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

• 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
• 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

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 目标指导行为的缺陷是许多神经精神疾病的标志。背部 纹状体（DMS）已成为目标指导动作的关键调解人，作为关键节点 感觉运动，动机和认知信息的整合。然而，细胞机制 介导这些基本行为仍然在很大程度上不清楚。我们最近发现低 DMS中的阈值尖峰中间神经元（LTSI）亚型是早期目标行动的关键调节器。 在行为期间，我们进行了这种细胞类型的第一个体内成像，我们发现了与奖励相关的强大奖励 当动物学习工具反应任务时，活动被下调。通过随后的中性 电路操作，我们证明了LTSI活动的减少可能会推动学习，同时持续 活动减慢了学习。在此提案中，我们跟进这些初步研究以探索细胞和中性 这些影响的电路机制。我们假设LTSI的下调增强了 纹状体电路的响应能力，这是在早期学习过程中推动行为的关键步骤。我们建议LTSI 下调通过两种协同机制增强纹状体增益：（1）局部纹状体多巴胺增加 水平和（2）通过减少进发剂抑制作用增强了对SPN的皮质纹状体输入。初步工作 证明LTSI抑制可以增强纹状体DA的释放，这可能是一种基本机制 驾驶增强的获取。我们将测试LTSI抑制是否可以通过 DA神经元末端和病毒表达的DA传感器的钙成像。更好地了解 该调制的机制，我们将采用光学诱发的急性切片电化学测量 LTSI活性操纵过程中多巴胺释放。最后，我们将使用da的电路目标操纵 投射到DM的神经元测试增强的纹状体DA释放是否是增强学习的中介者 参加LTSI降低调节。现有的文献和初步数据也表明LTSI是 参与了SPN树突的前馈控制，这是整合传入神经信号的关键部位。 首先，我们在解剖学和电生理学上都描述了LTSI如何在关键的皮质中整合到 丘脑纹状体电路。接下来，我们使用2光子显微镜将SPN树突和突触的水平缩小 刺，以了解LTSIS如何调节这些重要隔室中的钙信号传导。并行，我们 探索学习发生的长期突触变化。最后，我们测试LTSI介导的增益是否 特定的纹状体电路中的变化解释了学习的改变。完成后，这些目标将提供 我们首先了解了纹状体LTSIS门的学习方式，从而提高了我们对细胞机制的理解 调节目标指导行为。