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，定义为社交功能障碍、沟通障碍和重复行为。目前的治疗方法对ASD核心症状的益处证据有限。我们需要在了解病理生理学的基础上进行新的治疗。双胞胎研究发现，自闭症是最易遗传的行为定义障碍。ASD最有力的生物标志物是全血5-羟色胺(5-HT)升高，或高5-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，在ASD和强迫症(OCD)中都存在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的强迫性行为有关，在强迫症家族中也被发现。我们已经开发出一种可以表达这些最常见的变体SERT Ala56的小鼠。这只小鼠概括了升高的全血5-羟色胺生物标志物，并显示脑内5-羟色胺清除增加和5-羟色胺受体敏感性增加。SERT Ala56小鼠还表现出改变的社会行为和新颖的重复爬绳/悬挂行为。与其将这只小鼠作为ASD的一个模型作为一个类别，我们建议将重点放在行为领域，将对社会刺激的反应与重复行为分开考虑。就像在ASD易感性的其他模型中一样，需要进一步的工作来将神经元的变化与由此产生的行为联系起来。为了将行为表型与潜在的电路和分子障碍相匹配，我们将使用发育和基因表达方法。首先，我们将评估SERT功能增强对不同脑区的发育影响。其次，我们将通过即时早期基因表达(CFO)来定位神经元的激活模式，以应对社会刺激或重复行为的行为挑战。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，我们将检验基因表达变化和行为变化之间的因果关系。这一结果将为了解大量高5-羟色胺血症内表型儿童对ASD的易感性提供一个窗口，也将影响我们对影响这些行为领域的其他障碍的理解，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，以揭示治疗社交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.