Investigation into the role of lateral hypothalamus GABA and glutamate relative dynamics in encoding affective valence and modulating motivated behaviors

项目摘要/摘要 人类的多种疾病可以追溯到不适应的奖赏回路功能，包括吸毒成瘾， 它每年给美国造成超过7400亿美元的损失，并造成无法估量的人类 痛苦。了解影响情感效价和奖励行为的神经机制可能 促进发现治疗方法，以降低成瘾和其他疾病的发生率和严重程度 来自奖励电路。几十年的研究表明，外侧下丘脑(LHA)是一个关键的大脑 奖赏环路内的区域。电刺激LHA可以有力地增强行为，而且 削弱LHA降低了广泛行为的动机。最近对遗传学的研究- 已确定的LHA神经元群体已经发现，散布在LHA细胞群体中的LHA细胞发出响应信号 奖励事件，并能产生独立的行为。文献中的解释结果受到阻碍 由于对基因定义的细胞群体的实验已经在 不同的实验室和行为程序。该提案旨在确定信号传递动态 在情绪显著事件期间的多个LHA亚群，并确定 这些信号在调节奖赏行为。在这次培训期间，我将学习尖端技术 包括收集和分析行为小鼠的单细胞钙成像和因果操作 确定的神经元群体。在目标1中，我们将记录LHA基因定义的种群的活动 在情绪显著的事件中的细胞。这些实验将揭示多个 并将使我们了解这些群体如何对奖赏做出贡献。在AIM 2，我们将确定这些群体中的信号在调节奖励行为中的作用。这些 实验将使我们能够理解LHA亚群中信号的因果效应，并将 有助于从理论上理解LHA如何影响奖励行为。总而言之， 这个项目的结果将加强我们对散布的种群如何响应 情绪上突出的事件以及这些信号如何因果地塑造行为。我将在我的职业生涯中进行的工作 训练期将有助于更好地了解神经元对奖赏的处理，可能会通知未来 研究治疗成瘾和其他奖赏回路疾病的干预措施。

Project Summary/ Abstract Multiple diseases in humans can be traced to maladaptive reward circuit function including drug addiction, which costs the United States over 740 billion dollars annually and causes an incalculable amount of human suffering. Understanding the neural mechanisms that contribute to affective valence and reward behaviors may facilitate the discovery of therapies to reduce the rate and severity of addiction and other disorders that stem from reward circuitry. Decades of research demonstrates that the lateral hypothalamus (LHA) is a critical brain region within the reward circuit. Electrically stimulating the LHA can powerfully reinforce behavior and that lesioning the LHA reduces motivation across a broad range of behaviors. Recent research into genetically- defined populations of LHA neurons have found that interspersed populations of LHA cells signal in response to rewarding events and can produce independent behaviors. Interpreting results in the literature is hindered due to the fact that experiments into genetically-defined populations of cells have been conducted across different labs and behavioral procedures. This proposal seeks to determine the signaling dynamics of multiple LHA subpopulations during emotionally salient events and to determine the casual role of these signals in mediating reward behavior. During this training period I will learn cutting-edge techniques including collection and analysis of single cell calcium imaging in behaving mice and causal manipulations of defined populations of neurons. In Aim 1, we will record the activity of genetically defined populations of LHA cells during emotionally salient events. These experiments will reveal the signaling dynamics of multiple populations of LHA cells and will inform our understand of how these populations contribute to reward. In Aim 2, we will determine the role of signaling within these populations in mediating reward behavior. These experiments will allow us to understand the causal effect of signaling within LHA subpopulations and will contribute to a theoretical understanding of how the LHA contributes to reward behavior. Altogether, the results of this project will enhance our understanding of how interspersed populations signal in response to emotional salient events and how these signals causally shape behavior. The work I will conduct during my training period will contribute to a greater understanding of neuronal processing of reward may inform future research into interventions to treat addiction and other diseases of reward circuitry.