THE GENETIC AND NEUROANATOMICAL ORIGIN OF SOCIAL BEHAVIOR

描述(由申请人提供)：这项建议的首要目标是深入了解社会行为的可塑性，并确定有助于社会行为的神经解剖学和分子决定因素。社会行为既受遗传因素的制约，又受环境因素的制约，尽管为了人类健康需要更好地了解正常社会行为的遗传基础，但人们对正常社会行为的遗传基础研究仍然很少。最近的大量发现表明，自闭症谱系障碍(ASD)存在数十个易感基因，其核心特征包括明显的社交障碍。为了深入了解社会行为的基础，我们建议研究两种综合征自闭症小鼠模型--TSC1和Fmr1小鼠模型中的异常社会行为。单基因突变是综合症ASD的一个子集，这些疾病的小鼠模型提供了从实验上测试和了解这些基因如何影响自闭症样表型的机会。我们假设社会行为对TSC1或Fmr1基因功能的时间需求是敏感的。我们进一步假设，特定的神经元群体对社会刺激有反应，Tsc1或Fmr1的丢失可能会由于共同分子靶点的潜在缺陷而扰乱特定大脑区域的神经元激活模式。拟议工作的具体目的是i)通过删除和恢复这些基因在成年小鼠脑中的表达来研究Tsc1和Fmr1对正常社会行为的时间需求以及社会行为的可塑性；ii)通过分析TSC1和Fmr1小鼠模型中早期即刻基因的表达模式来确定对社会刺激有反应的神经元群体并检测他们的活动变化；iii)利用RNA测序、二维液相和质谱仪以及蛋白质抗体微阵列平台阐明TSC1和Fmr1小鼠模型中异常社会行为的分子决定因素。由于自闭症是一个突出的公共卫生问题，目前的患病率为每万名儿童中有60例，在某些人群中，每万名儿童中有超过110例，因此拟议的工作旨在确定在成年阶段的神经精神状况下，社会行为是否可以改变，并可能得到纠正。这项研究的目的还将告诉我们神经解剖学决定因素和分子靶标，这些可能在社会行为表型的表现中起关键作用。总之，我们的发现将为未来旨在通过遗传或药物手段改善人类社会行为表型的工作提供基础。 公共卫生相关性：自闭症是一组普遍的和破坏性的神经精神疾病，影响多达1：100-1：150的儿童。这项拟议的工作将确定社会行为缺陷，如自闭症的特征，在成年后是否可逆，并将确定决定健康社会互动的神经解剖学和分子途径。鉴于自闭症是一个日益严重的公共卫生问题，定义与社会行为障碍相关的根本神经元和分子变化对人类健康具有深远的好处。

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.