CRCNS Research Proposal: Stochastic Processes Driving the Ascending Reticular Activating System

University Of California-Santa Barbara, Santa Barbara CA

Investigators

Abstract

All brain circuits, including those that underlie consciousness and perception, are physically embedded in a dense meshwork of microscopic, meandering fibers. These fibers are active and release signaling molecules that profoundly affect the brain. However, individual fibers do not have well-defined destinations and appear to be randomly oriented within brain tissue, frequently changing their direction. This property makes them very different from point-to-point nerve connections. Because of the unpredictability of individual fiber trajectories, brain research to date has focused on overall fiber "densities." These densities vary across brain regions and have been associated with normal and altered functions of the brain. This research project aims to reveal how local, random-like decisions by individual fibers lead to specific fiber densities in brain regions. The research also intends to determine whether the behavior of the fibers has remained fundamentally the same in the last 250 million years of vertebrate evolution. This conceptually-novel, interdisciplinary approach brings together recent developments in high-resolution microscopy, automated image analysis (including machine learning), and stochastic processes. The causal models developed in the project are expected to provide essential tools for the prediction of fiber densities from the dynamics of single fibers and will lay a theoretical foundation for fiber density manipulations in fundamental and applied neuroscience. The project's data and analyses will be used in a newly created interdisciplinary laboratory course and will also strengthen an undergraduate training program in bio-image informatics. The project naturally brings together neurobiology, engineering, and mathematics; this and its visual appeal make it well-suited for planned STEM-oriented presentations for K-12 students, as well as for public talks. Since serotonergic fibers present unique computational challenges, the project will contribute to the development of image analysis algorithms. The project will also build a rigorous theoretical foundation for the structure of "diffuse" neurotransmission that is affected in several mental disorders, including depression, schizophrenia, and autism spectrum disorder. Virtually all neural processes in vertebrate brains take place in a dense matrix of fibers that release serotonin, norepinephrine, and other neurotransmitters. This ancient system originates in the brainstem and is known as the ascending reticular activating system (ARAS). Since ARAS fibers do not form well-defined projections and have extremely meandering trajectories, their current descriptions fall outside the scope of connectomics projects and are based on observed fiber "densities." This interdisciplinary project seeks to reconstruct the fundamental self-organizing process that builds and supports the ARAS in the brain. In a radical departure from current descriptive approaches, it hypothesizes that the behavior of single serotonergic fibers can be described by a three-dimensional stochastic process, which determines the resultant fiber density (as an emergent phenomenon). Vertebrate brains, spanning some 250 million years of evolution, will be used to elucidate this process. Single ARAS fibers will be visualized with immunohistochemistry (including tissue expansion) and imaged with confocal laser scanning microscopy. Long fiber trajectories in mice will be visualized using tissue-clearing techniques and whole-brain imaging with light-sheet microscopy. An image analysis algorithm will be developed to automatically detect and trace individual fiber trajectories in the 3D-space. The trajectories will be used to build an optimal stochastic model, by taking advantage of advanced computational methods. 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.