Integration and Dynamics of Neuromodulator Action in the Striatum

纹状体中神经调节剂作用的整合和动力学

• 批准号: 8878024
• 负责人: Yao Chen
• 金额: $ 6.21万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8878024
• 关键词: ADORA2A gene; Acetylcholine; Adaptive Behaviors; Adenosine; Amines; Animal Behavior; Behavior; Belief; Biochemical; Biosensor; Brain; Cells; Corpus striatum structure; Coupled; Cyclic AMP-Dependent Protein Kinases; DRD2 gene; Data; Dendrites; Disease; Dopamine; Dopamine Receptor; Drug abuse; Fiber; Fluorescence; Gene Expression; Image; Lead; Learning; Life; Light; Link; Mental Depression; Mental disorders; Microscopy; Monitor; Movement; Muscarinic Acetylcholine Receptor; Muscarinics; Nature; Neurodegenerative Disorders; Neuromodulator; Neuromodulator Receptors; Neurons; Opioid; Opioid Receptor; Output; Parkinson Disease; Pathway interactions; Pattern; Peptides; Pharmacology; Physiologic pulse; Process; Property; Receptor Activation; Regulation; Rewards; Role; Schizophrenia; Signal Transduction; Site; Slice; Specificity; Synapses; Synaptic Transmission; Synaptic plasticity; System; Time; addiction; base; behavioral outcome; cell type; differential expression; dopaminergic neuron; drug of abuse; fiber cell; human disease; neural circuit; neuronal cell body; neuroregulation; optogenetics; public health relevance; receptor; receptor coupling; receptor expression; response; spatiotemporal; two-photon

PROJECT SUMMARY/ABSTRACT Neuromodulators, such as dopamine and opioids, dynamically regulate synaptic strength and intrinsic properties of neurons, thereby modulating outputs of neural circuits and modifying behavior. Their alteration is linked to devastating diseases such as Parkinson's Disease and addiction. The striatum is an ideal system to study neuromodulation since it receives a large number of behaviorally-relevant neuromodulators. In addition to their effects on the electrical excitability of neurons, neuromodulators also exert biochemical changes that are thought to be crucial for adaptive behaviors. In the striatum, within one projection neuron, different neuromodulators have been proposed to competitively and bidirectionally regulate synaptic transmission and plasticity via modulation of protein kinase A (PKA) activity. Between direct and indirect striatal pathways, the same neuromodulator can lead to either opposite (e.g. dopamine) or the same (e.g. opioid) direction of change of PKA activity in the projection neurons, thereby coordinating the two pathways that are implicated to produce opposite behavioral outcomes. Since neuromodulator inputs are constantly changing during animal behavior, how PKA responds to these dynamic and diverse inputs are crucial to understanding neuromodulator action. Nevertheless, the nature of this dynamic response is poorly understood. One of the major challenges to understanding this question is the lack of a dynamic readout of PKA activity in response to ongoing neuromodulatory inputs. Given the role of PKA as a major integrator of neuromodulator action and regulator of circuit plasticity, I have recently developed a PKA activity biosensor that can be targeted to genetically defined neurons for 2-photon Fluorescence Lifetime Imaging Microscopy (2pFLIM) in live brain slices. To understand neuromodulator action in the striatum, I propose to image PKA activity in genetically identified neurons with high spatiotemporal precision. First, given the importance of dopamine in normal striatal function (e.g. modulating movement and reward-based learning) and pathological conditions (e.g. Parkinson's Disease and addiction), I will characterize the dynamics of PKA activity in direct and indirect pathway striatal neurons in response to dopamine release. Secondly, I will determine how dopamine interacts with other modulators such as acetylcholine and opioids to alter PKA activity. In summary, this study will reveal how intracellular biochemical changes dynamically respond to ongoing neuromodulatory inputs, and how neuromodulators coordinate circuit dynamics. Understanding the integration and dynamics of neuromodulator action in normal conditions will shed light onto how abnormal neuromodulator signaling alters striatal function in pathological conditions such as neurodegenerative diseases and addiction.

项目概要/摘要 神经调节剂，如多巴胺和阿片类药物，动态调节突触强度和内在 神经元的特性，从而调节神经回路的输出并改变行为。他们的改变 与帕金森病和成瘾等毁灭性疾病有关。纹状体是一个理想的系统 研究神经调节，因为它接受大量行为相关的神经调节剂。此外 除了对神经元电兴奋性的影响之外，神经调节剂还产生生化变化， 被认为对于适应性行为至关重要。在纹状体中，在一个投射神经元内，不同的 神经调节剂已被提议竞争性地和双向地调节突触传递和 通过调节蛋白激酶 A (PKA) 活性实现可塑性。在直接和间接纹状体通路之间， 相同的神经调节剂可以导致相反（例如多巴胺）或相同（例如阿片类药物）方向的变化 投射神经元中的 PKA 活性，从而协调与 产生相反的行为结果。由于神经调节剂输入在动物生长过程中不断变化 行为、PKA 如何响应这些动态和多样化的输入对于理解神经调节剂至关重要 行动。然而，人们对这种动态响应的本质知之甚少。面临的主要挑战之一 理解这个问题是因为缺乏对 PKA 活动的动态读出来响应正在进行的 神经调节输入。鉴于 PKA 作为神经调节作用和调节器的主要整合者的作用 为了研究电路的可塑性，我最近开发了一种 PKA 活性生物传感器，可以针对基因 在活体脑切片中使用 2 光子荧光寿命成像显微镜 (2pFLIM) 定义神经元。到 了解纹状体中的神经调节剂作用，我建议对基因鉴定的 PKA 活性进行成像 具有高时空精度的神经元。首先，鉴于多巴胺在正常纹状体中的重要性 功能（例如调节运动和基于奖励的学习）和病理状况（例如帕金森病） 疾病和成瘾），我将描述直接和间接通路纹状体中 PKA 活性的动态特征 神经元对多巴胺释放作出反应。其次，我将确定多巴胺如何与其他物质相互作用 乙酰胆碱和阿片类药物等调节剂可改变 PKA 活性。总之，这项研究将揭示如何 细胞内生化变化动态响应持续的神经调节输入，以及如何 神经调节器协调电路动力学。了解整合和动态 正常条件下神经调节剂的作用将揭示异常神经调节剂信号传导的机制 改变神经退行性疾病和成瘾等病理状况下的纹状体功能。