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

剖析纹状体细胞类型在异常重复行为和治疗反应中的作用

基本信息

批准号：
10334446
负责人：
Susanne Elizabeth Ahmari
金额：
$ 47.14万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-11 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10334446
关键词：
Animal Model Animals Behavior Behavioral Biological Models Brain Calcium Cells Childhood Clinical Research Compulsive Behavior Corpus striatum structure Data Development Electrophysiology (science)Equilibrium Event Fluoxetine Functional Imaging Generations Gilles de la Tourette syndrome Goals Grooming Hyperactivity Impairment Interneurons Knockout Mice Measures Mediating Microscopy Modeling Motor Motor Cortex Mus Neurons Obsessive-Compulsive Disorder Pathway interactions Pattern Pharmacological Treatment Prevention strategy Protocols documentation Publishing Resistance Reversal Learning Role Selective Serotonin Reuptake Inhibitor Symptoms Testing Thinking Work associated symptom autism spectrum disorder base behavioral response cell type comorbidity defined contribution effective therapy expectation improved in vivo maladaptive behavior neuroimaging neuropsychiatric disorder novel optogenetics prevent public health relevance relating to nervous system repetitive behavior response sequence learning theories treatment response treatment strategy

项目摘要

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.

项目概要/摘要尽管异常的重复行为是突出的、致残的和臭名昭著的治疗许多严重的儿童期发病的神经精神疾病的抵抗症状，例如强迫症强迫症（OCD）、图雷特综合症（TS）和自闭症，我们的了解仍然相当有限它们是如何在大脑中编码的。趋同的临床研究强调了皮质的重要性纹状体回路在异常重复行为发展中的作用，通过功能神经影像学研究一致证明 1) 与症状相关的纹状体过度活跃，2) 通过有效的方法解决治疗。然而，尚不清楚纹状体的两种主要相反的细胞类型 D1 和 D2-刺状细胞如何投射神经元（SPN）在这些异常行为期间导致纹状体过度活跃，以及活动如何这两种细胞类型受到药物治疗的影响。尽管流行的理论表明内在产生的异常重复运动模式可能是由于过度激活 D1 相关的直接途径或 D2 相关的间接途径的激活减少，几乎没有支持这个想法的直接证据。开始剖析 D1 和 D2-SPN 对纹状体的贡献多动症和这些适应不良行为，我们使用了一个动物模型系统来显示中央纹状体 (CS) 过度活跃和持续行为，包括强迫性梳理毛发和异常行为逆转学习（Manning 等人，准备中）：SAPAP3-KO 小鼠。使用活体显微镜自由移动动物，我们证明 SAPAP3-KO 可以增加与梳理相关的纹状体放电率，与已发表的作品一致。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，活动减少，表明减少 D1-SPNs 对体内皮质输入的反应。这种活动模式通过有效的氟西汀治疗。这些数据表明了一种新的模型，其中 D1-SPN 的活性降低，并且过度 D2-SPN 的活性促进异常重复行为的发生。在这个项目中，我们将使用状态 - 依赖光遗传学、体内显微镜和体内电生理学来直接测试该模型和确定有效的氟西汀治疗对纹状体 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：自由活动小鼠的体内显微镜和电生理学。在目标 2 中，我们将使用活体显微镜确定与氟西汀治疗成功相关的 D1-和 D2-SPN 活动模式，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，我们将探讨这种关系 FSI 活性与氟西汀治疗反应之间的关系。这些研究的最终目标是帮助完善基于神经刺激的治疗策略，用于消除持续性和强迫性行为。