Computational methods and modeling to decipher organelle nanophysiology

ongoing

Neuronal and glial physiology in nanodomains remains poorly understood due to the spatio-temporal limitation of direct unperturbed in vivo measurements. Yet, it is the scale of voltage regulation, ionic, proteins and molecular trafficking, metabolism control and local signal transduction. The goal of this proposal is to determine how the flow of ions and molecules is regulated in the cytoplasm in relation with organelles, such as the endoplasmic reticulum and mitochondria in various physiological conditions such as steady-state, induction of plastic changes or ionic depletion. The approach is based on mathematical modeling, large data analysis, simulation methods, and developing the associated fast and efficient algorithms. We developed in the past 15 years computational tools such as molecular modeling, stochastic simulations and data analysis at a molecular level to study various signals such as voltage recordings or super-resolution microscopy single particle trajectories (SPTs). However, these theoretical approaches are not sufficient today to face the novel data revolution coming from SPTs, but also voltage dyes, voltage recorded by nanopipettes, or photoconversion in nanocompartments. The aim of the project is to develop physical models of molecular diffusion and electro-diffusion. These models will be applied to reconstruct and interpret the local transport, which is not homogeneous because molecules or receptors could aggregate in some specific nano-regions. We will explore the mechanisms underlying this heterogeneity. Second, we will apply these modeling and numerical simulations to analyze data about flux regulation inside the cytoplasm but also in organelles, such as the ER and mitochondria.Third, we analyze calcium fluorescent data (photoactivation, local uncaging) to study how calcium is exchanged in nanodomains during synaptic transmission in dendrites and dendritic spines.