Development of Persistent Repetitive Behavior in Animals

描述（由申请人提供）：关于介导异常重复行为（例如，刻板印象，仪式）在自闭症谱系儿童和相关的神经发育障碍。这种知识的缺乏妨碍了有效的早期干预和预防战略。我们建议建立在生化和药理学研究结果，从我们以前的资助，支持我们的假设，减少间接基底神经节通路活动的动物，发展高水平的重复行为。因此，该项目的总体目标将是确定介导与高重复行为率相关的间接途径激活减少的特定形态学和蛋白质组学改变。具体来说，我们将确定树突形态和蛋白质表达的改变，介导减少间接途径激活和持续重复行为的发展（目标#1）。接下来，我们将检验以下假设：重复行为发展的经验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，我们将检验以下假设：通过选择药理学试剂加重或减弱重复行为会改变间接途径活性，这是一种通过改变该途径中表达的关键蛋白质介导的效应（目的#3）。这些目标的成功实现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治疗提供新的治疗靶点。 公共卫生相关性：对介导异常重复行为的发展和表达的神经生物学机制知之甚少（例如，刻板印象，仪式）在自闭症谱系和相关的神经发育障碍的儿童。这种知识的缺乏妨碍了有效的早期治疗和预防战略。该项目将使用动物模型来提供有关重复行为发展的大脑回路的重要新信息，以及可以为这些行为开发新的药物治疗方法。

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.