Dissecting the role of striatal cell types in abnormal repetitive behaviors and treatment response

项目总结/摘要 尽管事实上，异常重复行为是突出的，禁用，并臭名昭著的-治疗 许多严重的儿童期发作的神经精神障碍，如强迫症， 强迫症（OCD）、抽动秽语综合征（TS）和自闭症，我们仍然有一个相当有限的了解 它们在大脑中的编码方式。汇聚的临床研究强调了皮质- 纹状体回路在异常重复行为发展中的作用及功能性神经影像学研究 一致表明1）与纹状体活动过度相关的纹状体活动过度，2）通过有效的 治疗然而，目前还不清楚纹状体的两种主要的对立细胞类型，D1和D2-棘 投射神经元（SPNs），有助于在这些异常行为中纹状体过度活跃，以及活动如何 在这两种细胞类型中的作用受到药物治疗的影响。尽管一个流行的理论认为， 内在产生的异常重复运动模式可能是由于大脑中的过度激活引起的 D1相关的直接途径或D2相关的间接途径的活化减少， 直接证据来支持这一观点。开始分析D1和D2-SPNs对纹状体的作用， 多动和这些适应不良的行为，我们使用了一个动物模型系统， 中央纹状体（CS）活动过度和持续行为，包括强迫性梳理和异常 逆转学习（Manning等，准备中）：SAPAP 3-KO小鼠。使用活体显微镜在自由移动 在动物中，我们证明了SAPAP 3-科斯增加了梳理相关的纹状体放电率， 与出版的作品一致。令人惊讶的是，当我们选择性地检查D1-SPN时，与预期相反， 我们发现，与WT相比，在强迫性梳理事件开始时， D1-SPN对体内皮质输入的反应性。这种活动模式通过有效的措施得到了正常化 氟西汀治疗。这些数据表明了一种新的模型，其中D1-SPN的活性降低和过度的 D2-SPN的活性促进异常重复行为的起始。在这个项目中，我们将使用状态- 依赖于光遗传学、体内显微镜和体内电生理学，以直接测试该模型， 确定氟西汀有效治疗对纹状体D1、D2和FSI（快速尖峰中间神经元）的影响 活动模式。在目标1中，我们将使用以下方法识别异常重复行为期间的D2活动模式： 自由移动小鼠的体内显微镜和电生理学。在目标2中，我们将使用体内显微镜， 确定与氟西汀治疗成功相关的D1-和D2-SPN活性模式，并确定 沉默D2-SPN活性是否可以重现这种正常化。在目标3中，我们将探讨 FSI活性与氟西汀治疗反应之间的关系。这些研究的最终目的是帮助提炼 基于神经刺激的治疗策略，用于禁用持续和强迫行为。

PROJECT SUMMARY/ABSTRACT Despite the fact that abnormal repetitive behaviors are prominent, disabling, and notoriously-treatment resistant symptoms of many severe childhood onset neuropsychiatric disorders such as Obsessive Compulsive Disorder (OCD), Tourette Syndrome (TS), and autism, we still have a quite limited understanding of how they are encoded in the brain. Convergent clinical studies have highlighted the importance of cortico- striatal circuits in the development of abnormal repetitive behaviors, with functional neuroimaging studies consistently demonstrating 1) symptom-associated striatal hyperactivity that is 2) resolved by effective treatment. However, it is unknown how the two major opposing cell-types of the striatum, D1 and D2-spiny projection neurons (SPNs), contribute to striatal hyperactivity during these aberrant behaviors, and how activity in these two cell types is impacted by pharmacologic treatments. Although a prevailing theory suggests that intrinsically-generated abnormal repeated motor patterns might result from either excessive activation of the D1-associated direct pathway or decreased activation of the D2-associated indirect pathway, there is little direct evidence to support this idea. To begin to dissect the contributions of D1 and D2-SPNs to striatal hyperactivity and these maladaptive behaviors, we used an animal model system that displays both hyperactivity in central striatum (CS) and perseverative actions including compulsive grooming and abnormal reversal learning (Manning et al, in prep): SAPAP3-KO mice. Using in vivo microscopy in freely moving animals, we demonstrated that SAPAP3-KOs have increased grooming-associated striatal firing rates, consistent with published work. Surprisingly, when we selectively examined D1-SPNs, contrary to expectations we saw decreased activity compared to WT at initiation of compulsive grooming events, suggesting decreased responsiveness of D1-SPNs to cortical inputs in vivo. This activity pattern was normalized by effective fluoxetine treatment. These data suggest a novel model in which decreased activity in D1-SPNs and excessive activity in D2-SPNs promotes initiation of abnormal repetitive behaviors. In this project we will use state- dependent optogenetics, in vivo microscopy, and in vivo electrophysiology to both directly test this model and determine the impact of effective fluoxetine treatment on striatal D1, D2, and FSI (fast-spiking interneuron) activity patterns. In Aim 1, we will identify D2-activity patterns during abnormal repetitive behaviors using in vivo microscopy and electrophysiology in freely-moving mice. In Aim 2, we will use in vivo microscopy to identify D1- and D2-SPN activity patterns associated with successful fluoxetine treatment, and determine whether silencing D2-SPN activity can recapitulate this normalization. In Aim 3, we will explore the relationship between FSI activity and the fluoxetine treatment response. The ultimate goal of these studies is to help refine neurostimulation-based treatment strategies for disabling perseverative and compulsive behaviors.