Development of Persistent Repetitive Behavior in Animals

动物持续重复行为的发展

• 批准号: 8439309
• 负责人: MARK H LEWIS
• 金额: $ 37.3万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8439309
• 关键词: Acute; Animal Model; Animals; Attenuated; Autistic Disorder; Basal Ganglia; Behavior; Biochemical; Biological Assay; Brain; Child; Chronic; Clinical; Clinical Drug Development; Complex; Data; Deer Mouse; Dendritic Spines; Development; Diagnostic; Disease; Drug Combinations; Early treatment; Goals; Golgi Apparatus; Grant; Histocytochemistry; Intervention; Knowledge; Mediating; Mediator of activation protein; Metabolic Activation; Methods; Modeling; Morphology; Neurodevelopmental Disorder; Neurologic; Neurons; Outcome; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Prevention strategy; Proteins; Proteomics; Ritual compulsion; Staining method; Stains; Testing; Western Blotting; attenuation; base; cytochrome c oxidase; density; design; effective therapy; environmental enrichment for laboratory animals; experience; mature animal; neurobiological mechanism; neuropsychiatry; new therapeutic target; novel; protein expression; relating to nervous system; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Little is known about the neurobiological mechanisms that mediate the development and expression of abnormal repetitive behaviors (e.g., stereotypies, rituals) in children with autism spectrum, and related neurodevelopmental, disorders. This lack of knowledge precludes effective early intervention and prevention strategies. We propose to build on the biochemical and pharmacological findings from our previous grant that support our hypothesis of reduced indirect basal ganglia pathway activity in animals that develop high levels of repetitive behavior. Thus, the overall goal of this project wil be to identify specific morphological and proteomic alterations that mediate the reduced indirect pathway activation associated with high rates of repetitive behavior. Specifically, we will identif alterations in dendritic morphology and protein expression that mediate reduced indirect pathway activation and development of persistent repetitive behavior (Aim #1). Next, we will test the hypothesis that experience dependent attenuation of the development of repetitive behavior will result in higher levels of indirect pathway activation, an outcome mediated by altered dendritic spine density and protein expression (Aim #2). Finally, we will test the hypothesis that exacerbation or attenuation of repetitive behavior by select pharmacological agents alters indirect pathway activity, an effect mediated by alteration of key proteins expressed in this pathway (Aim #3). Successful completion of these aims will provide new and important information about specific neurobiological mechanisms that mediate the development and expression of repetitive behavior and provide novel therapeutic targets for the development of efficacious pharmacotherapies. PUBLIC HEALTH RELEVANCE: Little is known about the neurobiological mechanisms that mediate the development and expression of abnormal repetitive behaviors (e.g., stereotypies, rituals) in children with autism spectrum and related neurodevelopmental disorders. This lack of knowledge precludes effective early treatment and prevention strategies. This project will use an animal model to provide important, new information about the brain circuitry that underlies the development of repetitive behavior and what new drug treatments can be developed for these behaviors.

描述（由申请人提供）：对于介导自闭症谱系和相关神经发育障碍儿童异常重复行为（例如刻板印象、仪式）的发展和表达的神经生物学机制知之甚少。这种知识的缺乏阻碍了有效的早期干预和预防策略。我们建议以我们之前资助的生化和药理学发现为基础，这些发现支持我们的假设，即在产生高水平重复行为的动物中间接基底神经节通路活性减少。因此，该项目的总体目标是确定特定的形态学和蛋白质组学改变，这些改变介导与高重复行为率相关的间接途径激活减少。具体来说，我们将确定树突形态和蛋白质表达的改变，这些改变会介导间接途径激活的减少和持续重复行为的发展（目标#1）。接下来，我们将测试以下假设：重复行为发展的经历依赖性衰减将导致更高水平的间接途径激活，这是由树突棘密度和蛋白质表达改变介导的结果（目标#2）。最后，我们将测试这样的假设：通过选择药理学药物来加剧或减弱重复行为会改变间接途径活性，这是通过改变该途径中表达的关键蛋白质介导的效应（目标#3）。这些目标的成功完成将为介导重复行为的发展和表达的特定神经生物学机制提供新的重要信息，并为开发有效的药物疗法提供新的治疗靶点。 公共卫生相关性：对于介导自闭症谱系和相关神经发育障碍儿童异常重复行为（例如刻板印象、仪式）的发展和表达的神经生物学机制知之甚少。这种知识的缺乏阻碍了有效的早期治疗和预防策略。该项目将使用动物模型来提供有关重复行为发展背后的大脑回路的重要新信息，以及可以为这些行为开发哪些新药物治疗方法。