The effect of SHANK3 mutation in transgenic prairie voles on natural social behaviors and genetic mechanisms

项目摘要 自闭症谱系障碍（ASD）是一组相关的神经发育障碍，共同影响1 在美国的54名儿童中。Shank 3是一个ASD相关基因，因为有证据表明人类 Shank 3基因突变引起的ASD相关行为及其与ASD的关系 线Shank 3突变小鼠在纹状体中具有多个神经元缺陷（改变的突触结构和神经元损伤）。 功能，树突棘肥大，皮质纹状体连接过度，纹状体体积增大）， 纹状体中的转录组提示谷氨酸相关和激酶相关基因的额外失调。 关于Shank 3突变如何更广泛地影响ASD或社会行为的研究目前受到以下因素的限制 集中在一个单一的近交系小鼠物种。最近发现的Shank 3突变草原田鼠代表了 这是一个重要的进展，因为与老鼠不同，草原田鼠的基因多样， 与人类（一夫一妻制的伴侣关系，双亲照顾，社会损失引起的抑郁症，和同情心- 基于安慰），并且在自由生活的草原田鼠中， 自然条件。这项提议的目的是确定Shank 3突变在草原田鼠中的影响 在现场和实验室中复杂的社会行为，以及大脑中潜在的生物机制。 我们的中心假设是，草原田鼠中的Shank 3突变改变了纹状体转录调节社会性， 行为，与基因型相互作用，改变自然观察和实验室诱导的物种- 与自闭症相关的复杂社会行为。具体目标1将决定 由Shank 3突变引起的自然社会行为。我们将追踪自由的社会和生殖行为- 在半自然的野外围栏中，使用 自动行为监控系统、摄像机和社交网络分析。具体目标2将 确定并整合Shank 3突变田鼠的转录组、基因组和行为。我们将测试 实验室田鼠的行为电池，其独特的物种特异性的社会行为，然后序列 纹状体的转录组和基因组我们将联合收割机结合三个数据集使用多组学 一体化总之，这将提供关于分子和细胞改变的关键信息， 由Shank 3突变引起，这将直接关系到潜在的临床治疗和疗法。的 拟议中的研究还将验证转基因草原田鼠的最新创新， Shank 3相关自闭症研究。

Project Summary Autism spectrum disorder (ASD) is a cluster of related neurodevelopmental disorders that collectively impact 1 in 54 children in the United States. Shank3 is an ASD-associated gene because of evidence linking human Shank3 dysfunction to ASD and due to ASD-related behaviors caused by Shank3 mutations in two mouse lines. Shank3 mutant mice have multiple neuronal deficiencies in the striatum (altered synaptic structure and function, dendritic spine hypertrophy, corticostriatal hyperconnectivity, and enlarged striatal volume) and transcriptome in the striatum suggests additional dysregulation in glutamate-related and kinase-related genes. Research on how the Shank3 mutation affects ASD or social behavior more broadly is currently limited by the focus on a single inbred mouse species. The recent availability of a Shank3 mutant prairie vole represents a critical advance because, unlike mice, prairie voles are genetically diverse, share complex social behaviors with humans (monogamous pair bonding, bi-parental care, social loss-induced depression, and empathy- based consoling), and the full spectrum of social behaviors can be quantified in free-living prairie voles under natural conditions. The objective of this proposal is to determine the effects of Shank3 mutation in prairie voles on complex social behaviors in the field and laboratory, and the underlying biological mechanisms in the brain. Our central hypothesis is that Shank3 mutation in prairie voles alters striatal transcription regulating social behavior, which interacts with genotype to change both naturally observed and laboratory-induced species- specific complex social behaviors that are relevant to autism. Specific Aim 1 will determine the changes in natural social behaviors caused by Shank3 mutation. We will track social and reproductive behavior of free- living Shank3 mutant and wild-type prairie voles in semi-natural field enclosures over 3.5 months using an automated behavioral monitoring system, video cameras, and social network analyses. Specific Aim 2 will determine and integrate the transcriptome, genome and behavior of Shank3 mutant voles. We will test laboratory voles on a behavioral battery of their unique species-specific social behaviors, and then sequence the transcriptome and genome from dissected striatum. We will combine the three data sets using multi-omic integration. Together, this will provide critical information regarding the molecular and cellular alterations caused by Shank3 mutation, which will be directly relevant to potential clinical treatments and therapies. The proposed research will also validate the most recent innovation in transgenic prairie voles as a model for Shank3-related autism research.