Peter Jung - US grants

This award is made under the high performance connections portion of ANIR's "Connections to the Internet" announcement, NSF 98-102. It provides partial support for two years for a DS-3 connection to the vBNS. Applications involve virtual manufacturing and materials processing, on-line EEG data analysis using nonlinear methods, long-term study of TCP/IP (Internet) based applications on high-speed satellite networks; data transfer of nuclear and particle physics research being conducted on an international level between Ohio University and the Thomas Jefferson National Accelerator facility. Collaborating institutions include NASA Lewis Research Center, the Jefferson Lab, and the Children's Medical Center in Cincinnati.

The emerging picture of brain function is that of a complex communication network between neurons and astrocytes. It has now become clear that astrocytes - the most numerous types of non-neuronal cells in the brain - are important partners to the neurons. Astrocytes listen to the neuronal chatter, respond to it and talk back to the neurons, thus modulating their functions. Understanding the complex communication network of neurons and astrocytes is therefore significant for the understanding of the brain.
While this emerging field of research has been driven so far predominantly by methods of cellular and molecular biology, the main objective of this project is to add a new set of tools - mathematical and computational modeling - that can offer new avenues to explore the complex neural-glial communication network. A mathematical/computational model - consisting of functional coupled units - generates a unique conceptual framework that allows categorizing biologic processes and generating predictions.

Specifically, this award will enable an exploration of the generation of signals in astrocytes in response to neuronal activity, the spatial spread of the signal through the network of astrocytes, and the effect of the spreading signal back on the neuronal circuit, all significant aspects of interactions between neurons and astrocytes. Realistic mathematical models of these interactions will be developed. After the significant components of the neural-glial communication system are understood, neuronal circuitry with an architecture resembling that in the cortex can be modeled, and the influence of astrocytes on the network will be explored.

These goals will be achieved through the use of modern imaging tools employed in a cell biologist's laboratory, from which critical data on intracellular calcium signaling will be used to develop realistic mathematical modeling of the neural-glial interactions.

This project has significance far beyond the specific purpose of understanding the communication network of astrocytes and neurons in the central nervous system. Quantitative and conceptual understanding of neural-glial interactions may provide a basis for a better understanding of brain disorders such as migraine and epilepsy, in which a glial component is strongly suspected. Additionally, understanding of the intracellular calcium signaling, an important signaling pathway between astrocytes, is of critical importance for signaling in a variety of tissues, such as liver, where it contributes to the release of enzymes, and in corneal and bronchial epithelia where it is involved with wound response.

Nerve cells communicate by conducting electrical signals along slender cytoplasmic extensions known as axons. Animals have evolved two basic mechanisms for increasing axonal conduction velocity. One is to increase axonal diameter and the other is to insulate axons by a process called myelination, which is a tight spiral wrapping of the axons that is formed by myelinating cells. In vertebrates the growth of axon diameter is caused principally by the accumulation of space-filling cytoskeletal polymers called neurofilaments inside the axons, and this is regulated locally by chemical signals from the myelinating cells. It is known that neurofilaments are transported along axons and that they alternate between rapid movements and prolonged pauses. The proportion of the time that the neurofilaments spend pausing is likely to be a principal determinant of their residence time in axons. This is a collaborative experimental and modeling project involving a biologist at Ohio State University and a physicist at Ohio University. The central hypothesis to be tested is that myelinating cells control axonal caliber by regulating neurofilament pausing. A computational model will be developed that relates the moving and pausing behavior of neurofilaments to their distribution along axons. The model will be based on detailed kinetic parameters of neurofilament movement derived experimentally in cultured neurons and will be verified experimentally by fluorescence microscopy of neurofilament movement in myelinated axons in tissue culture. The proposed research will generate a rigorous and quantitative framework that relates the size and shape of axons, which is a key influence on their electrical properties, to the moving and pausing behavior of their internal constituents. The research will involve graduate and undergraduate students in both the physical and biological sciences, providing an integrated and cross-disciplinary training experience at the interface between computational and experimental biology.

Nerve cells communicate by sending electrical impulses along thin protrusions called axons. One mechanism by which animals increase velocity of electrical impulses is to expand axons' cross-sectional area. This expansion is caused by an accumulation of microscopic space-filling protein polymers called neurofilaments, which are transported into axons where they form a dynamic scaffold. This collaborative project will use microscopic imaging in conjunction with computational modeling to test the hypothesis that neurofilament accumulation in axons is caused by a slowing of neurofilament transport, much as cars pile up on highways when the traffic slows. This project will provide a rigorous and quantitative framework that relates the size and shape of axons, which is a key influence on their electrical properties, to the motile behavior of their internal constituents. This work will also shed light on the mechanism by which neurofilaments accumulate abnormally and excessively within axons in many neurodegenerative diseases.

This project will provide a unique training opportunity at the interface of computational and experimental biology for students with diverse backgrounds in the physical and life sciences. An emphasis will be placed on mentoring undergraduates lacking prior research experience, including women and minorities, through annual Research Experiences for Undergraduates fellowships. The investigators will also reach out to undergraduates by participating together in the Research for Undergraduates: Adventures in Mathematical Biology and its Applications curriculum at Ohio State University, which is an NSF-funded Undergraduate Biology and Mathematics program, and by serving as joint mentors in the Undergraduate Summer Research Program of the NSF-funded Mathematical Biosciences Institute at Ohio State University. Lastly, a neurofilament wiki page will be developed featuring information and resources on mathematical modeling of axonal transport to support these outreach activities and to facilitate the exchange of data between the two laboratories.