Biology subjects

Chardon, M.

Publications and source records attributed to Chardon, M..

3 recordsLinked to original sources

bioRxiv2022

A geometric approach to quantifying the neuromodulatory effects of persistent inward currents on single motor unit discharge patterns

ObjectiveAll motor commands flow through motoneurons, which entrain control of their innervated muscle fibers, forming a motor unit (MU). Owing to the high fidelity of action potentials within MUs, their discharge profiles detail the organization of ionotropic excitatory/inhibitory as well as metabotropic neuromodulatory commands to motoneurons. Neuromodulatory inputs (e.g., norepinephrine, serotonin) enhance motoneuron excitability and facilitate persistent inward currents (PICs). PICs introduce quantifiable properties in MU discharge profiles by augmenting depolarizing currents upon activation (i.e., PIC amplification) and facilitating discharge at lower levels of excitatory input than required for recruitment (i.e., PIC prolongation). Approach: Here, we introduce a novel geometric approach to estimate neuromodulatory and inhibitory contributions to MU discharge through exploiting discharge non-linearities introduced by PIC amplification during time-varying linear tasks. In specific, we quantify the deviation from linear discharge ("brace height") and the rate of change in discharge (i.e., acceleration slope, attenuation slope, angle). We further characterize these metrics on a simulated motoneuron pool with known excitatory, inhibitory, and neuromodulatory inputs and on human MUs (Tibialis Anterior: 1448, Medial Gastrocnemius: 2100, Soleus: 1062, First Dorsal Interosseus: 2296). Main ResultIn the simulated motor pool, we found brace height and attenuation slope to consistently indicate changes in neuromodulation and the pattern of inhibition (excitation-inhibition coupling), respectively, whereas the paired MU analysis ({Delta}F) was dependent on both neuromodulation and inhibition pattern. Furthermore, we provide estimates of these metrics in human MUs and show comparable variability in {Delta}F and brace height measures in MUs matched across multiple trials. SignificanceSpanning both datasets, we found brace height quantification to provide an intuitive method for achieving graded estimates of neuromodulatory and inhibitory drive to MUs on a single unit level. This complements common techniques and provides an avenue for decoupling changes in the level of neuromodulatory and pattern of inhibitory motor commands.

bioengineering↗

bioRxiv2021

Algorithmic Parameter Estimation and Uncertainty Quantification for Hodgkin-Huxley Neuron Models

Experimental data-based parameter search for Hodgkin-Huxley-style (HH) neuron models is a major challenge for neuroscientists and neuroengineers. Current search strategies are often computationally expensive, are slow to converge, have difficulty handling nonlinearities or multimodalities in the objective function, or require good initial parameter guesses. Most important, many existing approaches lack quantification of uncertainties in parameter estimates even though such uncertainties are of immense biological significance. We propose a novel method for parameter inference and uncertainty quantification in a Bayesian framework using the Markov chain Monte Carlo (MCMC) approach. This approach incorporates prior knowledge about model parameters (as probability distributions) and aims to map the prior to a posterior distribution of parameters informed by both the model and the data. Furthermore, using the adaptive parallel tempering strategy for MCMC, we tackle the highly nonlinear, noisy, and multimodal loss function, which depends on the HH neuron model. We tested the robustness of our approach using the voltage trace data generated from a 9-parameter HH model using five levels of injected currents (0.0, 0.1, 0.2, 0.3, and 0.4 nA). Each test consisted of running the ground truth with its respective currents to estimate the model parameters. To simulate the condition for fitting a frequency-current (F-I) curve, we also introduced an aggregate objective that runs MCMC against all five levels simultaneously. We found that MCMC was able to produce many solutions with acceptable loss values (e.g., for 0.0 nA, 889 solutions were within 0.5% of the best solution and 1,595 solutions within 1% of the best solution). Thus, an adaptive parallel tempering MCMC search provides a "landscape" of the possible parameter sets with acceptable loss values in a tractable manner. Our approach is able to obtain an intelligently sampled global view of the solution distributions within a search range in a single computation. Additionally, the advantage of uncertainty quantification allows for exploration of further solution spaces, which can serve to better inform future experiments.

neuroscience↗

bioRxiv2019

Dock5 is a new regulator of microtubule dynamic instability through GSK3β inhibition in osteoclasts

Background informationOsteoclast resorption is dependent on a podosome-rich structure, called sealing zone, which is stabilized by acetylated microtubules. It tightly attaches the osteoclast to the bone creating a favorable acidic microenvironment for bone degradation. We already established that Rac activation by Dock5 is necessary for osteoclast resorption. Indeed, inhibition of Dock5 in osteoclasts results in Rac1 decreased activity associated to impaired podosome assembly into sealing zones and resorbing activity.\n\nResultsIn this report, we show that Dock5 knockout osteoclasts also present a reduced acetylated tubulin level leading to a decreased length and duration of microtubule growth phases whereas their growth speed remains unaffected. Dock5 does not act by direct interaction with the polymerized tubulin but through inhibition of the microtubules destabilizing kinase GSK3{beta} downstream of Akt activation. Interestingly, we ruled out the implication of Rac1 in this process using specific inhibitors.\n\nConclusionOur data involve Dock5 as a new regulator of microtubule dynamic instability in osteoclast.\n\nSignificanceThe fact that Dock5 is a regulator of both actin cytoskeleton and microtubule dynamics makes it an interesting therapeutic target for osteolytic pathologies because of its dual role on sealing zone formation and stabilization.

cell biology↗