Functional connectivity at cellular resolution in brains with mutations in ASD genes

项目摘要 复杂的大脑疾病，如自闭症谱系障碍（ASD），精神分裂症，抑郁症， 焦虑症源于异质性遗传倾向（有时，与环境因素有关）。 影响）。这些疾病的共同标志是系统水平的脑功能障碍。虽然人类 遗传学研究已经确定了一系列疾病易感基因，其功能范围从 转录和翻译调节突触结构调节和神经传递，目前， 对于基因和相关的分子和细胞过程的破坏如何改变大脑， 连接性定义了每种疾病的某些行为特征。 这个探索性的R21应用程序旨在开发一个新的平台，以了解基本电路 水平，基因的破坏如何改变大脑的连接，从而试图连接分子细胞， 行为功能性磁共振成像（fMRI）研究探索了静息状态或任务相关的 功能连接，它测量人类大脑中不同神经生理事件之间的相关性。 这些研究提供了一个有价值的框架，但缺乏细胞分辨率，难以开展 在人类中的实验干扰排除了进一步的因果关系研究。为了揭开大脑 功能连接在系统水平与细胞分辨率，我们建议执行全脑钙 使用斑马鱼幼体进行成像和计算分析。作为脊椎动物遗传模式生物， 斑马鱼与人类在神经解剖学和基因组方面有相当大的相似性。斑马鱼幼体， 透明的大脑约有100K个神经元（相比之下，小鼠约为7500万，人类约为10亿）。 脑），特别适用于体内动态单细胞分辨率成像。在本申请中，通过 通过全脑钙成像和计算数据分析，我们提出确定遗传改变是如何影响大脑的， 可能会影响斑马鱼幼鱼细胞分辨率的脑功能连接。 预期成果和影响：如果成功，该项目将建立一个新的模式， 系统水平和细胞分辨率，遗传变化如何改变大脑连接。这些研究将奠定 为未来理解基因改变和电路活动之间的机制奠定了重要基础 变化，以及扩大研究到更多的基因。我们将开发包括 图像采集、处理和计算算法可用于广泛的研究社区。在 从长远来看，关于基因和大脑连接关系的新的基础知识将有助于开发新的 治疗理念高风险和高回报性质的拟议工作，使这一申请很好 适用于R21机制。

PROJECT SUMMARY Complex brain disorders such as the autism spectrum disorders (ASDs), schizophrenia, depression, and anxiety disorders stem from heterogeneous genetic predispositions (and at times, with environmental influences). A common hallmark of these disorders is a systems level brain dysfunction. Although human genetic studies have identified a repertoire of disease susceptibility genes with functions ranging from transcriptional and translational regulation to synaptic structural modulation and neurotransmission, at present, little is known as to how disruption of genes and associated molecular and cellular processes alter brain connectivity that define certain behavioral features of each disorder. This exploratory R21 application aims to develop a new platform for understanding, at the basic circuit level, how disruption of genes alters brain connectivity, thereby attempting to connect molecules cells and behavior. Functional Magnetic Resonance Imaging (fMRI) studies have explored resting-state or task-related functional connectivity, which measures correlations among distinct neurophysiological events in human brains. These studies have provided a valuable framework, but the lack of cellular resolution and difficulty to carry out experimental perturbation in humans precludes further cause-effect relationship studies. To uncover brain functional connectivity at systems levels with cellular resolution, we propose to perform brain-wide calcium imaging and computational analyses employing larval zebrafish. As a vertebrate genetic model organism, zebrafish shares considerable neuroanatomical and genomic similarity with humans. Larval zebrafish, with a transparent brain of ~100K neurons (as compared to ~75 million in the mouse, and ~1 billion in the human brain), is particularly suitable for dynamic single-cell resolution imaging in vivo. In this application, through brain-wide calcium imaging and computational data analyses, we propose to determine how genetic alterations may affect brain functional connectivity at cellular resolution in larval zebrafish. Expected outcomes and impact: If successful, this project will establish a new paradigm to uncover, at systems level and with cellular resolution, how genetic changes alter brain connectivity. These studies will lay critical foundation for future understanding of mechanisms between gene alterations and circuit activity changes, as well as expanding the studies to a greater number of genes. We will make technologies including image acquisition, processing, and computational algorithms available to the broad research community. In the long run, new basic knowledge about gene and brain connectivity relationships will aid in developing novel therapeutic ideas. The high risk and high reward nature of the proposed work makes this application well suited for the R21 mechanism.