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

• 批准号: 9913589
• 负责人: Susanne Elizabeth Ahmari
• 金额: $ 47.71万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-11 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9913589
• 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; Hyperactive behavior; 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; neuroimaging; neuropsychiatric disorder; novel; optogenetics; prevent; public health relevance; relating to nervous system; repetitive behavior; response; sequence learning; theories; treatment response; treatment strategy

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.

项目摘要/摘要 尽管异常重复行为是突出的，残疾和臭名昭著的 许多严重的童年发作的抗药性症状神经精神疾病，例如痴迷 强迫症（OCD），图雷特综合征（TS）和自闭症，我们的理解仍然非常有限 关于它们在大脑中的编码方式。融合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的发展中，功能性神经影像学研究 始终证明1）与症状相关的纹状体多动症，即2）通过有效解决 治疗。但是，尚不清楚纹状体的两个主要相反细胞类型，D1和D2刺 投射神经元（SPN），在这些异常行为过程中有助于纹状体多动症以及活动方式 在这两种细胞类型中，受到药理治疗的影响。虽然普遍的理论表明 本质上生成异常的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相关间接途径的激活减少，几乎没有 直接支持这一想法的证据。开始剖析D1和D2-SPN对纹状体的贡献 多动症和这些不良适应性行为，我们使用了一种显示同时显示的动物模型系统 中央纹状体（CS）和持久性作用的多动症，包括强迫层和异常 逆转学习（Manning等人，在准备中）：SAPAP3-KO小鼠。在自由移动中使用体内显微镜 动物，我们证明了SAPAP3-KOS已增加了与美容相关的纹状体放电率提高， 与已发表的工作一致。令人惊讶的是，当我们有选择地检查D1-SPN时，与期望相反 与WT相比，我们看到了在强迫修饰事件开始时的活动减少，这表明减少了 D1-SPN对体内皮质输入的响应能力。通过有效将这种活动模式标准化 氟西汀治疗。这些数据表明了一个新型模型，其中D1-SPN的活性降低和过度 D2-SPN中的活性促进了异常重复行为的启动。在这个项目中，我们将使用状态 - 依赖的光遗传学，体内显微镜和体内电生理学直接测试该模型和 确定有效的氟西汀治疗对纹状体D1，D2和FSI的影响（快速尖刺的中间神经元） 活动模式。在AIM 1中，我们将在使用异常重复行为期间确定D2活性模式 自由移动小鼠的体内显微镜和电生理学。在AIM 2中，我们将使用体内显微镜 确定与成功氟西汀治疗相关的D1和D2-SPN活性模式，并确定 沉默的D2-SPN活性是否可以概括此归一化。在AIM 3中，我们将探索关系 在FSI活性和氟西汀治疗反应之间。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，用于禁用持久性和强迫性行为。