Neuropeptide Y: Role in Ethanol Intake and Sensitivity

项目摘要 戒酒者的酒精(酒精)依赖和复发是整个 调节这些疾病的世界和神经化学途径目前正在调查中。然而， 狂饮背后的神经生物学，这是一种危险的行为模式，它会继续并导致 依赖性，受到的关注要少得多。因此，确定神经回路至关重要。 在调节酗酒的大脑中，这样的知识将提供对 酒精使用障碍(AUDS)。在这笔赠款的上一个资助期，我们表明NPY信号在区域中 延长型杏仁核通过与神经肽Y重叠的机制调节酗酒 与依赖类摄取有关的机制。本应用程序的目标是扩展我们的 对NPY神经回路调节暴饮式酒精饮酒的理解 神经回路起源于内侧前额叶皮质(MPFC)。MPFC提供了自上而下的监管 延伸的杏仁核，部分通过谷氨酸能mPFC杏仁基底外侧核(Bla)回路 受Y1受体(Y1R)信号调节。从拟议的研究中获得的知识将大大扩展 我们对NPY神经回路的理解，它通过连接在一起来调节类似狂欢的酒精摄入 皮质和延伸的杏仁核回路。MPFC整合了边缘和大脑皮层的信息。 它与调节目标导向(通过前置(PL)回路)和习惯性(通过下缘)有关 (Il)寻求酒精和滥用药物，以及焦虑和恐惧学习。最近的证据表明 揭示了NPY信号在mPFC中的关键作用，我们已经提供了强有力的试点证据表明 将Y1R激动剂注入mPFC的PL区，而不是IL区，可以钝化早期的体验狂欢 饮酒，以及源于PL并投射到BLA的Y1R+神经元的化学发生沉默 迟钝的早期体验狂欢。拟议的目标将使用强大和创新的化学遗传和 转基因工具、电生理学和组织学方法来确定酗酒史 饮酒诱导mPFC中NPY和NPY受体信号的改变(目标1)，如果局部定向注入 Y1R激动剂或Y2R拮抗剂或病毒介导的NPY在mPFC钝化狂欢样中的过度表达 酒精饮酒(目标2)，如果化学发生沉默的Y1R+锥体神经元的mPFC和 计划到白血球蛋白钝性暴饮式酒精摄入(目标3)。这些拟议研究的结果加在一起将 解决文献中关于mPFC、NPY信号在该区域的作用以及 MPFC和延髓杏仁核在调节暴饮性酒精摄入中的功能相互作用 在老鼠身上。

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.