THE GENETIC AND NEUROANATOMICAL ORIGIN OF SOCIAL BEHAVIOR

社会行为的遗传和神经解剖学起源

• 批准号: 8915278
• 负责人: Rodney C Samaco
• 金额: $ 10.07万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-20 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8915278
• 关键词: Accounting; Adult; Affect; Amygdaloid structure; Animal Model; Animals; Antibodies; Anxiety; Autistic Disorder; Brain; Brain region; Characteristics; Child; Clinical; Data; Defect; Development; Disease; Environmental Risk Factor; Foundations; Functional disorder; Future; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Mutation; Genes; Genetic; Goals; Health; Human; Immediate-Early Genes; Impairment; Knock-out; Life; Link; Maps; Molecular; Molecular Target; Mus; Nature; Neurons; Pathway interactions; Pattern; Phenotype; Plastics; Population; Predisposition; Prevalence; Prosencephalon; Proteins; Proteome; Public Health; RNA Sequences; Research; Role; Social Behavior; Social Interaction; Staging; Stimulus; Symptoms; TSC1 gene; Tamoxifen; Testing; Wild Type Mouse; Work; abstracting; autism spectrum disorder; base; behavior test; design; gene function; human FRAP1 protein; improved; insight; liquid chromatography mass spectrometry; mature animal; mouse model; neural information processing; neuronal patterning; neuropsychiatry; relating to nervous system; response; restoration; social; two-dimensional

THE GENETIC AND NEUROANATOMICAL ORIGIN OF SOCIAL BEHAVIOR PROJECT SUMMARY/ABSTRACT The overarching goal of this proposal is to gain insight into the plasticity of social behavior, and to identify the neuroanatomical and molecular determinants that contribute to social behavior. Social behavior is governed by both genetic and environmental factors, yet the genetic basis for normal social behavior remains poorly explored in spite of a need to better understand it for human health. This is underscored by numerous recent findings implicating dozens of susceptibility loci in autism spectrum disorders (ASDs), whose core features include marked deficits in social interaction. To gain insight into the underpinnings of social behavior, we propose to study abnormal social behavior in two mouse models of syndromic autism, the Tsc1 and Fmr1 mouse models. Single gene mutations account for a subset of syndromic ASD and mouse models of these disorders provide the opportunity to experimentally test and understand how these genes contribute to autism- like phenotypes. We hypothesize that social behavior is sensitive to the temporal requirement of either Tsc1 or Fmr1 gene function. We further hypothesize that specific neuronal populations are responsive to social stimuli, and that the loss of Tsc1 or Fmr1 may disrupt the pattern of neuronal activation in specific brain regions due to an underlying defect in common molecular targets. The Specific Aims of the proposed work are i) investigate the temporal requirement of Tsc1 and Fmr1 for normal social behavior and the plasticity of social behavior by deleteing and restoring the expression of these genes' functions in the adult mouse brain using conditionally inducible mouse models, ii) identify the neuronal populations responsive to social stimuli and examine alterations in their activity in Tsc1 and Fmr1 mouse models by analyzing the pattern of immediate early gene expression during social interaction, iii) elucidate the molecular determinants of abnormal social behavior in Tsc1 and Fmr1 mouse models using RNA sequencing, two-dimensional liquid chromatography and mass spectrometry, and protein antibody microarray platforms. Because ASDs are a prominent public health concern with a current prevalence rate of 60 cases per 10,000 children, and in some populations more than 110 cases per 10,000 children, the proposed work is designed to determine if social behavior can be modified, and possibly corrected, in neuropsychiatric conditions during the adult stage of life. The research aims will also inform us of the neuroanatomical determinants and molecular targets that may be critical in the manifestation of social behavior phenotypes. Together, our findings will provide the foundation for future work designed to improve social behavior phenotypes in humans by either genetic or pharmacological means.

社会行为的遗传学和神经解剖学起源 项目总结/摘要 这项提案的首要目标是深入了解社会行为的可塑性， 确定有助于社会行为的神经解剖学和分子决定因素。社会行为是 虽然受遗传和环境因素的影响，但正常社会行为的遗传基础仍然存在。 尽管需要更好地了解它对人类健康的影响，但对它的研究却很少。这一点被许多 最近的发现涉及自闭症谱系障碍（ASD）的数十个易感基因座，其核心 特征包括社会互动的明显缺陷。为了深入了解社会行为的基础， 我们建议研究两种综合征型自闭症小鼠模型Tsc 1和Fmr 1的异常社会行为， 小鼠模型。单基因突变可解释ASD综合征的一个子集， 疾病提供了实验测试和了解这些基因如何导致自闭症的机会， 就像表型一样我们假设社会行为对Tsc 1或Tsc 2的时间要求是敏感的。 Fmr 1基因功能。我们进一步假设特定的神经元群体对社会刺激有反应， Tsc 1或Fmr 1的缺失可能会破坏特定脑区的神经元激活模式， 普通分子靶点的潜在缺陷。拟议工作的具体目标是：i）调查 Tsc 1和Fmr 1对正常社会行为的时间需求以及社会行为的可塑性， 在成年小鼠脑中，使用条件性地删除和恢复这些基因功能的表达， 诱导型小鼠模型，ii）鉴定对社会刺激有反应的神经元群体， 通过分析立即早期基因的模式，在Tsc 1和Fmr 1小鼠模型中改变其活性 在社会互动过程中的表达，iii）阐明异常社会行为的分子决定因素， 使用RNA测序、二维液相色谱和质谱的Tsc 1和Fmr 1小鼠模型 光谱法和蛋白质抗体微阵列平台。因为自闭症是一个突出的公共健康 关切地注意到，目前的发病率为每10 000名儿童60例，在某些人群中， 每10,000名儿童中有110例，这项拟议的工作旨在确定社会行为是否可以改变， 并可能在成年阶段的神经精神疾病中得到纠正。研究目的将 还告诉我们，神经解剖决定因素和分子靶点，可能是关键的， 社会行为表型的表现。总之，我们的发现将为未来的工作奠定基础 旨在通过遗传或药理手段改善人类的社会行为表型。