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: 8211980
• 负责人: Rodney C Samaco
• 金额: $ 39.13万
• 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/8211980
• 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; 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

DESCRIPTION (provided by applicant): 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 deleting 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. PUBLIC HEALTH RELEVANCE: ASDs constitute a prevalent and devastating group of neuropsychiatric disorders affecting as many as 1:100 - 1:150 children. The proposed work will determine if social behavior deficits, such as those characteristic of ASDs, are reversible in adulthood, and will identify the neuroanatomical and molecular pathways that determine healthy social interactions. Defining the fundamental neuronal and molecular changes related to social behavior impairments has far-reaching benefits for human health, given that ASDs are a rising, prominent public health concern.

描述（由申请人提供）：本提案的总体目标是深入了解社会行为的可塑性，并确定影响社会行为的神经解剖学和分子决定因素。社会行为是由遗传和环境因素共同决定的，然而，正常社会行为的遗传基础仍未得到充分探索，尽管为了人类健康需要更好地了解它。最近的许多研究结果表明，自闭症谱系障碍（asd）中存在数十个易感位点，其核心特征包括明显的社会互动缺陷。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，Tsc1和Fmr1小鼠模型的异常社会行为。单基因突变是症候性ASD的一个子集，这些疾病的小鼠模型为实验测试和理解这些基因如何导致自闭症样表型提供了机会。我们假设社会行为对Tsc1或Fmr1基因功能的时间要求很敏感。我们进一步假设，特定的神经元群对社会刺激有反应，由于共同分子靶点的潜在缺陷，Tsc1或Fmr1的缺失可能会破坏特定大脑区域的神经元激活模式。本研究的具体目的是：1)利用条件诱导小鼠模型，通过删除和恢复成年小鼠大脑中Tsc1和Fmr1基因功能的表达，研究Tsc1和Fmr1基因对正常社会行为和社会行为可塑性的时间要求；ii)通过分析社交互动中Tsc1和Fmr1小鼠模型中即时早期基因表达模式，确定对社交刺激有反应的神经元群体，并检查其活性的变化；iii)利用RNA测序、二维液相色谱和质谱分析以及蛋白质抗体微阵列平台，阐明Tsc1和Fmr1小鼠模型中异常社交行为的分子决定因素。由于asd是一个突出的公共卫生问题，目前的患病率为每10,000名儿童中有60例，在某些人群中每10,000名儿童中有110例以上，因此拟议的工作旨在确定在成年阶段的神经精神疾病中，社会行为是否可以改变，并可能得到纠正。研究目的还将告诉我们神经解剖学的决定因素和分子目标，这可能是社会行为表型表现的关键。总之，我们的发现将为未来通过遗传或药理学手段改善人类社会行为表型的工作提供基础。