Section: New Results

Neuroscience & Neuroendocrinology: Regulation of the Gonadotrope axis

A numerical method for transport equations with discontinuous flux functions: application to mathematical modeling of cell dynamics

Participants : Benjamin Aymard, Frédérique Clément, Frédéric Coquel, Marie Postel.

We have proposed a numerical method to handle discontinuous fluxes arising in transport-like equations [35] . More precisely, we have studied hyperbolic PDEs with flux transmission conditions at interfaces between subdomains where coefficients are discontinuous. A dedicated finite volume scheme with a limited high order enhancement has been adapted to treat the discontinuities arising at interfaces. The validation of the method has been done on one- and two-dimensional toy problems for which exact solutions are available, allowing us to do a thorough convergence study. We have then applied the method to a biological model focusing on complex cell dynamics [40] that initially motivated this study and illustrates the full potentialities of the scheme.

Adaptive mesh refinement strategy for a nonconservative transport problem

Participants : Benjamin Aymard, Frédérique Clément, Marie Postel.

In the framework of transport equations it is usual to need long time simulations, and therefore large physical domains to cover a phenomenon. On the other hand it can happen that only a small time varying portion of the domain is interesting. This motivates the use of adaptivity for the spatial discretization. Biological models involving cell development are often nonconservative to account for cell division. In that case the threshold controlling the spatial adaptivity may have to be time-dependent in order to keep up with the progression of the solution. We have tackled the difficulties arising when applying a multiresolution method to a transport equation with discontinuous fluxes modeling localized mitosis [76] . The analysis of the numerical method is performed on a simplified model and numerical scheme. An original threshold strategy is proposed and validated thanks to extensive numerical tests. It is then applied to a biological model in both cases of distributed and localized mitosis.

Coupled Somatic Cell Kinetics and Germ Cell Growth: Multiscale Model-Based Insight on Ovarian Follicular Development

Participants : Frédérique Clément, Philippe Michel, Danielle Monniaux, Thomas Stiehl.

We have designed a stochastic individual-based model describing the first stages of follicular development, where the cell population is structured with respect to age (progression within the cell cycle) and space (radial distance from the oocyte) [39] . The model accounts for the molecular dialogue existing between the oocyte and granulosa cells. Three dynamically interacting scales are considered in the model: (i) a microscopic, local scale corresponding to an individual cell embedded in its immediate environment, (ii) a mesoscopic, semi-local scale corresponding to anatomical or functional areas of follicles and (iii) a macroscopic, global scale corresponding to the morphology of the follicle. Numerical simulations were performed to reproduce the 3D morphogenesis of follicles and follow simultaneously the detailed spatial distribution of individual granulosa cells, their organization as concentric layers or functional cell clones and the increase in the follicle size. Detailed quantitative simulation results have been provided in the ovine species, in which well characterized genetic mutations lead to a variety of phenotypic follicle morphogenesis. The model can help to explain pathological situations of imbalance between oocyte growth and follicular cell proliferation.

Innovative computational and theoretical tools for slow-fast dynamics

Participants : Mathieu Desroches, Maciej Krupa.

Mixed-Mode Bursting Oscillations: Dynamics created by a slow passage through spike-adding canard explosion in a square-wave burster [44] . This work concerns the phenomenon of Mixed-Mode Bursting Oscillations (MMBOs). These are solutions of fast-slow systems of ordinary differential equations that exhibit both small-amplitude oscillations (SAOs) and bursts consisting of one or multiple large-amplitude oscillations (LAOs). The name MMBO is given in analogy to Mixed-Mode Oscillations, which consist of alternating SAOs and LAOs, without the LAOs being organized into burst events. In this article, we show how MMBOs are created naturally in systems that have a spike-adding bifurcation or spike-adding mechanism, and in which the dynamics of one (or more) of the slow variables causes the system to pass slowly through that bifurcation. Canards are central to the dynamics of MMBOs, and their role in shaping the MMBOs is two-fold: saddle-type canards are involved in the spike-adding mechanism of the underlying burster and permit one to understand the number of LAOs in each burst event, and folded-node canards arise due to the slow passage effect and control the number of SAOs. The analysis is carried out for a prototypical fourth-order system of this type, which consists of the third-order Hindmarsh-Rose system, known to have the spike-adding mechanism, and in which one of the key bifurcation parameters also varies slowly. We also include a discussion of the MMBO phenomenon for the Morris-Lecar-Terman system. Finally, we discuss the role of the MMBOs to a biological modeling of secreting neurons.

Canards in piecewise-linear systems: explosions and super-explosions [43] . We show that a planar slow-fast piecewise-linear (PWL) system with three zones admits limit cycles that share a lot of similarity with van der Pol canards, in particular an explosive growth. Using phase-space compactification, we show that these quasi-canard cycles are strongly related to a bifurcation at infinity. Furthermore, we investigate a limiting case in which we show the existence of a continuum of canard homoclinic connections that coexist for a single-parameter value and with amplitude ranging from an order of ε to an order of 1, a phenomenon truly associated with the non-smooth character of this system and which we call super-explosion.

Some results have been obtained concerning numerical continuation techniques for planar slow-fast systems [42] and short-term synaptic plasticity in the deterministic Tsodyks-Markram model that leads to unpredictable network dynamics [41] .