Biophysics of Branched Cells: Intracellular Transport, Scaling Laws and The Supply of Metabolic Demand

Yale University, New Haven CT

Investigators

Abstract

Biological cells are active materials meaning that they continuously turn over their constituent molecules as they dissipate energy obtained from metabolic processes. The physics underlying this non-equilibrium state—the material and energy fluxes together with the constraints that they impose on the organism—is only just beginning to be defined. Branched cells, such as those of the nervous and immune systems, pose especially difficult and interesting metabolic challenges. In neurons, branched dendrites collect synaptic or sensory information over a large area; yet the narrow, often bifurcated, dendritic processes must also supply materials and energy to all parts of the cell, especially to those locations undergoing growth or high activity. This project will pursue a physics-inspired approach to understand how this balance between the retrograde flow of information and the anterograde flow of nutrients impacts the morphology and function of dendrites. In this project, the group will formulate and test a supply-and-demand model that proposes that the supply of nutrients by transport processes such as molecular motor proteins match the metabolic demands of neuronal growth, activity and maintenance. The model predicts that the diameters of branched dendrites change across branch points according to specific laws that in turn depend on which cellular processes have the highest metabolic demands. These laws will be tested in living cells by combining state-of-the-art microscopy techniques with genetic and physical manipulations. It is anticipated that this project will provide insight into how the brain computes using so little energy (compared to man-made computers) and may elucidate principles that could be used in computing and engineering. The work may also improve our understanding of neurological diseases, which often arise due to the disruption of metabolic or transport processes. This work will entail training undergraduate, postgraduate and post-doctoral physics and biology students What sets the profile of diameters in branched neurons? While electrical considerations must be crucial for setting diameters, it is also necessary that axons and dendrites be of sufficient girth to provide the flux of nutrients and energy to support the growth and activity of the cell, including cytoplasm, membrane, and synapses. What are the tradeoffs between information processing and material transport? Answering these questions is important for three reasons: It will provide design rules and models that increase our basic understanding of branched cells and tissues in general; it may facilitate the segmentation of neurons for making connectomic maps and classifying cell types; and it may provide insight into why aberrant dendritic morphologies are associated with disease. Reconciliation of the different interpretations of dendrite branching may give insight into how the brain computes so energy efficiently, a holy grail for engineers and computer scientists. Because of the deep mathematical connections between electrotonic spread and diffusion, and between action potentials and active intracellular transport, optimizing information processing and material flow may not be mutually exclusive. Indeed, shared signaling and transport constraints may have permitted the development of sophisticated brains that compute efficiently. This insight, if it holds up to the scrutiny of this project, may change the way we view evolution of the brain and may have applications in computing and engineering. 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.