Genetic and physiological dissection of the circuit mechanisms in the striatum.

纹状体回路机制的遗传和生理解剖。

• 批准号: 10189709
• 负责人: Tianyi Mao
• 金额: $ 38.5万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189709
• 关键词: Absence of pain sensation; Address; Adverse effects; Affect; Affective; Agonist; Analgesics; Anterior; Brain; Brain region; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Decision Making; Development; Dissection; Dopamine; Electrophysiology (science); Elements; Expression Profiling; Funding; Future; Genetic; Goals; Individual; Learning; Medial Dorsal Nucleus; Mediating; Mediator of activation protein; Monitor; Mus; Neurons; Opioid; Opioid Receptor; Opioid agonist; Pain; Pathway interactions; Pharmacology; Pharmacotherapy; Physiological; Play; Preparation; Presynaptic Terminals; Receptor Activation; Regulation; Research; Rewards; Role; Signal Transduction; Site; Slice; Specificity; Synapses; Synaptic Transmission; Thalamic structure; Tissues; addiction; base; cell type; cingulate cortex; connectome; executive function; experimental study; imaging capabilities; imaging modality; motor control; mouse genetics; neurotransmission; novel; opiate tolerance; opioid epidemic; optogenetics; postsynaptic; presynaptic; receptor; response; side effect; spatiotemporal; tool

PROJECT ABSTRACT With the ongoing opioid crisis, there is a tremendous need for an in-depth understanding of opioid actions and the underlying mechanisms at the cellular and circuit levels. The striatum integrates excitatory inputs from the interconnected cortex and thalamus to form a triangular circuit that mediates critical brain functions, including motor control, affective pain, decision-making, and reward. Opioids impose strong modulation of this circuit, but their specific actions, such as “where” and “how” they act, are not fully understood. The overarching goal of our proposal is to comprehensively elucidate how individual elements in the thalamo-cortico-striatal triangular circuit are modulated by distinct opioid receptor agonists and how these modulations alter the function of the circuit. The thalamo-cortico-striatal circuit is organized based on specific subregions within the cortex, thalamus, and striatum. During the previous funding period, we established the first comprehensive thalamo-cortico-striatal circuit wiring diagram, which allowed us to identify and delineate subregion- specific connectivity. In our preliminary studies, we have identified the exact convergent sites of the anterior cingulate cortex (ACC) and the mediodorsal (MD) thalamus, both of which play critical roles in affective pain and reward, in the dorsomedial striatum (DMS). This MD-ACC-DMS circuit presumably drives pain and reward-associated executive functions. Different subtypes of opioid receptors are expressed in all three of these brain regions, making this circuit a likely substrate for opioids. However, the precise actions of agonists in the context of specific opioid receptor types, cell types, and brain subregions are poorly characterized in this circuit. In the current proposal, we will use cutting-edge tools to dissect subregion-specific, cell type-specific, opioid receptor type-specific, and synapse-specific modulation of the synapses in the MD-ACC-DMS circuit. Specifically, we will take advantage of our unique research strengths, including the novel connectomic information we acquired during the previous funding period, our novel imaging capability for directly visualizing subcellular cAMP/PKA signaling downstream of opioid receptors in living tissue, and our establishment of novel brain slice preparations for monitoring opioid modulation of multi-synaptic information propagation. Using these approaches, we will identify the action sites (Aim 1), the underlying intracellular signaling mechanisms (Aim 2), and the functional impacts (Aim 3) of distinct activated opioid receptors. Our proposed experiments will result in an in-depth, mechanistic understanding of the actions of opioid receptors in the MD-ACC-DMS circuit that may facilitate the development of strategies to more effectively address the role of opioids in analgesia and addiction.

项目摘要 随着持续的绿oi危危机，需要深入了解opioid 动作以及细胞和电路水平的基本机制。纹状体整合 来自互连皮质和丘脑的兴奋性输入，形成了介导的三角电路 关键的大脑功能，包括运动控制，情感疼痛，决策和奖励。阿片类药物 对该电路施加强烈的调节，但是他们的具体行动，例如“何处”和“如何”行为， 不完全理解。我们提案的总体目标是全面阐明 Thalamo-cortico-r-纹状体三角电路中的个体元素由独特的Ooid调节 受体激动剂以及这些调制如何改变电路的功能。 基于皮质内的特定子区域组织丘脑 - 皮质纹状体电路， 丘脑和纹状体。在上一个资金期间，我们建立了第一个综合 Thalamo-cortico-Sriatal电路接线图，这使我们能够识别和描述子区域 - 特定连通性。在我们的初步研究中，我们确定了确切的收敛位点 前扣带回皮质（ACC）和培养皿（MD）丘脑，这两者都在 在背侧纹状体（DMS）中，情感疼痛和奖励。这个MD-ACC-DMS电路大概是 驱动疼痛并与奖励相关的执行职能。阿片类药物接收器的不同亚型是 在这三个大脑区域中表达，使该电路成为阿片类药物的底物。然而， 激动剂在特定的阿片类型受体类型，细胞类型和大脑中的精确作用 该电路中的子区域的特征很差。在当前的建议中，我们将使用尖端工具 剖析亚区域特异性，细胞类型特异性，阿片受体类型和突触特异性 MD-ACC-DMS电路中突触的调制。具体来说，我们将利用我们的 独特的研究优势，包括我们在 以前的资金期，我们的新型成像能力直接可视化亚细胞营地/PKA 活组织中阿片受体下游的信号传导，以及我们建立新型大脑切片 监测多突触信息传播的阿片类药物调制的准备。使用这些 方法，我们将确定动作位点（AIM 1），基础细胞内信号传导机制 （AIM 2），以及不同活化的阿片类药物受体的功能影响（AIM 3）。我们提出的 实验将导致对阿片受体在中的作用的深入，机械理解 MD-ACC-DMS电路可能支持制定策略以更有效地解决 阿片类药物在镇痛和成瘾中的作用。