Cross-Species Multi-Modal Neuroimaging to Investigate GABA Physiology in Fragile X Syndrome

在过去的二十年里，我们已经进入了一个更深层次的 对脆性X综合征(FXS)的科学认识；同时，我们对内在 导致大脑功能障碍的致病机制的复杂性已经增加。新发现 对新的动物模型和患有FXS的人类进行细粒度的发育分析是必不可少的 为了实现必要的突破，以便我们最终能够设计出能够产生 为受影响的个人带来重大的、长期的好处。因此，调查人员组成了 斯坦福大学合作脆性X中心寻求从根本上和实质性地促进知识 对FXS的病理生理学进行多层次的科学研究(分子、基因、突触、脑 电路/系统、行为)，在新的动物模型和受影响的人类中，以及从 大脑成熟的发育动力学。我们进一步寻求提供关于以下方面的重要新信息 有针对性的环境、药理学和行为方法如何积极影响 FXS大脑。为实现这些目标，将解决4个具体目标：目标1(科学)： 聘请高度协作、跨学科的调查人员团队，他们将专注于 通过三个相互作用、相互依赖和 强调创新的跨物种实验和比较的协同项目(新颖 小鼠模型和患有FXS的人类)。总的来说，这些项目采取了多层次的、最先进的 科学方法，跨越分子，受体，突触，电路和行为表型， 以及评估对有针对性的环境、药理学和行为探针的反应。这 研究将产生代表我们的实质性和翻译相关进展的信息 对FXS发病机制的认识。目标2(管理)：保持有效的行政管理 结构和有效的科学监督，通过建立一个行政核心 促进协调、沟通和协作，提供财务监督、专家简历 统计咨询和数据库管理，促进人类研究人员的招聘 参与者，并与中心行政和咨询委员会互动。目标3 (调查人员)：直接和实质性地让早期调查人员和调查人员参与， 中心科学活动的主要专业领域不在FXS。目标4(培训和 教育)：建立和管理选定的教育和培训机会，包括 暑期本科生计划，每月FXS杂志俱乐部和参加年度研讨会。

Over the past two decades, we have arrived at a deeper scientific understanding of fragile X syndrome (FXS); concurrently, our awareness ofthe intrinsic complexity of pathogenic mechanisms contributing to brain dysfunction has grown. New discoveries from fine-grained, developmental analyses of novel animal models and humans with FXS are essential for achieving needed breakthroughs, so that we can eventually design interventions that produce significant, long-term benefits for affected individuals. Accordingly, investigators comprising the Collaborative Fragile X Center at Stanford seek to fundamentally and substantively advance knowledge ofthe pathophysiology of FXS at multiple levels of scientific inquiry (molecular, gene, synapse, brain circuits/systems, behavior), in novel animal models and affected humans, and from the perspective of the developmental dynamics of brain maturation. We further seek to provide vital new information about how targeted environmental, pharmacologic and behavioral approaches can positively affect function of the FXS brain. To accomplish these objectives, 4 specific aims will be addressed: Aim 1 (Science): To engage a highly collaborative, trans-disciplinary team of investigators who will address focused and challenging questions concerning FXS pathophysiology through three interactive, interdependent and synergistic projects that emphasize innovative cross-species experiments and comparisons (novel mouse models and humans with FXS). Collectively, these projects take multi-level, state-of-the-art scientific approaches, spanning molecules, receptors, synapses, circuits and behavioral phenotypes, and assessing response to targeted environmental, pharmacological and behavioral probes. This research will yield information that represents substantive and translation-relevant advances in our understanding of FXS pathogenesis. Aim 2 (Management): To maintain an efficient administrative structure and effective scientific oversight through the establishment of an Administrative Core that promotes coordination, communication and collaboration, provides financial oversight, expert bio statistical consultation and database management, facilitates recruitment of human research participants, and interacts with the Center Administrative and Advisory Committees. Aim 3 (Investigators): To directly and substantively involve early-stage investigators and investigators whose primary field of expertise is outside of FXS in Center scientific activities. Aim 4 (Training and Education): To establish and manage selected educational and training opportunities including a summer undergraduate program, monthly FXS journal club and participation in an annual symposium.