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

项目总结 复杂的大脑疾病，如自闭症谱系障碍(ASDS)、精神分裂症、抑郁症和 焦虑症源于不同的遗传倾向(有时，与环境有关 影响)。这些疾病的一个共同特征是系统水平的大脑功能障碍。虽然是人类 遗传学研究已经确定了一系列疾病易感基因，其功能范围包括 转录和翻译对突触结构调节和神经传递的调节，目前， 关于基因的破坏以及相关的分子和细胞过程如何改变大脑，人们知之甚少。 定义每个障碍的特定行为特征的连接性。 这一探索性的R21应用旨在开发一个新的理解平台，在基本电路 水平，基因中断如何改变大脑连接，从而尝试连接分子细胞和 行为。功能磁共振成像(FMRI)研究探索了与静息状态或任务相关的 功能连通性，它衡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 在人类身上的实验扰动排除了进一步的因果关系研究。揭开脑洞 在系统水平上的功能连接与细胞分辨率，我们建议执行全脑钙 利用斑马鱼幼体进行成像和计算分析。作为一种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学上有相当大的相似性。斑马鱼幼体，有一个 透明的大脑，约100K神经元(相比之下，小鼠约7500万个，人类约10亿个 脑)，特别适合于活体内动态单细胞分辨率成像。在此应用程序中，通过 全脑钙成像和计算数据分析，我们建议确定基因改变如何 可能在细胞分辨率上影响斑马鱼幼体的大脑功能连通性。 预期结果和影响：如果成功，该项目将建立一个新的范例来揭示，在 在系统水平和细胞分辨率下，基因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关键基础 变化，以及将研究扩大到更多的基因。我们将制造包括 图像采集、处理和计算算法可供广泛的研究社区使用。在 从长远来看，关于基因和大脑连接关系的新基础知识将有助于开发新的 治疗的想法。拟议工作的高风险和高回报的性质使这一应用很好 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.