Profiling direct/indirect basal ganglia cells in restricted repetitive behavior

分析受限重复行为中的直接/间接基底神经节细胞

基本信息

批准号：
8465301
负责人：
AMBER M Muehlmann
金额：
$ 4.67万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-21 至 2013-03-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8465301
关键词：
Animal Model Attention Autistic Disorder Basal Ganglia Behavior Behavior Disorders Behavioral Biological Brain C58/J Mouse Cell Separation Cell membrane Cell surface Cells Clinical Cognitive Complication Corpus striatum structure Coupled Data Dementia Developmental Disabilities Disease Drug Delivery Systems Drug Design Evaluation Exhibits Fluorescence Fragile X Syndrome G-Protein-Coupled Receptors G-protein-coupled receptor 44 GTP-Binding Proteins Gene Expression Gene Proteins Gilles de la Tourette syndrome Goals Hand Head Banging Inbred Strain Inbred Strains Mice Individual Intracellular Membranes Investigation Laboratories Learning Measures Mental disorders Modeling Motor Mouse Strains Mus Nature Neurobiology Neurodevelopmental Disorder Neurologic Neurotransmitter Receptor Output Pathway interactions Pattern Pharmaceutical Preparations Pharmacotherapy Polymerase Chain Reaction Proteins Receptor Gene Receptor Signaling Relative (related person)Research Personnel Rett Syndrome Reverse Transcription Ritual compulsion Role Sampling Schizophrenia Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Sleep disturbances Surgical Flaps System Time Tissues Vesicle Vulnerable Populations Western Blotting Work base cell type clinical efficacy crosslink efficacy testing follow-up ganglion cell gastrointestinal interest mind control mouse model nervous system disorder neurobiological mechanism novel patient population protein expression public health relevance receptor receptor expression research study

项目摘要

DESCRIPTION (provided by applicant): Restricted repetitive behaviors are seen in many different neurodevelopmental, neurological, and psychiatric disorders (e.g. autism, Fragile X syndrome, Rett syndrome, dementias, OCD, and schizophrenia). These behaviors are classified as highly repetitive, invariant, and without obvious function. In neurodevelopmental disorders specifically, there is a wide array of repetitive behaviors exhibited, ranging from rhythmic hand flapping or head banging to circumscribed interests and insistence of sameness. Although these behaviors are extremely common in these patient populations, the neurobiological basis of the behavior disorder is relatively unknown and treatment is challenging. The overarching goals of our lab are to elucidate the neurobiological mechanisms responsible for the expression of restricted repetitive behaviors and to reduce these behaviors in individuals with neurodevelopmental disorders. Animal models of restricted repetitive behaviors allow researchers to identify the neurobiological basis of these particular maladaptive behaviors without the influence or complication of other biological problems associated with the neurodevelopmental disorders. Animal models also allow for the determination of clinical efficacy of potential pharmacological therapies before clinical experimentation is attempted in these very vulnerable populations. Evidence from a mouse model of restricted repetitive behavior indicates that specific pathways in the brain that make up cortico-basal ganglia circuitry are disregulated. These two pathways, the direct and indirect pathways, normally work in a coordinated, yet antagonistic fashion to control cortical activation and behavioral output. Data from our lab suggests that the activation of the indirect pathway is reduced in mice that exhibit repetitive behavior and this leaves the direct pathway to overexcite the cortex and produce aberrant behaviors. To achieve our goals of elucidating the neurobiological basis of repetitive behavior, we will use mice that exhibit spontaneous repetitive behaviors and profile the gene and protein expression within the direct and indirect basal ganglia pathways. First, we will use fluorescence assisted cell sorting to separate direct from indirect pathway cells. Then we will use RT-PCR arrays to simultaneously measure the expression of 41 G-protein coupled receptors and 44 signal transduction molecules in the separate cell groups. We will then analyze the amount of those receptors that are inserted in to the cell membrane (and are therefore biologically active) and the amount of those receptors that are packaged in to intracellular vesicles. Measures from mice that exhibit high rates of repetitive behavior (C58/J mice) will be compared to measures from a closely related mouse strain (C57BL/6J mice) that express no repetitive behavior. Based on the results of our gene and protein analyses we will design drug challenge experiments to identify whether any of the targets elucidated by the first two experiments offer potential pharmacotherapy for restricted repetitive behaviors. PUBLIC HEALTH RELEVANCE: Many people with developmental disabilities, neurological problems, or psychiatric issues show restricted repetitive behaviors. These behaviors are repetitive in nature and serve no obvious function (e.g. hand flapping, head banging, insistence on sameness, and compulsions). We are investigating what genes and proteins are expressed differently in mice that show these kinds of behaviors and in mice that do not in order to learn how the brain controls these behaviors and what kind of drugs may be used to reduce them.

描述（由申请人提供）：在许多不同的神经发育，神经系统和精神疾病（例如自闭症，脆弱的X综合征，RETT综合征，痴呆症，OCD和精神分裂症）中可以看到受限制的重复行为。这些行为被归类为高度重复，不变且没有明显的功能。特别是在神经发育障碍中，表现出广泛的重复行为，从节奏的手拍打或头部敲打到限制的利益和坚持相同的兴趣。尽管这些行为在这些患者人群中非常普遍，但行为障碍的神经生物学基础相对未知，治疗具有挑战性。我们实验室的总体目标是阐明负责限制重复行为表达的神经生物学机制，并减少神经发育障碍患者的这些行为。重复行为受限制行为的动物模型使研究人员能够识别这些特定的适应不良行为的神经生物学基础，而没有与神经发育障碍相关的其他生物学问题的影响或并发症。动物模型还允许在这些非常脆弱的人群中尝试在临床实验之前确定潜在药理疗法的临床疗效。来自限制重复行为的小鼠模型的证据表明，构成皮质 - 基质神经节回路的大脑中的特定途径被忽略了。这两种途径（直接和间接途径）通常以协调但拮抗的方式来控制皮层激活和行为输出。我们实验室的数据表明，在表现出重复行为的小鼠中，间接途径的激活减少，这留下了过度兴奋的皮质并产生异常行为的直接途径。为了实现我们阐明重复行为的神经生物学基础的目标，我们将使用表现出自发重复行为的小鼠，并在直接和间接的基础神经节途径中介绍基因和蛋白质表达。首先，我们将使用荧光辅助细胞分类来直接与间接途径细胞分开。然后，我们将使用RT-PCR阵列同时测量在单独的细胞组中41 G蛋白偶联受体和44个信号转导分子的表达。然后，我们将分析插入到细胞膜中的那些受体的量（因此具有生物活性），以及包装到细胞内囊泡中的那些受体的量。将表现出较高重复行为率（C58/J小鼠）的小鼠的测量与密切相关的小鼠菌株（C57BL/6J小鼠）的度量进行比较。根据我们的基因和蛋白质分析的结果，我们将设计药物挑战实验，以确定前两个实验阐明的任何目标是否为受限重复行为提供了潜在的药物治疗。公共卫生相关性：许多发育障碍，神经系统问题或精神病问题的人都表现出受限制的重复行为。这些行为本质上是重复性的，没有明显的功能（例如，手拍打，敲打，坚持相同性和强迫性）。我们正在研究哪些基因和蛋白质的表达方式不同，这些小鼠表明这些行为和小鼠在不想学习大脑如何控制这些行为以及可以使用哪种药物来减少它们的小鼠中。