Role of dorsomedial striatum low-threshold spiking interneurons in goal-directed behavior

背内侧纹状体低阈值尖峰中间神经元在目标导向行为中的作用

• 批准号: 9396789
• 负责人: Elizabeth N. Holly
• 金额: $ 5.71万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9396789
• 关键词: Active Learning; Affect; Animals; Anterior; Association Learning; Autistic Disorder; Behavior; Behavioral; Cognitive; Corpus striatum structure; Data; Decision Making; Electrophysiology (science); Excitatory Synapse; Fiber; Goals; Halorhodopsins; Impairment; Interneuron function; Interneurons; Learning; Lesion; Link; Mediating; Mediator of activation protein; Mental Depression; Motivation; Mus; Neurons; Operant Conditioning; Outcome; Pharmacology; Phase; Physiology; Play; Population; Positioning Attribute; Recruitment Activity; Reporting; Rewards; Role; Schizophrenia; Shapes; Synapses; Synaptic plasticity; Testing; Thalamic structure; Training; Viral; Work; Yin; addiction; base; cell type; cingulate cortex; daily functioning; experimental study; flexibility; inward rectifier potassium channel; learned behavior; nerve supply; neuropsychiatric disorder; optogenetics; overexpression; stem

PROJECT 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. Low-threshold spiking interneurons (LTSIs) exert strong inhibitory control over striatal spiny projection neurons (SPNs) and are positioned to regulate plasticity at cortico-SPN synapses through dendritic inhibition. While LTSIs are poised to play a key role in regulating goal-directed behavior, no evidence of DMS LTSI involvement in learning behavior has presently been reported. The overarching aim of this proposal is therefore to explore the role of DMS LTSIs in goal- directed behavior and examine how learning alters LTSI physiology and plasticity. The first proposed experiment investigates whether LTSIs are important for the acquisition of goal-directed behavior. To provide initial evidence for LTSI involvement in learning and behavioral flexibility, excitability of LTSIs has been reduced using cell-type specific viral expression of Kir2.1, an inwardly rectifying potassium channel, and mice subsequently trained in a goal-directed operant task. Preliminary data demonstrates that this reduction in LTSI excitability significantly enhances task acquisition. Efficient goal-directed behavior is comprised of learning action-outcome associations, selecting an appropriate action, evaluating the resultant outcome, and adjusting behavior if necessary. To temporally delineate the role of LTSIs in action selection and outcome valuation during the acquisition of an action-outcome contingency, an optogenetic approach will be implemented. Using halorhodopsin, DMS LTSIs will be selectively inhibited during the interval preceding lever choice (action selection period) or as mice retrieve and consume their reward (outcome valuation period). Prior work has shown a key role of the anterior cingulate cortex (ACC) in action selection, while the orbitofrontal cortex (OFC) has been strongly linked to outcome valuation. Interestingly, preliminary cell type-specific monosynaptic tracing data shows DMS LTSIs receive the densest innervation from the ACC and OFC. While results from the optogenetics experiment may implicate the ACC and/or OFC in LTSI function during goal-directed behavior, it will be important to more directly pursue the functional role of these circuits. As LTSIs are highly excitable and tonically active, learning may involve silencing their inhibitory effects within the striatum. This can be achieved through reductions in LTSI excitability, enhanced depression of excitatory ACC-LTSI or OFC-LTSI synapses, or reduced efficacy at LTSI-SPN synapses. The second set of ex vivo electrophysiology experiments will directly test these possibilities using projection-specific optogenetic recruitment of ACC and OFC synapses onto LTSI neurons in mice that have learned the goal-directed behavior task.

项目摘要 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。低阈值发放中间神经元 对纹状体多刺投射神经元（SPN）施加强抑制性控制，并被定位为调节 通过树突抑制在皮质-SPN突触的可塑性。虽然LTSI准备在以下方面发挥关键作用： 调节目标导向的行为，目前没有证据表明DMS LTSI参与学习行为， 被举报。因此，本提案的总体目标是探讨旅游管理系统长期投资体制在实现以下目标方面的作用： 指导行为，并研究学习如何改变LTSI生理和可塑性。第一个拟议 实验研究LTSI对于获得目标导向行为是否重要。提供 LTSI参与学习和行为灵活性的初步证据，LTSI的兴奋性已经被 使用Kir2.1（一种内向整流钾通道）的细胞类型特异性病毒表达减少， 随后在目标导向的操作性任务中训练。初步数据表明，LTSI的减少 兴奋性显著增强任务获得。有效的目标导向行为包括学习 行动-结果关联，选择适当的行动，评估结果，并调整 必要时的行为。暂时描述LTSI在行动选择和结局评价中的作用 在获得行动-结果偶然事件期间，将实施光遗传学方法。使用 盐视紫红质、DMS LTSI将在杠杆选择（动作）之前的间隔期间被选择性地抑制 选择期）或当小鼠取回并消耗它们的奖励时（结果评价期）。以前的工作有 表明前扣带皮层（ACC）在动作选择中起关键作用，而眶额皮层（OFC） 与成果评价密切相关。有趣的是，初步的细胞类型特异性单突触追踪 数据显示DMS LTSI接受来自ACC和OFC的失神经支配。虽然结果从 光遗传学实验可能暗示ACC和/或OFC在目标导向行为中的LTSI功能， 将是重要的，更直接地追求这些电路的功能作用。由于LTSI是高度兴奋的， 紧张性活跃，学习可能涉及沉默它们在纹状体内的抑制作用。可以实现这一点 通过降低LTSI兴奋性，增强兴奋性ACC-LTSI或OFC-LTSI突触的抑制， 或降低LTSI-SPN突触的功效。第二组离体电生理学实验将 使用ACC和OFC突触的投射特异性光遗传学募集直接测试这些可能性 在学习了目标导向行为任务的小鼠的LTSI神经元上。