CRCNS US-German Research Proposal: Stochastic Axon Systems: From Spatial Dynamics to Self-Organization

在微观层面上，构成大脑连接的轴突和树突都在一个密集而活跃的薄纤维网络中运作。这些纤维起源于脑干，以各自独特的轨迹在脑组织中编织，并释放血清素，这是一种可以追溯到所有动物起源的化学信号。这个项目的重点是基本的计算原理，这些原理指导了这个普遍但神秘的矩阵的自组装。为了了解其深层结构，该项目汇集了一个跨学科的研究团队，将实验神经生物学、多粒子物理学、超级计算和应用数学联系起来。该项目将建立一个理论框架，以理解单个纤维轨迹的不确定性如何导致大脑区域中可预测的纤维密度。它试图最终解释人类大脑中纤维基质的发展，并计算任意（灭绝的，改变的或理论上设计的）大脑中纤维密度的分布，给定它们的形状和其他空间特性。这项研究将促进基础神经科学和应用神经科学的发展：血清素释放基质对感知和认知有深远的影响，在许多精神障碍中受到影响，并显示出显著的再生能力。此外，该项目的结果可能会提出人工神经网络的生物学启发创新，其当前架构不包括类似网状的组件。本项目为三所研究机构的两名研究生、一名博士后和一名本科生研究助理提供了跨学科神经科学的优秀培训机会。大脑中所有的神经过程在物理上都嵌入一个密集的细纤维基质（轴突），释放5-羟色胺（5-HT）。这个矩阵支持感知和认知，它的异常与许多精神障碍和状况有关，包括抑郁症、自闭症和接触精神活性药物。该项目将开发一个严谨的随机过程模型，该模型是单个血清素能纤维行为的基础，并导致它们大规模的自组织。随机过程的结构及其参数将根据转基因小鼠模型的高分辨率显微镜图像确定。该模型的预测能力将通过类似大脑的3D几何图形的超级计算模拟得到验证。此外，该研究将通过将该模型扩展到鲨鱼的大脑，来检验该模型是否可以广泛应用于整个脊椎动物分支。该项目汇集了一个跨学科的团队，将推进对随机轴突系统的基本理解。在方法上，它也将有助于反常扩散过程的理论，并可能提出人工神经网络的创新。德国联邦教育和研究部（BMBF）正在资助一个伙伴项目。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

At the microscopic level, the axons and dendrites that form the connections of the brain all operate in a dense and active meshwork of thin fibers. These fibers originate in the brainstem, weave through brain tissue in individually unique trajectories, and release serotonin, a chemical signal that dates back to the origin of all animals. This project focuses on the fundamental computational principles that guide the self-assembly of this pervasive, but enigmatic matrix. In order to understand its deep structure, the project brings together an interdisciplinary research team that bridges experimental neurobiology, multi-particle physics, supercomputing, and applied mathematics. The project will develop a theoretical framework to understand how the uncertainty of individual fiber trajectories can lead to predictable fiber densities in brain regions. It seeks to ultimately explain the development of the fiber matrix in the human brain and to compute the distribution of fiber densities in arbitrary (extinct, altered, or theoretically designed) brains, given their shape and other spatial properties. The study will advance both fundamental and applied neuroscience: the serotonin-releasing matrix has profound effects on perception and cognition, is affected in many mental disorders, and shows remarkable regenerative capabilities. In addition, the results of the project may suggest biologically-inspired innovations in artificial neural networks whose current architectures do not include meshwork-like components. The project presents an excellent training opportunity in interdisciplinary neuroscience for two graduate students, a postdoctoral researcher, and undergraduate research assistants at three institutions.All neural processes in the brain are physically embedded in a dense matrix of thin fibers (axons) that release serotonin (5-HT). This matrix supports perception and cognition, and its abnormalities have been associated with a number of mental disorders and conditions, including depression, autism, and exposure to psychoactive drugs. The project will develop a rigorous model of the stochastic process that underlies the behavior of single serotonergic fibers and leads to their large-scale self-organization. The structure of the stochastic process and its parameters will be determined based on high-resolution microscopy images in transgenic mouse models. The predictive power of the model will be validated with supercomputing simulations in brain-like 3D geometries. In addition, the study will examine if the model can be applied broadly across the vertebrate clade by extending it to shark brains. The project brings together an interdisciplinary team and will advance the fundamental understanding of stochastic axon systems. Methodologically, it will also contribute to the theory of anomalous diffusion processes and may suggest innovations in artificial neural networks. A companion project is being funded by the Federal Ministry of Education and Research, Germany (BMBF).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.