Collaborative Research: Control of Information Processing and Learning in Neuronal Networks through Light-mediated Programming of Genomic Networks

通信和网络在生物有机体的发展和运作中发挥着关键作用。基因组或基因网络中的物理DNA相互作用决定了基因活动，从而决定了细胞的发育和功能，类似于软件决定计算机中硬件的操作。因此，能够对基因组相互作用进行编程，从而发展通信神经元网络是变革性应用的基础。在这个方向上，光基因组学，或通过光控制基因组功能，被提出。光基因组学提供了一种前所未有的手段来控制器官，特别是大脑的发育和功能，甚至癌症和其他疾病的新的纠正治疗。这种控制将通过开发新型的定向发光纳米器件来实现。这个跨学科项目的目标是研究由基因组的光操作编排的神经网络中的信息处理和学习(因此，最终是记忆)。为此，将开发新的光子和电子工具来对神经元基因组进行编程，并研究由此导致的活神经元网络结构和活动的变化。该项目将为研究生和本科生提供跨学科的培训机会，他们将精通纳米光子学和纳米电子学以及神经细胞研究。光遗传平台旨在利用光控制细胞与细胞的相互作用，光基因组系统允许控制基因组中的DNA相互作用，从而控制细胞发育和功能的编程。在这个项目中，将开发新的光基因组工具来控制神经元网络的发育、信息处理和学习。在建议的系统中，神经干细胞将被导入优化的光基因组构建，该构建结合了光激活的藻类蛋白和哺乳动物基因组调控因子。作为系统的输入，这些结构将通过基于LED的均匀照明在整个细胞培养过程中被全局激活。利用染色质构象捕捉HIC/HiChIP、原子力显微镜和RNAseq结合Nextgene全球基因组测序，将分析光诱导的基因组3D结构和功能的变化。该系统的输出将是光基因组构建的神经元网络中信号处理的光电生理学分析，创新的透明柔性波束形成纳米光子器件与灵活的高密度微电极阵列相结合，使用尖峰计时相关可塑性、Hebbian学习和网络科学等指标。将首次开发一个完整的基因组-神经元功能模型，将基因组拓扑网络与功能基因网络相关联，并最终与在人脑-脑器官3D模型中形成的神经网络的特性相关联。该奖项反映了NSF的法定使命，并已通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Communication and networking play a key role in the development and functioning of living organisms. The physical DNA interactions within the genome, or network of genes, determine gene activities and thereby the development and function of cells, similarly as the software determines the operation of the hardware in a computer. Therefore, being able to program genomic interactions and thereby the development of communicating neuronal networks is at the basis of transformative applications. In this direction, optogenomics, or the control of the genome function through light, is proposed. Optogenomics offers an unprecedented means to control organ and specifically brain development and functions, or even new corrective treatments of cancer and other diseases. Such control will be enabled through development of novel directional light emitting nano-devices. The goal of this inter-disciplinary project is to study information processing and learning (and, thus, ultimately memory) in neuronal networks orchestrated by the light manipulation of the genome. For this, new photonic and electronic tools will be developed to program the genome in neurons and to study both the resulting changes in the structure and activity in networks of living neurons. This project will provide inter-disciplinary training opportunities for graduate and undergraduate students, who will become versed in both nanophotonics and nanoelectronics as well as neuronal cell studies.Beyond optogenetic platforms, which are aimed at the use of light to control cell-cell interactions, optogenomic systems allow the control of DNA interactions in the genome and, thus, the programming of the cell development and function. In this project, new optogenomic tools will be developed to control the development and information processing and learning in neuronal networks. In the proposed system, neural stem cells will be transfected with optimized optogenomic constructs that combine light-activated algae proteins and mammalian genome regulators. As the input to the system, the constructs will be activated globally across the cell culture through LED-based homogeneous illumination. The light-induced changes in the genome 3D structure and function will be analyzed using Chromatin Conformation Capture HiC/HiChIP, Atomic Force Microscopy, and RNAseq with the NextGene global genome sequencing. The output of the system will be the opto-electrophysiological analysis of signal processing in optogenomically constructed neuronal networks, with innovative transparent flexile beamforming nanophotonic devices combined with flexible high-density microelectrode arrays, using metrics like Spike-Timing-Dependent Plasticity, Hebbian learning and network science. An integrated Genome-Neuronal Function Model will be developed for the first time by correlating genomic topological networks to the functional gene networks and ultimately to the properties of the resultant neuronal network as they form in 3D model of the human brain – cerebral organoids.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.