A Novel Role for Local Striatal Interneuron Regulation of Goal-Directed Action

局部纹状体中间神经元调节目标导向行动的新作用

基本信息

批准号：
10338165
负责人：
Marc V Fuccillo
金额：
$ 56.89万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-07 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10338165
关键词：
Acute Anatomy Animals Automobile Driving Behavior Behavioral Calcium Calcium Signaling Cells Cognitive Complex Corpus striatum structure Data Dendrites Dopamine Down-Regulation Electrophysiology (science)Excitatory Synapse Exhibits Goals Image Interneurons Laser Scanning Microscopy Learning Literature Maps Measures Mediating Mediator of activation protein Methods Microdialysis Motivation Motor Motor output Neurons Operant Conditioning Optics Outcome Output Pathway interactions Performance Periodicity Pharmacology Physiological Population Population Heterogeneity Process Property Regulation Rewards Role Scanning Shapes Signal Transduction Slice Specificity Synapses Synaptic plasticity System Testing Thalamic structure Vertebral column Viral Work cell type dopaminergic neuron driving behavior follow-up improved in vivo in vivo imaging inhibitory neuron integration site motor control neural circuit neuropsychiatric disorder neurotransmission novel optogenetics response sensor transmission process two photon microscopy two-photon virus genetics

项目摘要

Summary Deficits in goal-directed behavior are the hallmark of many neuropsychiatric diseases. The dorsomedial striatum (DMS) has emerged as a key mediator of goal-directed actions, serving as a critical node for integration of sensorimotor, motivational, and cognitive information. Nevertheless, the cellular mechanisms mediating these fundamental behaviors remain largely unclear. We have recently discovered that the low threshold spiking interneuron (LTSI) subtype within the DMS is a key regulator of early goal-directed actions. Performing the first in vivo imaging of this cell type during behavior, we uncovered robust reward-related activity that was down-regulated as animals learned an instrumental response task. Via subsequent neural circuit manipulations, we demonstrated that this reduction in LTSI activity could drive learning, while sustained activity slowed learning. In this proposal, we follow up these initial studies to explore the cellular and neural circuit mechanisms of these effects. We hypothesize that downregulation of LTSIs enhances the responsiveness of striatal circuits, a key step in driving behavior during early learning. We suggest LTSI downmodulation enhances striatal gain via two synergistic mechanisms: (1) increased local striatal dopamine levels and (2) enhanced corticostriatal input to SPNs via reductions in feedforward inhibition. Preliminary work demonstrates that LTSI inhibition can enhance striatal DA release, which may be an underlying mechanism driving enhanced acquisition. We will test whether LTSI inhibition enhances striatal DA during learning via calcium imaging of DA neuron terminals and virally-expressed DA sensors. To better understand the mechanism of this modulation, we will employ acute slice electrochemical measures of optically-evoked dopamine release during manipulation of LTSI activity. Finally, we will use circuit-targeted manipulations of DA neurons projecting to DMS to test whether enhanced striatal DA release is a mediator of the enhanced learning accompanying LTSI down regulation. Existing literature and preliminary data also suggest that LTSI are engaged in feed-forward control of SPN dendrites – a key site for the integration of incoming neural signals. First, we describe both anatomically and electrophysiologically, how LTSIs integrate within key cortico- and thalamostriatal circuits. Next we use 2-photon microscopy to zoom into the level of SPN dendrites and synaptic spines, to understand how LTSIs regulate calcium signaling in these important compartments. In parallel, we explore long-term synaptic changes that accompany learning. Finally, we test whether LTSI-mediated gain changes within specific striatal circuits accounts for altered learning. When completed, these aims will provide our first glimpse into how striatal LTSIs gate learning, improving our understanding of the cellular mechanisms modulating goal-directed behavior.

概括目标导向行为的缺陷是许多神经精神疾病的标志。纹状体 (DMS) 已成为目标导向行动的关键调解者，充当目标导向行动的关键节点然而，感觉运动、动机和认知信息的整合是细胞机制的。我们最近发现，调节这些基本行为的机制在很大程度上仍不清楚。 DMS 内的阈值尖峰中间神经元 (LTSI) 亚型是早期目标导向行动的关键调节因子。在行为过程中对这种细胞类型进行首次体内成像，我们发现了与奖励相关的强大功能当动物通过随后的神经系统学习工具反应任务时，活动被下调。电路操作，我们证明了 LTSI 活动的减少可以推动学习，同时持续在这个提案中，我们跟进这些初步研究来探索细胞和神经。我们谦虚地认为 LTSI 的下调会增强这些效应的电路机制。纹状体回路的反应能力是早期学习过程中驾驶行为的关键步骤。下调通过两种协同机制增强纹状体增益：（1）增加局部纹状体多巴胺水平和（2）通过减少前馈抑制来增强皮质纹状体对 SPN 的输入。表明 LTSI 抑制可以增强纹状体 DA 释放，这可能是潜在机制我们将测试 LTSI 抑制是否会在学习过程中增强纹状体 DA。 DA 神经元末端和病毒表达的 DA 传感器的钙成像。为了了解这种调制的机制，我们将采用光学诱发的急性切片电化学测量最后，我们将使用 DA 的电路靶向操作。神经元投射到 DMS 以测试增强的纹状体 DA 释放是否是增强学习的中介现有文献和初步数据也表明 LTSI 下调。参与 SPN 树突的前馈控制——SPN 树突是整合传入神经信号的关键位点。首先，我们从解剖学和电生理学角度描述 LTSI 如何整合到关键皮质和接下来我们使用 2 光子显微镜放大 SPN 树突和突触的水平。为了了解 LTSI 如何调节这些重要区室中的信号传导，我们同时进行了研究。探索伴随学习的长期突触变化最后，我们测试 LTSI 是否介导增益。特定纹状体回路内的变化会影响学习。完成后，这些目标将提供。我们第一次了解纹状体 LTSI 如何控制学习，提高我们对细胞机制的理解调节目标导向的行为。