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

调查下丘脑外侧 GABA 和谷氨酸相对动态在编码情感效价和调节动机行为中的作用

• 批准号: 10462244
• 负责人: Adam G Gordon-Fennell
• 金额: $ 7.03万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10462244
• 关键词: Affective; Animals; Appetitive Behavior; Behavior; Behavioral; Brain; Brain region; Calcium; Cells; Collection; Consummatory Behavior; Consumption; Custom; Desire for food; Disease; Drug Addiction; Emotional; Equilibrium; Event; Genetic; Glutamates; Head; Homeostasis; Human; Hypothalamic structure; Image; Imaging Techniques; Intervention; Investigation; Lateral; Learning; Lesion; Literature; Machine Learning; Measures; Mediating; Modality; Motivation; Mus; Negative Valence; Neurons; Neurotransmitters; Operant Conditioning; Population; Positive Valence; Procedures; Quinine; Research; Rewards; Role; Severities; Shapes; Signal Transduction; Sodium; Sodium Chloride; Stimulus; Sucrose; Taste Perception; Techniques; Time; Training; United States; Video Recording; Work; addiction; behavior measurement; behavioral outcome; brain reward regions; cost; design; experimental study; gamma-Aminobutyric Acid; human disease; in vivo; machine learning classifier; motivated behavior; neural circuit; neuromechanism; novel; optogenetics; orofacial; reinforced behavior; relating to nervous system; response; reward circuitry; reward processing; single cell analysis; stem; targeted treatment; theories; therapy development; tool; training opportunity; two-photon

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.

项目概要/摘要 人类的多种疾病都可以追溯到适应不良的奖赏回路功能，包括毒瘾、 美国每年为此损失超过 7400 亿美元，并造成难以估量的人力损失。 痛苦。了解有助于情感效价和奖励行为的神经机制可能会 促进治疗方法的发现，以降低成瘾和其他由成瘾引起的疾病的发生率和严重程度 来自奖励电路。数十年的研究表明，下丘脑外侧 (LHA) 是一个关键的大脑 奖励回路内的区域。电刺激 LHA 可以有力地强化行为，并且 损害 LHA 会降低多种行为的动机。最近的基因研究—— 确定的 LHA 神经元群体发现，散布的 LHA 细胞群体发出响应信号 奖励事件并能产生独立的行为。文献结果的解释受到阻碍 由于事实上已经对基因定义的细胞群进行了实验 不同的实验室和行为程序。该提案旨在确定信号动态 情绪显着事件期间的多个 LHA 亚群，并确定 这些信号在调节奖励行为中。在这次培训期间我将学习前沿技术 包括行为小鼠的单细胞钙成像的收集和分析以及因果操作 定义的神经元群体。在目标 1 中，我们将记录基因定义的 LHA 群体的活动 情绪显着事件期间的细胞。这些实验将揭示多种信号的动态变化 LHA 细胞群，并将帮助我们了解这些细胞群如何对奖励做出贡献。瞄准 2，我们将确定这些人群中的信号在调节奖励行为中的作用。这些 实验将使我们能够了解 LHA 亚群内信号传导的因果效应，并将 有助于从理论上理解 LHA 如何促进奖励行为。总而言之， 该项目的结果将增强我们对散布人群如何发出信号以响应的理解 情绪显着事件以及这些信号如何因果塑造行为。我在职期间将进行的工作 训练期将有助于更好地理解奖励的神经元处理可能为未来提供信息 研究治疗成瘾和其他奖赏回路疾病的干预措施。