Zalc, B. | bioRxiv Science

bioRxiv2025

Neuronal activity promotes repair by microglial reprogramming following demyelination

Microglia, the resident immune cells of the central nervous system (CNS), play a multifaceted role in neurological disorders. In multiple sclerosis (MS), a chronic demyelinating and neurodegenerative disease, microglia contribute to inflammation and tissue damage, but can also support repair by clearing myelin debris, limiting inflammation and promoting remyelination and neuroprotection. The timely transition from their pro-inflammatory to pro-regenerative states is essential for effective repair and, in chronic MS, persistent, defective microglial activation contributes to disease progression. Yet, the mechanisms underlying the microglial switch remain largely unknown. In this study, we demonstrate that neuronal activity can modulate microglial signature at the onset of remyelination in MS models, in a pattern-dependent manner. Transcriptomic analyses reveal a downregulation of pro-inflammatory, disease-associated microglial signatures alongside an upregulation of genes associated with oxidative phosphorylation and lipid metabolism, indicative of a shift toward pro-regenerative states following physiological activity enhancement. This activity-dependent reprogramming also extends to infiltrating monocytes and macrophages, collectively fostering a microenvironment favoring repair.

neuroscience↗

bioRxiv2023

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 (20mg/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. HighlightsO_LIOur investigation points the deleterious effects of PFOS incorporation into the myelin sheath C_LIO_LIPFOS interfere dramatically with the generation of remyelinating and functional repair of demyelinating lesions C_LIO_LIOur study points to a potential link between these persistent pollutants and the recent increase in prevalence of multiple sclerosis C_LI

pharmacology and toxicology↗