THE GENETIC AND NEUROANATOMICAL ORIGIN OF SOCIAL BEHAVIOR

社会行为的遗传学和神经解剖学起源 项目摘要/摘要 这项建议的首要目标是洞察社会行为的可塑性，并 确定对社会行为有贡献的神经解剖学和分子决定因素。社会行为是 受遗传和环境因素的支配，但正常社会行为的遗传基础仍然存在 尽管有必要更好地了解它对人类健康的影响，但对它的探索很少。这一点得到了许多人的强调 最近的发现涉及自闭症谱系障碍(ASDS)的数十个易感基因，其核心是 这些特征包括社交方面的明显缺陷。为了深入了解社会行为的基础， 我们建议研究两种综合征自闭症小鼠模型TSC1和Fmr1的异常社会行为 老鼠模型。单基因突变是ASD综合征和小鼠模型的一个子集 障碍提供了从实验上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TSC1或TSC1的时间要求很敏感 FMR1基因的功能。我们进一步假设，特定的神经元群体对社会刺激有反应， Tsc1或Fmr1的缺失可能会扰乱特定脑区神经元的激活模式，这是由于 普通分子靶标的潜在缺陷。拟议工作的具体目的是：1)调查 Tsc1和Fmr1对正常社会行为的时间需求和社会行为的可塑性 有条件地删除和恢复这些基因在成年小鼠脑中的功能表达 可诱导的小鼠模型，II)识别对社会刺激反应的神经元群体并检查 通过分析即刻早期基因模式在TSC1和Fmr1小鼠模型中它们的活性变化 在社会交往中的表达，III)阐明了异常社会行为的分子决定因素 TSC1和Fmr1小鼠模型的RNA测序、二维液相色谱和质量分析 光谱分析和蛋白质抗体微阵列平台。因为自闭症是一个突出的公共卫生问题 感到关切的是，目前的流行率为每10 000名儿童中有60例病例，在一些人口中超过 每10,000名儿童中有110例，拟议的工作旨在确定社会行为是否可以改变， 在成年阶段的神经精神状态下，可能还会得到纠正。研究的目的将是 也告诉我们神经解剖学上的决定因素和分子靶点可能在 社会行为表型的表现。总之，我们的发现将为未来的工作提供基础 旨在通过遗传或药物手段改善人类的社会行为表型。

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.