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: 10558680
• 负责人: Marc V Fuccillo
• 金额: $ 54.42万
• 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/10558680
• 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; Methods; Microdialysis; Motivation; Motor; Motor output; Neuromodulator; 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; neuronal excitability; 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.

总结 目标导向行为的缺陷是许多神经精神疾病的标志。背内侧 纹状体（DMS）已经成为目标导向行动的关键调解人，作为一个关键节点， 感觉运动、动机和认知信息的整合。然而，细胞机制 调节这些基本行为的机制在很大程度上仍不清楚。我们最近发现， DMS内的阈值尖峰中间神经元（LTSI）亚型是早期目标导向动作的关键调节器。 在行为过程中对这种细胞类型进行了首次体内成像，我们发现了与奖励相关的强有力的 当动物学习工具性反应任务时，这种活性被下调。通过随后的神经 电路操作，我们证明了LTSI活动的减少可以驱动学习，同时持续 活动减缓了学习。在这个建议中，我们跟进这些初步研究，以探索细胞和神经 这些效应的电路机制。我们假设LTSIs的下调增强了 纹状体回路的反应性，在早期学习过程中驾驶行为的关键步骤。我们建议LTSI 下调通过两种协同机制增强纹状体增益：（1）增加局部纹状体多巴胺 水平和（2）通过减少前馈抑制增强皮质纹状体对SPN的输入。前期工作 表明LTSI抑制可以增强纹状体DA释放，这可能是一个潜在的机制 推动增强收购。我们将通过以下方式测试LTSI抑制是否在学习过程中增强纹状体DA DA神经元末梢和病毒表达的DA传感器的钙成像。更好地了解 这种调制的机制，我们将采用急性切片电化学措施的光诱发 多巴胺释放过程中操纵LTSI活动。最后，我们将使用DA的电路目标操作 投射到DMS的神经元，以测试是否增强的纹状体DA释放是增强学习的介质 伴随着LTSI下调。现有的文献和初步数据也表明，LTSI是 参与SPN树突的前馈控制-输入神经信号整合的关键部位。 首先，我们从解剖学和电生理学两方面描述了LTSI如何整合到关键的皮质和 丘脑纹状体回路接下来，我们使用双光子显微镜放大到SPN树突和突触的水平。 脊椎，了解LTSIs如何调节这些重要的车厢钙信号。同时，我们 探索伴随学习的长期突触变化。最后，我们测试LTSI介导的增益是否 特定纹状体回路内的变化解释了学习的改变。这些目标完成后， 我们第一次看到纹状体LTSIs如何控制学习，提高了我们对细胞机制的理解， 调节目标导向行为