THE GENETIC AND NEUROANATOMICAL ORIGIN OF SOCIAL BEHAVIOR

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，并确定有助于社会行为的神经解剖学和分子决定因素。社会行为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很少探索，尽管需要更好地了解人类健康。最近的许多发现强调了这一点，这些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显着缺陷。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小鼠模型的异常社会行为。单基因突变解释了综合征型ASD的一个子集，这些疾病的小鼠模型提供了实验测试和理解这些基因如何促成自闭症样表型的机会。我们假设，社会行为是敏感的Tsc 1或Fmr 1基因功能的时间要求。我们进一步假设特定的神经元群体对社会刺激有反应，并且由于共同分子靶点的潜在缺陷，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。本研究的具体目的是：i）通过条件诱导小鼠模型，删除和恢复Tsc 1和Fmr 1基因在成年小鼠脑中的表达，研究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，ii）第二阶段鉴定对社会刺激有反应的神经元群体，并通过分析Tsc 1和Fmr 1小鼠模型中的社会互动过程中的即时早期基因表达，iii）使用RNA测序、二维液相色谱和质谱以及蛋白抗体微阵列平台阐明Tsc 1和Fmr 1小鼠模型中异常社会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，社会行为是否可以被修改并可能被纠正。研究目标还将告知我们可能在社会行为表型的表现中至关重要的神经解剖学决定因素和分子靶点。总之，我们的研究结果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。 公共卫生相关性：ASD是一种流行的和毁灭性的神经精神疾病，影响多达1：100 - 1：150儿童。这项工作将确定社交行为缺陷（如ASD的特征）在成年后是否可逆，并将确定决定健康社交互动的神经解剖学和分子途径。确定与社会行为障碍相关的基本神经元和分子变化对人类健康具有深远的意义，因为ASD是一个日益突出的公共卫生问题。

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.