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

University Of California-Santa Barbara, Santa Barbara CA

Investigators

Abstract

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.