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、脆性 X 综合征、雷特综合征、痴呆症、强迫症和精神分裂症）中都可以看到受限的重复行为。这些行为被归类为高度重复、不变且没有明显功能的行为。特别是在神经发育障碍中，会表现出各种各样的重复行为，从有节奏的拍手或撞头到受限制的兴趣和坚持千篇一律。尽管这些行为在这些患者群体中极为常见，但行为障碍的神经生物学基础相对未知，治疗也具有挑战性。我们实验室的首要目标是阐明导致受限重复行为表达的神经生物学机制，并减少患有神经发育障碍的个体的这些行为。受限重复行为的动物模型使研究人员能够确定这些特定适应不良行为的神经生物学基础，而不受与神经发育障碍相关的其他生物学问题的影响或并发症。在对这些非常脆弱的人群进行临床实验之前，动物模型还可以确定潜在药物疗法的临床疗效。来自受限重复行为小鼠模型的证据表明，大脑中构成皮质基底神经节回路的特定通路受到失调。这两种途径，即直接途径和间接途径，通常以协调但对抗的方式发挥作用，以控制皮质激活和行为输出。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，这留下了过度兴奋皮层并产生异常行为的直接途径。为了实现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，并分析直接和间接基底神经节通路内的基因和蛋白质表达。首先，我们将使用荧光辅助细胞分选来分离直接途径细胞和间接途径细胞。然后我们将使用RT-PCR阵列同时测量不同细胞组中41个G蛋白偶联受体和44个信号转导分子的表达。然后，我们将分析插入细胞膜（因此具有生物活性）的这些受体的数量以及包装到细胞内囊泡中的这些受体的数量。将表现出高重复行为率的小鼠（C58/J 小鼠）的测量值与不表现重复行为的密切相关的小鼠品系（C57BL/6J 小鼠）的测量值进行比较。根据我们的基因和蛋白质分析结果，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潜在的药物疗法。公共卫生相关性：许多患有发育障碍、神经系统问题或精神问题的人表现出有限的重复行为。这些行为本质上是重复性的，没有明显的功能（例如拍手、撞头、坚持相同和强迫）。我们正在研究哪些基因和蛋白质在表现出此类行为的小鼠和没有表现出此类行为的小鼠中表达不同，以便了解大脑如何控制这些行为以及可以使用哪种药物来减少这些行为。