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 随着阿片类药物危机持续存在，迫切需要深入了解阿片类药物 细胞和电路层面的作用和潜在机制。 来自相互连接的皮层和丘脑的兴奋性输入形成一个调解的三角电路 关键的大脑功能，包括运动控制、情感疼痛、决策和奖励。 该电路的强调制，但它们的具体行为会强加诸如它们“在哪里”和“如何”起作用， 我们提案的总体目标是全面阐明如何进行。 丘脑-皮质-纹状体三角回路中的各个元件由不同的阿片类药物调节 受体激动剂以及这些调节如何改变电路的功能。 丘脑-皮质-纹状体回路是根据皮质内的特定子区域进行组织的， 在上一个资助期间，我们建立了第一个全面的丘脑和纹状体。 丘脑-皮质-纹状体电路接线图，使我们能够识别和描绘分区- 在我们的初步研究中，我们已经确定了确切的收敛位点。 前扣带皮层（ACC）和内侧丘脑（MD），两者都在 情感疼痛和奖赏，可能在背内侧纹状体（DMS）中。 驱动疼痛和奖励相关的执行功能。 在所有这三个大脑区域中表达，使该回路可能成为阿片类药物的底物。 激动剂在特定阿片受体类型、细胞类型和大脑中的精确作用 在当前的提案中，我们将使用尖端工具。 剖析亚区域特异性、细胞类型特异性、阿片受体类型特异性和突触特异性 具体来说，我们将利用我们的 MD-ACC-DMS 电路中的突触调制。 独特的研究优势，包括我们在研究期间获得的新颖的连接组学信息 在之前的资助期间，我们的新型成像能力可直接可视化亚细胞 cAMP/PKA 活体组织中阿片受体的下游信号传导，以及我们新型脑切片的建立 使用这些来监测阿片类药物对多突触信息传播的调制。 方法，我们将确定作用位点（目标 1），即潜在的细胞内信号传导机制 （目标 2），以及不同激活的阿片受体的功能影响（目标 3）。 实验将导致对阿片受体作用的深入、机制理解 MD-ACC-DMS 电路可以促进策略的制定，以更有效地解决 阿片类药物在镇痛和成瘾中的作用。