Machine learning based estimation of axonal permeability: validation on cuprizone treated in-vivo mouse model of axonal demyelination

Estimating axonal permeability reliably is extremely important, however not yet achieved because mathematical models that express its relationship to the MR signal accurately are intractable. Recently introduced machine learning based computational model showed to outperforms previous approximate mathematical models. Here we apply and validate this novel method experimentally on a highly controlled in-vivo mouse model of axonal demyelination, and demonstrate for the first time in practice the power of machine learning as a mechanism to construct complex biophysical models for quantitative MRI

Deep neural network based framework for in-vivo axonal permeability estimation

This study introduces a novel framework for estimating permeability from diffusion-weighted MRI data using deep learning. Recent work introduced a random forest (RF) regressor model that outperforms approximate mathematical models (Kärger model). Motivated by recent developments in machine learning, we propose a deep neural network (NN) approach to estimate the permeability associated with the water residence time. We show in simulations and in in-vivo mouse brain data that the NN outperforms the RF method. We further show that the performance of either ML method is unaffected by the choice of training data, i.e. raw diffusion signals or signal-derived features yield the same results

Negative regulation of central nervous system myelination by polysialylated-neural cell adhesion molecule

Many factors have been shown to promote myelination, but few have been shown to be inhibitory. Here, we show that polysialylated-neural cell adhesion molecule (PSA-NCAM) can negatively regulate myelin formation. During development, PSA-NCAM is first expressed on all growing fibers; then, axonal expression is down-regulated and myelin deposition occurs only on PSA-NCAM-negative axons. Similarly, in cocultures of oligodendrocytes and neurons, PSA-NCAM expression on axons is initially high, but decreases as myelination proceeds. Importantly, if expression of PSA-NCAM is prematurely decreased in cultures, by either antibody-mediated internalization or enzymatic removal of the PSA moieties with endoneuraminidase N (endo-N), myelination increases 4- to 5-fold. In the optic nerve, premature cleavage of PSA moieties by intravitreous injection of endo-N also induces a transient increase in the number of myelinated internodes, but does not interfere with the onset of myelination. Previously, we showed that axonal electrical activity strongly induced myelination, which could be prevented by tetrodotoxin (TTX), an action potential blocker. Interestingly, removal of PSA moieties does not reverse the inhibition of myelination by TTX. Together, this suggests that myelination is tightly controlled by both positive (electrical activity) and negative (PSA-NCAM expression) regulatory signals

Impact d’une exposition développementale à des perturbateurs endocriniens sur le système nerveux central et la thyroïde

L’incidence des maladies non transmissibles (eg sléroses en plaques) et d’hypothyroïdies congénitales en France ont augmenté significativement depuis 30 ans (Barry et al., 2016).Étant connu le rôle essentiel de l’iode et des hormones thyroïdiennes (HT) dans le développement normal du cerveau des mammifères, une hypothèse plausible est qu’un contact embryonnaire avec des produits chimiques perturbant l’axe thyroïdien, serait à l’origine d’une part de ces augmentations. L’exposition à des molécules qui engendrent ou amplifient des variations dans les niveaux en HTs, au niveau cellulaire ou lors de phases critiques de développement ou de réparation cellulaires sont donc particulièrement préoccupantes.À l’aide de modèles pertinents et complémentaires, embryons de xénope, larves de xénope, cellules souches neurales et thyroïde fœtale de souris, nous avons investigué les effets, de ce mélange et de certaines molécules le constituant, sur le développement cérébral et sur la mise en place de la thyroïde. Dans l’ensemble, ces résultats montrent que des molécules chimiques présentes à faibles doses, durant des phases critiques du développement, peuvent impacter la prolifération des cellules souches neurales, la myélinisation et la remyélinisation axonale, le ratio neurone/glie et la mise en place de la thyroïde fœtale. De plus, nous avons également commencé à investiguer les conséquences comportementales de ces expositions.Nos travaux illustrent l’avantage de l’utilisation de stratégies complémentaires pour la recherche des mécanismes et des effets délétères de molécules, mais aussi la nécessité de considérer les mélanges dans les études expérimentales ainsi que dans l’évaluation des risques

Deleterious functional consequences of perfluoroalkyl substances accumulation into the myelin sheath

Exposure to persistent organic pollutants during the perinatal period is of particular concern because of the potential increased risk of neurological disorders in adulthood. Here we questioned whether exposure to perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) could alter myelin formation and regeneration. First, we show that PFOS, and to a lesser extent PFOA, accumulated into the myelin sheath of postnatal day 21 (p21) mice, whose mothers were exposed to either PFOA or PFOS (20 mg/L) via drinking water during late gestation and lactation, suggesting that accumulation of PFOS into the myelin could interfere with myelin formation and function. In fact, PFOS, but not PFOA, disrupted the generation of oligodendrocytes, the myelin-forming cells of the central nervous system, derived from neural stem cells localised in the subventricular zone of p21 exposed animals. Then, cerebellar slices were transiently demyelinated using lysophosphatidylcholine and remyelination was quantified in the presence of either PFOA or PFOS. Only PFOS impaired remyelination, a deleterious effect rescued by adding thyroid hormone (TH). Similarly to our observation in the mouse, we also showed that PFOS altered remyelination in Xenopus laevis using the Tg(Mbp:GFP-ntr) model of conditional demyelination and measuring, then, the number of oligodendrocytes. The functional consequences of PFOS-impaired remyelination were shown by its effects using a battery of behavioural tests. In sum, our data demonstrate that perinatal PFOS exposure disrupts oligodendrogenesis and myelin function through modulation of TH action. PFOS exposure may exacerbate genetic and environmental susceptibilities underlying myelin disorders, the most frequent being multiple sclerosis