Topic: oligodendrocytes

Epilepsy is one of the most common neurological diseases according to the World Health Organization (WHO) affecting around 70 million people worldwide [WHO]. Patients who suffer from epilepsy also suffer from a variety of neuro-psychiatric co-morbidities, which they can experience as crippling as the seizure condition itself. Adequate organization of cerebral white matter is utterly important for cognitive development. The failure of integration of neurologic function with cognition is reflected in neuro-psychiatric disease, such as autism spectrum disorder (ASD). However, in epilepsy we know

Epilepsy is one of the most common neurological diseases according to the World Health Organization (WHO) affecting around 70 million people worldwide [WHO]. Patients who suffer from epilepsy also suffer from a variety of neuro-psychiatric co-morbidities, which they can experience as crippling as the seizure condition itself. Adequate organization of cerebral white matter is utterly important for cognitive development. The failure of integration of neurologic function with cognition is reflected in neuro-psychiatric disease, such as autism spectrum disorder (ASD). However, in epilepsy we know

Our goal is to understand why myelin repair fails in multiple sclerosis and to develop regenerative medicines for the nervous system. A central obstacle for progress in this area has been the complex biology underlying the response to CNS injury. Acute CNS damage is followed by a multicellular response that encompasses different cell types and spans different scales. Currently, we do not understand which factors determines lesion recovery. Failure of inflammation to resolve is a key underlying reason of poor regeneration, and one focus is therefore on the biology of microglia during de- and re

The gradual accumulation of hyperphosphorylated forms of the Tau protein (pTau) in the human brain correlate with cognitive dysfunction and neurodegeneration. I will present our recent findings on the consequences of human pTau aggregation in the hippocampal formation of a mouse tauopathy model. We show that pTau preferentially accumulates in deep-layer pyramidal neurons, leading to their neurodegeneration. In aged but not younger mice, pTau spreads to oligodendrocytes. During ‘goal-directed’ navigation, we detect fewer high-firing pyramidal cells, but coupling to network oscillations is maint

The CNS is responsive to an ever-changing environment. Until recently, studies of neural plasticity focused almost exclusively on functional and structural changes of neuronal synapses. In recent years, myelin plasticity has emerged as a potential modulator of neural networks. Myelination of previously unmyelinated axons, and changes in the structure on already-myelinated axons, can have large effects on network function. The heterogeneity of the extent of how axons in the CNS are myelinated offers diverse scope for dynamic myelin changes to fine-tune neural circuits. The traditionally held vi

The amyloid cascade hypothesis for Alzheimer disease ((Hardy and Selkoe, 2002; Hardy and Higgins, 1992; Selkoe, 1991), updated in (Karran et al., 2011) provides a linear model for the pathogenesis of AD with Aβ accumulation upstream and Tau pathology, inflammation, synaptic dysfunction, neuronal loss and dementia downstream, all interlinked, initiated and driven by Aβ42 peptides or oligomers. The genetic mutations causing familial Alzheimer disease seem to support this model. The nagging problem remains however that the postulated causal, and especially the ’driving’ role of abnormal Aβ aggr

Bridging Investigator 1 is a known c-Myc inhibitor highly enriched in oligodendrocytes (OL), and its genetic variant confers a strong risk for sporadic Alzheimer’s disease (AD). BIN1 expression is tightly regulated by the alternative splicing of 20 exons, resulting in twelve protein isoforms. In human brain, as a nucleocytoplasmic protein, BIN1 regulates tau endocytosis, but its canonical nuclear function as a cell cycle regulator remains unknown. We aim to characterize BIN1 expression in the OL population of AD brains. To investigate, BIN1 expression was examined in two cohorts of post-mortem

Oligodendrocytes produce central nervous system myelin and provide metabolic support to axons. Myelin formation and repair are energetically expensive and oligodendrocyte metabolic defects have been postulated as a cause of neurodegeneration. Endocannabinoids modulate neuronal and astroglial metabolism and attenuate inflammatory demyelination in multiple sclerosis (MS) through the activation of CB1 receptors (CB1Rs). Myelinating oligodendrocytes and precursor cells (OPCs) express CB1Rs that mediate protection from excitotoxicity and promote lineage progression but the metabolic implications of

A hallmark of nervous system aging is a decline of white matter volume and function, but the underlying mechanisms leading to white matter pathology are unknown. In the present study, we found age-related alterations of oligodendrocyte cell state with a reduction in total oligodendrocyte density in aging murine white matter. Using single-cell RNA-sequencing, we identified interferon (IFN)-responsive oligodendrocytes, which localize in proximity to CD8+ T cells in aging white matter. Absence of functional lymphocytes decreased the number of IFN-responsive oligodendrocytes and rescued oligodendr

Neonatal hypoxic ischemia (HI) causes motor impairment affecting daily activity. Rehabilitation is frequently implemented to improve motor performance, but its effects are often insufficient for acquiring fine motor coordination. Recently, myelin plasticity has been pointed out necessary for improving motor skills. However, the significance of myelination for motor improvement after HI remains unclear.To address this issue, we investigated the effect of rehabilitation exercise on myelination in a neonatal HI rat model. We then examined the effectiveness of pharmacological promotion of myelinat

Oligodendrocyte precursor cells (OPCs) serve as progenitors for oligodendrocytes (OLs) throughout their life, contributing to developmental and adaptive myelination, as well as myelin repair. OPCs are known to make synaptic and extra-synaptic contacts with axons, but the mechanisms by which they integrate the information relayed by the neuronal activity into Ca2+ signals, which in turn influence their fate and survival, are still unclear. Using newly developed transgenic mouse lines to express genetically encoded Ca2+ sensors in OPCs, we performed 2-photon microscopy in the somatosensory corte

Maternal high-fat diet (HFD) during pregnancy and lactation induces depression-like phenotype and provokes myelin-related changes in rat offspring, which persist even to adulthood. Due to the plasticity of the developing brain, we decided to analyze whether depression-like phenotypes and myelin-related changes in the early lifetime induced by maternal HFD could be reversed by the omega-3 fatty acid-enriched diet (Ω3D). We investigated the effects of the Ω3D from the post-weaning period until adulthood (63rd day of life) in offspring on the depressive-like behavior (forced swimming test, locomo

Calcium is a key intracellular messenger that regulates many vital cellular processes. Calcium signals in oligodendrocytes, the myelinating glia of the CNS, are known to translate environmental information to cellular processes such as proliferation, differentiation and myelination. Myelination is an adaptive process that depends on neuronal activity. We recently demonstrated that neuronal activity in vivo enhances remyelination in demyelinated lesions (Ortiz et al., 2019, JCI Insight). Here, we investigate whether calcium singal in oligodendroglia play a role in remyelination and whether beha

Myelin, produced by oligodendrocytes (OLs), is a lipid-rich structure that wraps axons, facilitating the saltatory conduction and providing metabolic support to neurons. Myelin is a highly adaptable structure whose role in regulating synaptic transmission in the healthy and diseased brain have not been extensively examined and may be relevant for understanding neuronal dysfunctions associated with myelin-related disorders. Here, we investigated excitatory (EPSCs) and inhibitory (IPSCs) post-synaptic currents in layer IV of the somatosensory (barrel) cortex using a cuprizone-induced demyelinati

In human, genetic predispositions or deleterious environmental conditions may cause adverse effects on the developing brain. In preterm neonates, oligodendrocytes are particularly vulnerable and hypoxic conditions may result in white matter lesions leading to cerebral palsy and long-term disabilities. The glutamatergic transmission plays a critical role in the pathophysiology of these lesions but it is also a key actor involved in developmental mechanisms such as cell differentiation. Previous studies demonstrated a strong expression of the N-methyl-D-aspartate receptor by endothelial cells (e

Advancements in spatial imaging technologies (SIT) have broadened transcriptomic discovery capacity. Yet, development of orthogonal technologies for follow-up translational studies have trailed. We have developed MSIA that utilizes non-temporal, optical barcodes by combining the advantages of RNAscope™ double-Z probes and Hiplex v2 signal amplification technology.Fresh-frozen and FFPE brain coronal sections were collected from C57BL/6J mice of 3 age groups: 1 month, 6 months, and 12 months, respectively. MSIA was executed in 3 cycles, with 100 RNA targets in cycles 1&2 and then up to 4 pro

The hippocampus is crucial for episodic memories and is characterized by unique sharp wave ripple complexes (SWRs). These hallmark oscillations, 150-250 Hz in the local field potential (LFP), are produced by fast signaling between synaptically coupled pyramidal neurons (PNs) and parvalbumin-positive basket cells (PV+BCs). Although much has been learned about the synaptic and microcircuit properties mediating ripple oscillations, whether and how myelination of the hippocampus contributes remains unresolved. Here, we performed LFP measurements in combination with paired recordings between PV+BCs

Human brain development is affected by very preterm (VP) birth. For example, cortical thickness (CT) is aberrant on average in groups of VP neonates, children, and adults. However, distinct postmortem findings of severely impacted preterm neonates, diverse behavioral outcomes of preterm survivors, and the spatially widespread nature of hypoxia-driven pathomechanisms after VP birth imply a regionally variable and individually heterogenous impact of VP birth on brain development. We hypothesized that CT follows this pattern, from birth to adulthood, mediated by the same cell types, and relevant

The voltage-dependent chloride channel ClC-2 is a member of the CLC channel/transporter superfamily. A functional ClC-2 channel comprises a dimeric structure, with each monomer containing 18 intracellular or transmembrane α-helices (helices A to R). ClC-2 is ubiquitously expressed and has been detected in astrocytes and oligodendrocytes, where ClC-2 colocalizes with the adhesion molecule GlialCAM at astrocyte-astrocyte junctions. Mutations in human genes encoding ClC-2 or GlialCAM have been linked to the white matter disease leukodystrophy. A disease-causing mutation significantly increasing t

3D printed scaffold represents a promising approach for treatment of spinal cord injury (SCI). Here we suggest an innovative biotechnological approach for free-form 3D printing of scaffolds with a biomimetic architecture at a spatial resolution up to a micrometer, which were used for implantation in treatment of SCI in one-month-old Wistar rats. The approach is based on 2-photon photopolymerization of organic polymers and is scalable to lesion geometries. The scaffolds were implemented as multiple densely packed parallel micro-tunnels (~50 μm) running through their whole length. Having thin wa

Multiple System Atrophy (MSA) is a progressive neurodegenerative disorder due to the loss of various neuronal populations, including the GABAergic and the dopaminergic systems in the striatum and in the midbrain. The resulting degeneration of the nigro-striatal circuit is responsible for a severe neurological involvement characterized by parkinsonism and cerebellar phenotypes. The neuropathological hallmarks of MSA consist of alpha-synuclein aggregations in oligodendrocytes and neurons. No disease-modifying therapy is available for this disorder, resulting in a reduced life-span of affected pa

Parkinson’s disease (PD) is characterized by the selective loss of dopaminergic neurons in the Substantia Nigra and Lewy body formation, resulting in a progressive neurodegenerative disorder with movement defects. The impairment of dopaminergic innervation in PD hinders the two main projection systems from the dorsal striatum (Putamen, Pu, and Caudate Nucleus, CN) from effectively responding to cortical and thalamic signals.A potential role of Oligodendrocytes (OLs) in PD was pointed out by recent works describing GWAS PD variants associated with OLs (Bryois et al, Nat Genet, 2020), PD genes e

Oligodendrocytes, the myelinating glial cells of the central nervous system (CNS), surround axons with their membrane extensions, forming the myelin sheath. Loss of oligodendrocytes and/or myelin (demyelination) occurs in traumatic brain injury or pathologies such as multiple sclerosis. Since, there is no specific treatment for demyelination; we are interested in enhancing myelin endogenous repair. We focus our work on A Disintegrin and Metalloprotease (ADAM) 10, the major CNS α-secretase, which generates the neuroprotective soluble fragment sAPPα via cleavage of the Amyloid Precursor Protein

The reduction of amyloid beta (Aβ) has been shown to be effective in treating Alzheimer’s Disease (AD), but an underlying assumption that neurons are the main source of pathogenic Aβ remains untested. Here we show that oligodendrocytes produce significant amounts of Aβ, which in turn promotes abnormal neuronal hyperactivity in AD. Initially, we assessed publicly available single cell RNA-sequencing and proteomics databases and showed that oligodendrocytes express all the components required to produce Aβ. By employing RNAscope in situ hybridisation we revealed that the brains of AD patients ha