Development of Persistent Repetitive Behavior in Animals

描述(由申请人提供)：自闭症儿童异常重复行为(例如，刻板印象、仪式)的发展和表达的神经生物学机制，以及相关的神经发育障碍，目前知之甚少。由于缺乏知识，因此无法采取有效的早期干预和预防战略。我们建议建立在我们之前资助的生化和药理学发现的基础上，这些发现支持我们的假设，即在发展高水平重复行为的动物中，间接基底节通路活动减少。因此，该项目的总体目标将是确定特定的形态和蛋白质组变化，这些变化介导了与高重复行为相关的间接途径激活减少。具体地说，我们将确定树突状细胞形态和蛋白表达的变化，这些变化介导了间接途径激活减少和持续性重复行为的发展(目标1)。接下来，我们将检验这一假设，即经验依赖的重复行为发展的减弱将导致更高水平的间接途径激活，这一结果是由树突棘密度和蛋白质表达改变所介导的(目标2)。最后，我们将检验这一假说，即选定的药物对重复行为的加剧或减弱会改变间接途径的活性，这一效应是通过改变该途径中表达的关键蛋白来实现的(目标#3)。这些目标的成功完成将为调节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。由于缺乏知识，因此无法采取有效的早期治疗和预防战略。这个项目将使用一个动物模型来提供关于大脑回路的重要新信息，这些回路是重复行为发展的基础，以及可以为这些行为开发哪些新药治疗。

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.