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.

项目摘要/摘要 人类中多种疾病可以追溯到适应不良的奖励电路功能，包括吸毒成瘾， 每年花费美国超过7400亿美元，并导致人类数量不可估量 痛苦。了解有助于情感价和奖励行为的神经机制可能 促进发现疗法以降低成瘾的速度和严重程度和其他疾病 来自奖励电路。数十年的研究表明，下丘脑（LHA）是关键大脑 奖励电路中的区域。电刺激LHA可以有力地加强行为，并且 病变LHA会减少各种行为的动力。最近对遗传学的研究 定义的LHA神经元种群发现，散布的LHA细胞群信号以响应 奖励事件并可以产生独立的行为。解释文献中的结果受到阻碍 由于事实是，已经对细胞的遗传定义群体进行了实验 不同的实验室和行为程序。该建议旨在确定 情绪重大事件期间的多个LHA亚群，并确定 这些信号中调解了奖励行为。在此培训期间，我将学习最先进的技术 包括在行为小鼠中收集和分析单细胞钙成像的 定义的神经元种群。在AIM 1中，我们将记录LHA遗传定义种群的活性 情绪显着事件中的细胞。这些实验将揭示多个的信号传导动力学 LHA细胞的种群，并将告知我们了解这些人群如何贡献奖励。目标 2，我们将确定信号在这些人群中的作用在中介奖励行为中。这些 实验将使我们能够了解LHA亚群中信号传导的因果关系，并将 有助于对LHA如何贡献奖励行为的理论理解。总共 该项目的结果将增强我们对散布人群如何发出信号的理解 情感显着事件以及这些信号如何塑造行为。我将在我的工作期间进行的工作 培训期将有助于对奖励的神经元处理有更多的了解可能会为未来提供信息 研究干预措施以治疗成瘾和奖励电路的其他疾病。