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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.

项目总结/文摘