Neurobiological Signatures of Social Dysfunction and Repetitive Behavior

社交功能障碍和重复行为的神经生物学特征

• 批准号: 8294648
• 负责人: Jeremy Veenstra-VanderWeele
• 金额: $ 39.57万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294648
• 关键词: Adult; Affect; Age; Animal Model; Animals; Autistic Disorder; Behavior; Behavioral; Biological Markers; Blood; Brain; Brain Mapping; Brain region; Categories; Child; Code; Communication; Development; Developmental Gene; Developmental Process; Disease; Family; Fluoxetine; Functional disorder; Gene Activation; Gene Expression; Gene Expression Profile; Genes; Goals; High Pressure Liquid Chromatography; Hydroxyindoleacetic Acid; Immediate-Early Genes; Immunohistochemistry; Individual; Life; Maps; Measures; Mediating; Microdialysis; Modeling; Molecular; Mus; Neurobiology; Neurons; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Pathway interactions; Pattern; Phenotype; Predisposition; Proteins; Reverse Transcriptase Polymerase Chain Reaction; Serotonin; Social Behavior; Social Functioning; Social Phobia; Stimulus; Symptoms; Testing; Tissues; Transcript; Transgenic Mice; Twin Studies; Variant; Whole Blood; Work; autism spectrum disorder; base; data mining; endophenotype; extracellular; genetic association; genetic linkage; mouse model; neuronal patterning; novel; receptor sensitivity; research study; response; serotonin transporter; social

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.

描述（由申请人提供）：自闭症谱系障碍（ASD）在三岁之前出现，并由社会功能障碍，沟通缺陷和重复行为定义。当前的治疗表明有限的核心ASD症状有益证据。我们需要基于对病理生理学的理解的新疗法。双胞胎研究将ASD视为最可遗传的行为定义疾病。最强的ASD生物标志物是升高全血清素（5-HT）或高超过25％的ASD儿童。遗传连锁和关联研究指向ASD和强迫症（OCD）中的5-羟色胺转运蛋白转运蛋白（SERT）基因，它们具有重复行为的核心症状。罕见的SERT变体与ASD中的刚性强迫行为有关，并且在强迫症家族中也已确定。我们开发了一种表示这些变体中最常见的鼠标Sert Ala56。该小鼠概括了升高的全血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 ALA56鼠标还显示出改变的社会行为和一种新颖的重复攀爬/悬挂行为。我们没有将这只小鼠视为ASD的模型，而是建议专注于行为领域，考虑对社会刺激的改变，分别与重复行为分别响应社会刺激。与其他ASD敏感性模型一样，需要进一步的工作来连接神经元的变化和产生的行为。为了使行为表型与基本电路和分子障碍匹配，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展影响。其次，我们将通过立即的早期基因表达（CFO）来绘制神经元激活模式，以应对社会刺激或重复行为期间的行为挑战。第三，我们将确定由发育和行为挑战实验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。结果将为大批患有性血症内型的大批儿童提供ASD敏感性的窗口，它们还将影响我们对影响这些行为领域的其他疾病的理解，例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。