Alessio Franci

An Organizing Center in a Planar Model of Neuronal Excitability

This paper studies the excitability properties of a generalized FitzHugh--Nagumo model. The model differs from the classical FitzHugh--Nagumo model in that it accounts for the effect of cooperative gating variables such as activation of calcium currents. Excitability is explored by unfolding a pitchfork bifurcation that is shown to organize five different types of excitability. In addition to the three classical types of neuronal excitability, two novel types are described and distinctly associated to the presence of cooperative variables.

A Balance Equation Determines a Switch in Neuronal Excitability

We use the qualitative insight of a planar neuronal phase portrait to detect an excitability switch in arbitrary conductance-based models from a simple mathematical condition. The condition expresses a balance between ion channels that provide a negative feedback at resting potential (restorative channels) and those that provide a positive feedback at resting potential (regenerative channels). Geometrically, the condition imposes a transcritical bifurcation that rules the switch of excitability through the variation of a single physiological parameter. Our analysis of six different published conductance based models always finds the transcritical bifurcation and the associated switch in excitability, which suggests that the mathematical predictions have a physiological relevance and that a same regulatory mechanism is potentially involved in the excitability and signaling of many neurons.

A Novel Phase Portrait for Neuronal Excitability

Fifty years ago, FitzHugh introduced a phase portrait that became famous for a twofold reason: it captured in a physiological way the qualitative behavior of Hodgkin-Huxley model and it revealed the power of simple dynamical models to unfold complex firing patterns. To date, in spite of the enormous progresses in qualitative and quantitative neural modeling, this phase portrait has remained a core picture of neuronal excitability. Yet, a major difference between the neurophysiology of 1961 and of 2011 is the recognition of the prominent role of calcium channels in firing mechanisms. We show that including this extra current in Hodgkin-Huxley dynamics leads to a revision of FitzHugh-Nagumo phase portrait that affects in a fundamental way the reduced modeling of neural excitability. The revisited model considerably enlarges the modeling power of the original one. In particular, it captures essential electrophysiological signatures that otherwise require non-physiological alteration or considerable complexification of the classical model. As a basic illustration, the new model is shown to highlight a core dynamical mechanism by which calcium channels control the two distinct firing modes of thalamocortical neurons.

Modeling the Modulation of Neuronal Bursting: A Singularity Theory Approach

Exploiting the specific structure of neuron conductance-based models, the paper investigates the mathematical modeling of neuronal bursting modulation. The proposed approach combines singularity theory and geometric singular perturbations to capture the geometry of multiple time-scale attractors in the neighborhood of high-codimension singularities. We detect a three--time-scale bursting attractor in the universal unfolding of the winged cusp singularity and discuss the physiological relevance of the bifurcation and unfolding parameters in determining a physiological modulation of bursting. The results suggest generality and simplicity in the organizing role of the winged cusp singularity for the global dynamics of conductance-based models.

Dynamic Input Conductances Shape Neuronal Spiking

Reliable neuron activity is ensured by a tight regulation of the ion channels that resides in the neuron’s membrane. Understanding the causal mechanisms that relate this regulation to physiological and pathological neuronal activity is a necessary step for developing efficient therapies for neurological diseases associated with abnormal nervous system activity. Abstract Assessing the role of biophysical parameter variations in neuronal activity is critical to the understanding of modulation, robustness, and homeostasis of neuronal signalling. The paper proposes that this question can be addressed through the analysis of dynamic input conductances. Those voltage-dependent curves aggregate the concomitant activity of all ion channels in distinct timescales. They are shown to shape the current−voltage dynamical relationships that determine neuronal spiking. We propose an experimental protocol to measure dynamic input conductances in neurons. In addition, we provide a computational method to extract dynamic input conductances from arbitrary conductance-based models and to analyze their sensitivity to arbitrary parameters. We illustrate the relevance of the proposed approach for modulation, compensation, and robustness studies in a published neuron model based on data of the stomatogastric ganglion of the crab Cancer borealis.

A positive feedback at the cellular level promotes robustness and modulation at the circuit level.

This article highlights the role of a positive feedback gating mechanism at the cellular level in the robustness and modulation properties of rhythmic activities at the circuit level. The results are presented in the context of half-center oscillators, which are simple rhythmic circuits composed of two reciprocally connected inhibitory neuronal populations. Specifically, we focus on rhythms that rely on a particular excitability property, the postinhibitory rebound, an intrinsic cellular property that elicits transient membrane depolarization when released from hyperpolarization. Two distinct ionic currents can evoke this transient depolarization: a hyperpolarization-activated cation current and a low-threshold T-type calcium current. The presence of a slow activation is specific to the T-type calcium current and provides a slow positive feedback at the cellular level that is absent in the cation current. We show that this slow positive feedback is required to endow the network rhythm with physiological modulation and robustness properties. This study thereby identifies an essential cellular property to be retained at the network level in modeling network robustness and modulation.

Realization of nonlinear behaviors from organizing centers

Borrowing the concept of organizing center from singularity theory, the paper proposes a methodology to realize nonlinear behaviors such as switches, relaxation oscillators, or bursters from core circuits that reveal the fundamental role of monotonicity and feedback in their robustness and modulation.

Neuronal behaviors: A control perspective

The purpose of this tutorial is to introduce and analyze models of neurons from a control perspective and to show how recently developed analytical tools help to address important biological questions. A first objective is to review the basic modeling principles of neurophysiology in which neurons are modeled as equivalent nonlinear electrical circuits that capture their excitable properties. The specific architecture of the models is key to the tractability of their analysis: in spite of their high-dimensional and nonlinear nature, the model properties can be understood in terms of few canonical positive and negative feedback motifs localized in distinct timescales. We use this insight to shed light on a key problem in experimental neurophysiology, the challenge of understanding the sensitivity of neuronal behaviors to underlying parameters in empirically-derived models. Finally, we show how sensitivity analysis of neuronal excitability relates to robustness and regulation of neuronal behaviors.

Switchable slow cellular conductances determine robustness and tunability of network states

Neuronal information processing is regulated by fast and localized fluctuations of brain states. Brain states reliably switch between distinct spatiotemporal signatures at a network scale even though they are composed of heterogeneous and variable rhythms at a cellular scale. We investigated the mechanisms of this network control in a conductance-based population model that reliably switches between active and oscillatory mean-fields. Robust control of the mean-field properties relies critically on a switchable negative intrinsic conductance at the cellular level. This conductance endows circuits with a shared cellular positive feedback that can switch population rhythms on and off at a cellular resolution. The switch is largely independent from other intrinsic neuronal properties, network size and synaptic connectivity. It is therefore compatible with the temporal variability and spatial heterogeneity induced by slower regulatory functions such as neuromodulation, synaptic plasticity and homeostasis. Strikingly, the required cellular mechanism is available in all cell types that possess T-type calcium channels but unavailable in computational models that neglect the slow kinetics of their activation.

A Three-Scale Model of Spatio-Temporal Bursting

We study spatio-temporal bursting in a three-scale reaction diffusion equation organized by the winged cusp singularity. For large time-scale separation the model exhibits traveling bursts, whereas for large space-scale separation the model exhibits standing bursts. Both behaviors exhibit a common singular skeleton, whose geometry is fully determined by persistent bifurcation diagrams of the winged cusp. The modulation of spatio-temporal bursting in such a model naturally translates into paths in the universal unfolding of the winged-cusp.