Neurobiological Signatures of Social Dysfunction and Repetitive Behavior

描述（由申请人提供）：自闭症谱系障碍（ASD）出现在三岁之前，并被定义为社交功能障碍，沟通障碍和重复行为。目前的治疗显示对核心ASD症状有益的证据有限。我们需要基于对病理生理学的理解的新治疗方法。双胞胎研究将ASD确定为最可遗传的行为定义障碍。最强有力的ASD生物标志物是全血5-羟色胺（5-HT）升高，或高羟色胺血症，存在于超过25%的ASD儿童中。遗传连锁和关联研究指出，ASD和强迫症（OCD）中的5-羟色胺转运体（SERT）基因，这两种疾病都有重复行为的核心症状。罕见的SERT变异与ASD中的刚性强迫行为相关，并且在强迫症家族中也被发现。我们已经开发了一种表达这些变体中最常见的SERT Ala 56的小鼠。该小鼠重现了升高的全血5-HT生物标志物，并显示出增加的脑5-HT清除率和5-HT受体敏感性。SERT Ala 56小鼠还显示出改变的社会行为和新的重复电线攀爬/悬挂行为。而不是考虑这种小鼠作为一个模型的ASD作为一个类别，我们建议把重点放在行为领域，考虑改变社会刺激单独的重复行为。与其他ASD易感性模型一样，需要进一步的工作来连接神经元变化和由此产生的行为。为了将行为表型与潜在的电路和分子紊乱相匹配，我们将使用发育和基因表达方法。首先，我们将评估SERT功能增加对不同大脑区域的发育影响。其次，我们将映射神经元激活模式的即时早期基因表达（cFos）在响应行为挑战与社会刺激或在重复行为。第三，我们将确定发育和行为挑战实验所涉及的关键大脑区域的下游转录组变化。最后，我们将研究基因表达变化和行为改变之间的因果关系。这些结果将为患有高胆固醇血症内表型的一大群儿童的ASD易感性提供一个窗口，它们也将影响我们对影响这些行为领域的其他疾病的理解，如社交恐惧症或强迫症。最终目标是扩大对这些神经生物学特征的研究，以揭示治疗社会功能障碍和重复行为的新选择。

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) emerges before the age of three and is defined by social dysfunction, communication deficits, and repetitive behaviors. Current treatments show limited evidence of benefit for core ASD symptoms. We need new treatments based upon an understanding of pathophysiology. Twin studies identify ASD as the most heritable behaviorally defined disorder. The most robust ASD biomarker is elevated whole blood serotonin (5-HT), or hyperserotonemia, present in more than 25% of children with ASD. Genetic linkage and association studies point to the serotonin transporter (SERT) gene in both ASD and obsessive compulsive disorder (OCD), which share the core symptom of repetitive behavior. Rare SERT variants are associated with rigid-compulsive behavior in ASD and have also been identified in OCD families. We have developed a mouse that expresses the most common of these variants, SERT Ala56. This mouse recapitulates the elevated whole blood 5-HT biomarker and shows increased brain 5-HT clearance and 5-HT receptor sensitivity. The SERT Ala56 mouse also shows altered social behavior and a novel repetitive wireclimbing/ hanging behavior. Rather than consider this mouse as a model of ASD as a category, we propose to focus on behavioral domains, considering alterations in response to social stimuli separately from repetitive behaviors. As in other models of ASD susceptibility, further work is needed to connect neuronal changes and resulting behaviors. To match the behavioral phenotypes to underlying circuitry and molecular disturbances, we will use developmental and gene expression approaches. First, we will assess the developmental impact of increased SERT function on different brain regions. Second, we will map neuronal activation patterns by immediate early gene expression (cFos) in response to behavioral challenge with social stimuli or during repetitive behavior. Third, we will identify downstream transcriptome changes in the key brain regions implicated by developmental and behavioral challenge experiments. Finally, we will examine the causal relationship between gene expression changes and altered behaviors. The results will provide a window into ASD susceptibility in the large group of children with the hyperserotonemia endophenotype, and they will also impact our understanding of other disorders that affect these behavioral domains, such as social phobia or OCD. The ultimate goal is to expand studies of these neurobiological signatures to reveal new options for treatment of social dysfunction and repetitive behavior.