http://www.cell.com/article/S0092867422007139/pdf

Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation

Disruption of Oligodendrogenesis Impairs Memory Consolidation in Adult Mice.

Experience-dependent myelination is hypothesized to shape neural circuit function and subsequent behavioral output. Using a contextual fear memory task in mice, we demonstrate that fear learning induces oligodendrocyte precursor cells to proliferate and differentiate into myelinating oligodendrocytes in the medial prefrontal cortex. Transgenic animals that cannot form new myelin exhibit deficient remote, but not recent, fear memory recall. Recording population calcium dynamics by fiber photometry, we observe that the neuronal response to conditioned context cues evolves over time in the medial prefrontal cortex, but not in animals that cannot form new myelin. Finally, we demonstrate that pharmacological induction of new myelin formation with clemastine fumarate improves remote memory recall and promotes fear generalization. Thus, bidirectional manipulation of myelin plasticity functionally affects behavior and neurophysiology, which suggests that neural activity during fear learning instructs the formation of new myelin, which in turn supports the consolidation and/or retrieval of remote fear memories.

Preservation of a remote fear memory requires new myelin formation.

Oligodendrocyte loss in neurological disease leaves axons vulnerable to damage and degeneration, and activity-dependent myelination may represent an endogenous mechanism to improve remyelination following injury. Here we report that, while learning a forelimb reach task transiently suppresses oligodendrogenesis, it subsequently increases oligodendrocyte precursor cell differentiation, oligodendrocyte generation and myelin sheath remodeling in the forelimb motor cortex. Immediately following demyelination, neurons exhibit hyperexcitability, learning is impaired and behavioral intervention provides no benefit to remyelination. However, partial remyelination restores neuronal and behavioral function, allowing learning to enhance oligodendrogenesis, remyelination of denuded axons and the ability of surviving oligodendrocytes to generate new myelin sheaths. Previously considered controversial, we show that sheath generation by mature oligodendrocytes is not only possible but also increases myelin pattern preservation following demyelination, thus presenting a new target for therapeutic interventions. Together, our findings demonstrate that precisely timed motor learning improves recovery from demyelinating injury via enhanced remyelination from new and surviving oligodendrocytes.

Motor learning promotes remyelination via new and surviving oligodendrocytes.

http://www.cell.com/article/S0896627322009102/pdf

The neurobiology of long COVID

Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment

Diffuse midline gliomas (DMGs) are universally lethal malignancies occurring chiefly during childhood and involving midline structures of the central nervous system, including thalamus, pons, and spinal cord. These molecularly related cancers are characterized by high prevalence of the histone H3K27M mutation. In search of effective therapeutic options, we examined multiple DMG cultures in sequential quantitative high-throughput screens (HTS) of 2706 approved and investigational drugs. This effort generated 19,936 single-agent dose responses that inspired a series of HTS-enabled drug combination assessments encompassing 9195 drug-drug examinations. Top combinations were validated across patient-derived cell cultures representing the major DMG genotypes. In vivo testing in patient-derived xenograft models validated the combination of the multi-histone deacetylase (HDAC) inhibitor panobinostat and the proteasome inhibitor marizomib as a promising therapeutic approach. Transcriptional and metabolomic surveys revealed substantial alterations to key metabolic processes and the cellular unfolded protein response after treatment with panobinostat and marizomib. Mitigation of drug-induced cytotoxicity and basal mitochondrial respiration with exogenous application of nicotinamide mononucleotide (NMN) or exacerbation of these phenotypes when blocking nicotinamide adenine dinucleotide (NAD+) production via nicotinamide phosphoribosyltransferase (NAMPT) inhibition demonstrated that metabolic catastrophe drives the combination-induced cytotoxicity. This study provides a comprehensive single-agent and combinatorial drug screen for DMG and identifies concomitant HDAC and proteasome inhibition as a promising therapeutic strategy that underscores underrecognized metabolic vulnerabilities in DMG.

Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening

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Loss of Adaptive Myelination Contributes to Methotrexate Chemotherapy-Related Cognitive Impairment

Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening