Neurobiological Signatures of Social Dysfunction and Repetitive Behavior

描述（由申请人提供）：自闭症谱系障碍（ASD）在三岁之前出现，表现为社交功能障碍、沟通缺陷和重复行为。目前的治疗方法显示对核心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疗法。双胞胎研究确定自闭症谱系障碍是最具遗传性的行为定义障碍。最可靠的ASD生物标志物是全血血清素（5-HT）升高，或高血清素血症，在超过25%的ASD患儿中存在。遗传联系和关联研究指出，5 -羟色胺转运蛋白（SERT）基因在ASD和强迫症（OCD）中都存在，这两种疾病都有重复行为的核心症状。罕见的SERT变异与ASD中的刚性强迫行为有关，并且在强迫症家庭中也被发现。我们已经开发了一种表达这些变体中最常见的SERT Ala56的小鼠。这只小鼠再现了全血5-HT生物标志物升高，并显示出大脑5-HT清除率和5-HT受体敏感性增加。SERT Ala56小鼠也表现出改变的社会行为和一种新的重复爬线/悬挂行为。与其将这只小鼠作为ASD的一个类别模型，我们建议将重点放在行为领域，将对社会刺激的反应变化与重复行为分开考虑。与其他ASD易感性模型一样，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干扰相匹配，我们将使用发育和基因表达方法。首先，我们将评估SERT功能增加对不同脑区发育的影响。其次，我们将通过即时早期基因表达（cFos）来绘制神经元激活模式，以应对社会刺激的行为挑战或重复行为。第三，我们将通过发育和行为挑战实验确定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。这些结果将为研究大量高血清素血症内表型儿童的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.