Compartment-specific signaling of striatal opioid peptides in reward-guided behavior

奖励引导行为中纹状体阿片肽的区室特异性信号传导

• 批准号: 9378801
• 负责人: Matthew R. Banghart
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9378801
• 关键词: Acute; Agonist; Anatomy; Area; Attention deficit hyperactivity disorder; Basal Ganglia; Behavior; Behavioral; Behavioral Assay; Biological Assay; Brain; Calcium; Cells; Chemicals; Corpus striatum structure; Decision Making; Defect; Disease; Disease model; Dorsal; Drug abuse; Electrophysiology (science); Endorphins; Gene Transfer; Genetic; Gilles de la Tourette syndrome; Goals; Huntington Disease; Image; Lead; Learning; Limbic System; Link; Mediating; Mental disorders; Mentors; Methods; Monitor; Motivation; Motor; Mus; Nervous system structure; Neuromodulator; Neurons; Neuropeptides; Neurotransmitters; Obsessive-Compulsive Disorder; Operative Surgical Procedures; Opiates; Opioid; Opioid Peptide; Opioid Receptor; Parkinson Disease; Pathway interactions; Pattern; Pharmaceutical Preparations; Pharmacology; Prefrontal Cortex; Process; Property; Psychological reinforcement; Psychopathology; Reagent; Reporter; Reporting; Resolution; Rewards; Rodent Model; Role; Shapes; Signal Transduction; Signaling Molecule; Slice; Social Interaction; Substance abuse problem; Substance of Abuse; Sucrose; Synapses; Synaptic Transmission; System; Techniques; Training; Translating; Viral; Work; addiction; behavioral response; cellular targeting; chemical genetics; endogenous opioids; experimental study; feeding; goal oriented behavior; in vivo; interest; motor learning; neural circuit; neurochemistry; new therapeutic target; novel; opioid use; optical sensor; optogenetics; public health relevance; receptor; receptor expression; repaired; spatiotemporal; striosome; tool; transmission process; two-photon

DESCRIPTION (provided by applicant): The striatum integrates limbic and sensorimotor information to drive goal-directed behaviors. Opioid peptides and their receptors are abundant in the striatum, but a clear role for endogenous opioid signaling in action selection has not been established. This proposal aims to define key components of the striatal circuitry that process limbic information in mice and to understand how opioid peptides alter these circuits in the context of reward-guided behavior. A systematic anatomical and functional analysis of limbic projections to opioid-rich striatal microcircuits will be conducted using genetic tracing methods and ontogenetic tools in brain slices. New photochemical reagents will be employed in combination with ontogenetic to identify opioid-sensitive circuit components and determine how intercompartmental volume transmission shapes the spatiotemporal dynamics of opioid signaling. Genetically-targeted calcium imaging experiments will reveal how these actions translate into changes in network function. To provide evidence for endogenous opioid release in the context of goal-directed behaviors, activity patterns observed during reward-guided tasks will be driven in brain slices ontogenetically while electrophysiological monitoring opioid signaling in brain slices. To identify a functional role, opioid receptors will be blocked during reward-guided behavioral assays using a new photoactivatable antagonist that enables transient inhibition within discrete striatal sub-regions in vivo. To detect the release and spread of endogenous opioids with high sensitivity good spatiotemporal resolution, optical sensors will be developed by chemically modifying receptors so that they report the presence of endogenous agonists. A chemical- genetic strategy for cell-specific pharmacology will be developed to reveal which cellular targets of opioid signaling underlie behavioral responses to opioid peptides and opiate drugs. By targeting native receptors in genetically-identified cells, ths tool provides a powerful means to study opioidergic pathways in the brain. Collectively, these studies will uncover mechanisms by which opioids modulate a neural circuit involved in goal-oriented behavior. By quantifying signaling dynamics in new ways, the role of volume transmission will emerge. Although these novel techniques focus on opioids, the underlying principles are general, and should be applicable to signaling molecules beyond the nervous system. The anticipated findings should facilitate our understanding of disorders in which goal-directed actions are compromised such as Parkinson's and Huntington's diseases as well as attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), and addiction to substances of abuse.

描述（由申请人提供）：纹状体整合边缘系统和感觉运动信息，以驱动目标导向行为。阿片肽及其受体在纹状体中丰富，但内源性阿片信号在作用选择中的明确作用尚未确定。该提案旨在定义处理小鼠边缘系统信息的纹状体回路的关键组成部分，并了解阿片肽如何在奖励引导行为的背景下改变这些回路。将使用脑切片中的遗传追踪方法和个体发育工具对边缘系统向富含阿片类物质的纹状体微电路的投射进行系统的解剖学和功能分析。新的光化学试剂将与个体发育相结合，以确定阿片类药物敏感的电路组件，并确定室间体积传输如何塑造阿片类药物信号的时空动态。遗传靶向钙成像实验将揭示这些行为如何转化为网络功能的变化。为了提供目标导向行为背景下内源性阿片样物质释放的证据，在奖励引导任务期间观察到的活动模式将在脑切片中个体发育驱动，同时电生理监测脑切片中的阿片样物质信号传导。为了鉴定功能作用，阿片受体将在奖励引导的行为测定期间使用新的光活化拮抗剂被阻断，所述光活化拮抗剂能够在体内在离散的纹状体子区域内进行瞬时抑制。为了检测病毒的释放和传播 对于具有高灵敏度和良好时空分辨率的内源性阿片类药物，将通过化学修饰受体来开发光学传感器，以便它们报告内源性激动剂的存在。将开发用于细胞特异性药理学的化学-遗传学策略，以揭示阿片样物质信号传导的细胞靶点是对阿片样物质肽和阿片类药物的行为反应的基础。通过靶向遗传鉴定细胞中的天然受体，该工具为研究大脑中的阿片样物质通路提供了强有力的手段。总的来说，这些研究将揭示阿片类药物调节参与目标导向行为的神经回路的机制。通过以新的方式量化信号动态，音量传输的作用将显现出来。虽然这些新技术主要集中在阿片类药物上，但其基本原理是通用的，应该适用于神经系统以外的信号分子。预期的发现应该有助于我们理解目标导向行为受损的疾病，如帕金森病和亨廷顿病，以及注意力缺陷多动障碍（ADHD），强迫症（OCD）和滥用物质成瘾。