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

项目概要/摘要 人类的多种疾病可以追溯到不适应的奖励回路功能，包括药物成瘾， 每年花费美国超过7400亿美元，并造成无法估量的人类死亡。 痛苦了解有助于情感效价和奖励行为的神经机制， 促进发现治疗方法，以减少成瘾和其他疾病的发生率和严重程度， 从奖励电路中分离出来几十年的研究表明，外侧下丘脑（LHA）是一个关键的大脑 奖励回路中的区域。电刺激LHA可以有力地加强行为， 损伤LHA会降低广泛行为的动机。最近的研究表明，基因- 已确定的LHA神经元群体已经发现，散布的LHA细胞群体响应 奖励事件，并能产生独立的行为。解释文献中的结果受到阻碍 由于对遗传上确定的细胞群的实验已经在 不同的实验室和行为程序该提议寻求确定以下的信令动态： 多个LHA亚群在情绪突出的事件，并确定因果作用， 这些信号在调节奖励行为中的作用。在培训期间，我将学习尖端技术 包括收集和分析表现良好的小鼠的单细胞钙成像和因果操作， 定义的神经元群体。在目标1中，我们将记录LHA遗传定义群体的活性 细胞在情绪上的反应这些实验将揭示多个信号的信号动力学 LHA细胞的群体，并将告知我们这些群体如何有助于奖励的理解。在Aim中 2，我们将确定这些人群中的信号在介导奖励行为中的作用。这些 实验将使我们能够理解LHA亚群内信号传导的因果效应， 有助于从理论上理解LHA如何影响奖励行为。一切器皿的银子 该项目的结果将提高我们对散布种群如何响应信号的理解， 情绪突出事件以及这些信号如何因果地塑造行为。我将在我的任期内进行的工作 训练期间将有助于更好地了解神经元的奖励处理可能会告知未来 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.