研究调节这些疾病的世界和神经化学途径。然而，在这方面， 酗酒是一种危险的行为模式，这种行为模式会导致 依赖性，受到的关注要少得多。因此，识别神经回路是至关重要的。 在大脑中调节酗酒，因为这样的知识将提供洞察的初始阶段， 酒精使用障碍（AUDs）。在这项资助的最后一个资助期，我们发现， 杏仁核的延伸通过与神经肽Y重叠的机制来调节酗酒 与依赖性摄入有关的机制。本申请的目标是扩展我们的发明。 了解神经肽Y的神经回路，调节酗酒样乙醇饮用与一个新的重点是神经肽Y 起源于内侧前额叶皮层（mPFC）的神经回路。mPFC提供自上而下的监管， 延伸的杏仁核，部分是通过一个神经元能mPFC-基底外侧杏仁核（BLA）回路， 由Y1受体（Y1 R）信号调节。从拟议的研究中获得的知识将大大扩展 我们对神经肽Y神经回路的理解，神经肽Y神经回路通过连接在一起来调节酒精摄入量， 皮层和杏仁核的延伸回路mPFC整合来自边缘和皮层区域的信息 并参与调节目标导向（通过边缘前（PL）回路）和习惯性（通过边缘下 (IL)回路）寻求酒精和滥用药物，以及焦虑和恐惧学习。最近的证据 揭示了NPY信号在mPFC中的关键作用，我们提供了强有力的试点证据，表明 将Y1 R激动剂注入mPFC的PL区域，而不是IL区域， 饮水，以及来自PL并投射到BLA的Y1 R+神经元的化学发生沉默 早期经验暴饮暴食拟议的目标将使用强大的和创新的化学遗传学和 转基因工具，电生理学和组织学方法，以确定是否有酗酒样乙醇的历史 饮酒诱导mPFC中NPY和NPY受体信号传导的改变（目的1），如果定点输注 Y1 R激动剂或Y2 R拮抗剂，或病毒介导的mPFC中NPY过表达， 乙醇饮用（目的2），如果化学沉默的Y1 R+锥体神经元的mPFC， 项目BLA钝暴食样乙醇摄入量（目标3）。这些拟议研究的结果将 解决了文献中关于mPFC，该区域NPY信号传导的作用以及 前额叶皮层和杏仁核在酒精摄入调节中的相互作用 对小鼠

Project Summary Alcohol (ethanol) dependence and relapse in abstinent alcoholics are major health problems throughout the world and neurochemical pathways that modulate these disorders are currently under investigation. However, the neurobiology underlying binge drinking, a dangerous pattern of behavior that proceeds and contributes to dependence, has received far less attention. Thus, it is of paramount importance to identify the neurocircuitry in the brain that modulates binge drinking as such knowledge will provide insight into the initial stages of alcohol use disorders (AUDs). In the last funding period of this grant we showed that NPY signaling in regions of the extended amygdala modulate binge-like ethanol drinking via mechanisms that overlap with NPY mechanisms involved with dependence-like intake. The goal of the present application is to extend our understanding of the NPY neurocircuitry that modulates binge-like ethanol drinking with a novel focus on NPY neurocircuitry originating in the medial prefrontal cortex (mPFC). The mPFC provides top-down regulation of the extended amygdala, in part through a glutamatergic mPFC  basolateral amygdala (BLA) circuit that is modulated by Y1 receptor (Y1R) signaling. Knowledge obtained from the proposed studies will greatly expand our understanding of the NPY neurocircuitry that modulates binge-like ethanol intake by linking together cortical and extended amygdala circuitry. The mPFC integrates information from limbic and cortical regions and has been implicated in modulating goal-directed (via prelimbic (PL) circuits) and habitual (via infralimbic (IL) circuits) seeking of ethanol and drugs of abuse, as well as anxiety and fear learning. Recent evidence has revealed a critical role for NPY signaling in the mPFC, and we have provided strong pilot evidence showing that infusion of an Y1R agonist into the PL, but not IL, region of the mPFC blunts early-experience binge drinking, and that chemogenetic silencing of Y1R+ neurons originating from the PL and projecting to the BLA blunt early-experience binge intake. The proposed aims will use powerful and innovative chemogenetic and transgenic tools, electrophysiology, and histological approaches to determine if a history of binge-like ethanol drinking induces alterations of NPY and NPY receptor signaling in the mPFC (Aim 1), if site-directed infusion of a Y1R agonist or Y2R antagonist, or viral-mediated overexpression of NPY in the mPFC blunts binge-like ethanol drinking (Aim 2), and if chemogenetic silencing of Y1R+ pyramidal neurons of the mPFC and which project to the BLA blunt binge-like ethanol intake (Aim 3). Together results from these proposed studies will address a critical gap in the literature regarding the role of the mPFC, NPY signaling in this region, and the functional interaction between the mPFC and extended amygdala in the modulation of binge-like ethanol intake in mice.