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

项目总结 目标导向行为缺陷是许多神经精神疾病的标志。背内侧表盘 纹状体(DMS)已成为目标定向行为的关键中介，是 感觉运动、动机和认知信息的整合。低阈值放电中间神经元(LTSI) 对纹状体棘投射神经元(SPN)施加强烈的抑制控制，并定位于调节 皮质-SPN突触通过树突抑制的可塑性。当LTSI准备发挥关键作用的时候 调节目标导向的行为，目前没有证据表明DMS LTSI参与了学习行为 已经上报了。因此，这项建议的首要目标是探讨DMS LTSI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。第一个建议 实验考察LTSI对于目标导向行为的习得是否重要。要提供 LTSI参与学习和行为灵活性的初步证据是LTSI的兴奋性 利用细胞类型特异性病毒表达Kir2.1(一种内向整流钾通道)和小鼠 随后在目标导向的操作任务中接受培训。初步数据表明，LTSI的这种减少 兴奋性显著增强任务习得。有效的目标导向行为由学习组成 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。在行动选择和结果评估中暂时描述LTSI的作用 在获得行动-结果偶发事件期间，将实施光遗传方法。vbl.使用 在杠杆选择(动作)之前的间隔期间，卤视紫质、DMS LTSI将被选择性地抑制 选择期)或当小鼠取回并消费其奖励时(结果评价期)。之前的工作已经完成 前扣带回皮质(ACC)在动作选择中起关键作用，而眶前叶皮质(OFC) 与结果评估密切相关。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从ACC和OFC获得最密集的神经支配。虽然结果来自于 光遗传学实验可能暗示ACC和/或OFC在目标定向行为中的LTSI功能，它 对于更直接地追求这些电路的功能作用将是重要的。因为LTSI是高度兴奋的 在音调活跃的情况下，学习可能涉及在纹状体中沉默它们的抑制效应。这是可以实现的 通过降低LTSI的兴奋性，增强兴奋性ACC-LTSI或OFC-LTSI突触的抑制， 或降低LTSI-SPN突触的疗效。第二套体外电生理学实验将 通过对ACC和OFC突触进行投射特异性光遗传募集，直接测试这些可能性 到已经学习了目标导向行为任务的小鼠的LTSI神经元上。

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.