Oligodendrocyte Cell Research Articles

The GPR17 Receptor-A Promising Goal for Therapy and a Potential Marker of the Neurodegenerative Process in Multiple Sclerosis.

One of the most important goals in the treatment of demyelinating diseases such as multiple sclerosis (MS) is, in addition to immunomodulation, reconstruction of the lost myelin sheath. The modulator of the central nervous system myelination is the metabotropic receptor coupled to the G-protein: GPR17. GPR17 receptors are considered to be sensors of local damage to the myelin sheath, and play a role in the reconstruction and repair of demyelinating plaques caused by ongoing inflammatory processes. GPR17 receptors are present on nerve cells and precursor oligodendrocyte cells. Under physiological conditions, they are responsible for the differentiation and subsequent maturation of oligodendrocytes, while under pathological conditions (during damage to nerve cells), their expression increases to become mediators in the demyelinating processes. Moreover, they are essential not only in both the processes of inducing damage and the death of neurons, but also in the local repair of the damaged myelin sheath. Therefore, GPR17 receptors may be recognized as the potential goal in creating innovative therapies for the treatment of the neurodegenerative process in MS, based on the acceleration of the remyelination processes. This review examines the role of GRP17 in pathomechanisms of MS development.

Brain inflammation and injury at 48 h is not altered by human amnion epithelial cells in ventilated preterm lambs.

Mechanical ventilation of preterm neonates is associated with neuroinflammation and an increased risk of adverse neurological outcomes. Human amnion epithelial cells (hAECs) have anti-inflammatory and regenerative properties. We aimed to determine if intravenous administration of hAECs to preterm lambs would reduce neuroinflammation and injury at 2 days of age. Preterm lambs were delivered by cesarean section at 128-130 days' gestation (term is ~147 days) and either ventilated for 48 h or humanely killed at birth. Lambs received 3 mL surfactant (Curosurf) via endotracheal tube prior to delivery (either with or without 90 × 106 hAECs) and 3 mL intravenous phosphate-buffered saline (with or without 90 × 106 hAECs, consistent with intratracheal treatment) after birth. Ventilation increased microglial activation, total oligodendrocyte cell number, cell proliferation and blood-brain barrier permeability (P < 0.05, PBS + ventilation and hAEC + ventilation vs. control), but did not affect numbers of immature and mature oligodendrocytes. Ventilation reduced astrocyte and neuron survival (P < 0.05, PBS + ventilation and hAEC + ventilation vs. control). hAEC administration did not alter markers of neuroinflammation or injury within the white or gray matter. Mechanical ventilation for 48 h upregulated markers of neuroinflammation and injury in preterm lambs. Administration of hAECs did not affect markers of neuroinflammation or injury. Mechanical ventilation of preterm lambs for 48 h, in a manner consistent with contemporary neonatal intensive care, causesneuroinflammation, neuronal loss and pathological changes in oligodendrocyte and astrocyte survival consistent with evolving neonatal brain injury.Intravenous administration of hAECs immediately after birth did not affect neonatal cardiorespiratory function and markers of neuroinflammation or injury.Reassuringly, our findings in a translational large animal model demonstrate that intravenous hAEC administration to the preterm neonate is safe.Considering that hAECs are being used in phase 1 trials for the treatment of BPD in preterm infants, with future trials planned for neonatal neuroprotection, we believe these observations are highly relevant.

A critical role for the inward rectifying potassium channel Kir7.1 in oligodendrocytes of the mouse optic nerve

Inward rectifying potassium channels (Kir) are a large family of ion channels that play key roles in ion homeostasis in oligodendrocytes, the myelinating cells of the central nervous system (CNS). Prominent expression of Kir4.1 has been indicated in oligodendrocytes, but the extent of expression of other Kir subtypes is unclear. Here, we used qRT-PCR to determine expression of Kir channel transcripts in the mouse optic nerve, a white matter tract comprising myelinated axons and the glia that support them. A novel finding was the high relative expression of Kir7.1, comparable to that of Kir4.1, the main glial Kir channel. Significantly, Kir7.1 immunofluorescence labelling in optic nerve sections and in isolated cells was localised to oligodendrocyte somata. Kir7.1 are known as a K+ transporting channels and, using patch clamp electrophysiology and the Kir7.1 blocker VU590, we demonstrated Kir7.1 channels carry a significant proportion of the whole cell potassium conductance in oligodendrocytes isolated from mouse optic nerves. Notably, oligodendrocytes are highly susceptible to ischemia/hypoxia and this is due at least in part to disruption of ion homeostasis. A key finding of this study is that blockade of Kir7.1 with VU590 compromised oligodendrocyte cell integrity and compounds oligodendroglial loss in ischemia/hypoxia in the oxygen–glucose deprivation (OGD) model in isolated intact optic nerves. These data reveal Kir7.1 channels are molecularly and functionally expressed in oligodendrocytes and play an important role in determining oligodendrocyte survival and myelin integrity.

Antidepressant Paroxetine Exerts Developmental Neurotoxicity in an iPSC-Derived 3D Human Brain Model.

Selective serotonin reuptake inhibitors (SSRIs) are frequently used to treat depression during pregnancy. Various concerns have been raised about the possible effects of these drugs on fetal development. Current developmental neurotoxicity (DNT) testing conducted in rodents is expensive, time-consuming, and does not necessarily represent human pathophysiology. A human, in vitro testing battery to cover key events of brain development, could potentially overcome these challenges. In this study, we assess the DNT of paroxetine—a widely used SSRI which has shown contradictory evidence regarding effects on human brain development using a versatile, organotypic human induced pluripotent stem cell (iPSC)-derived brain model (BrainSpheres). At therapeutic blood concentrations, which lie between 20 and 60 ng/ml, Paroxetine led to an 80% decrease in the expression of synaptic markers, a 60% decrease in neurite outgrowth and a 40–75% decrease in the overall oligodendrocyte cell population, compared to controls. These results were consistently shown in two different iPSC lines and indicate that relevant therapeutic concentrations of Paroxetine induce brain cell development abnormalities which could lead to adverse effects.

The transcription factor NKX2-2 regulates oligodendrocyte differentiation through domain-specific interactions with transcriptional corepressors

The homeodomain protein NK2 homeobox 2 (NKX2-2) is a transcription factor that plays a critical role in the control of cell fate specification and differentiation in many tissues. In the developing central nervous system, this developmentally important transcription factor functions as a transcriptional repressor that governs oligodendrocyte (OL) differentiation and myelin gene expression, but the roles of various NKX2-2 structural domains in this process are unclear. In this study, using in situ hybridization, immunofluorescence, and coimmunoprecipitation, we determined the structural domains that mediate the repressive functions of murine NKX2-2 and identified the transcriptional corepressors that interact with it in OL cells. Through in ovo electroporation in embryonic chicken spinal cords, we demonstrate that the N-terminal Tinman domain and C-terminal domain synergistically promote OL differentiation by recruiting distinct transcriptional corepressors, including enhancer of split Groucho 3 (GRG3), histone deacetylase 1 (HDAC1), and DNA methyltransferase 3 α (DNMT3A). We also observed that the NK2-specific domain suppresses the function of the C-terminal domain in OL differentiation. These findings delineate the distinct NKX2-2 domains and their roles in OL differentiation and suggest that NKX2-2 regulates differentiation by repressing gene expression via multiple cofactors and molecular mechanisms.

Interleukin-1 receptor antagonist ameliorates the pain hypersensitivity, spinal inflammation and oxidative stress induced by systemic lipopolysaccharide in neonatal rats

Perinatal inflammation-induced reduction in pain threshold may alter pain sensitivity to hyperalgesia or allodynia which may persist into adulthood. In this study, we investigated the anti-inflammatory protective effect of interleukin-1 receptor antagonist (IL-1ra), an anti-inflammatory cytokine, on systemic lipopolysaccharide (LPS)-induced spinal cord inflammation and oxidative stress, thermal hyperalgesia, and mechanical allodynia in neonatal rats. Intraperitoneal (i.p.) injection of LPS (2 mg/kg) or sterile saline was performed in postnatal day 5 (P5) rat pups, and IL-1ra (100 mg/kg) or saline was administered (i.p.) 5 min after LPS injection. Pain reflex behavior, spinal cord inflammation and oxidative stress were examined 24 h after LPS administration. Systemic LPS exposure led to a reduction of tactile threshold in the von Frey filament tests (mechanical allodynia) and pain response latency in the tail-flick test (thermal hyperalgesia) of P6 neonatal rats. Spinal cord inflammation was indicated by the increased numbers of activated glial cells including microglia (Iba1+) and astrocytes (GFAP+), and elevated levels of pro-inflammatory cytokine interleukin-1β (IL-1β), cyclooxygenase-2 (COX-2), and prostaglandin E2 (PGE2) 24 h after LPS treatment. LPS treatment induced spinal oxidative stress as evidenced by the increase in thiobarbituric acid reactive substances (TBARS) content in the spinal cord. LPS exposure also led to a significant increase in oligodendrocyte lineage population (Olig2+) and mature oligodendrocyte cells (APC+) in the neonatal rat spinal cord. IL-1ra treatment significantly reduced LPS-induced effects including hyperalgesia, allodynia, the increased number of activated microglia, astrocytes and oligodendrocytes, and elevated levels of IL-1β, COX-2, PGE2, and lipid peroxidation (TBARS) in the neonatal rat spinal cord. These data suggest that IL-1ra provides a protective effect against the development of pain hypersensitivity, spinal cord inflammation and oxidative stress in the neonatal rats following LPS exposure, which may be associated with the blockade of LPS-induced pro-inflammatory cytokine IL-1β.

Murine maternal dietary restriction affects neural Humanin expression and cellular profile.

To understand the cellular basis for the neurodevelopmental effects of intrauterine growth restriction (IUGR), we examined the global and regional expression of various cell types within murine (Mus musculus) fetal brain. Our model employed maternal calorie restriction to 50% daily food intake from gestation day 10-19, producing IUGR offspring. Offspring had smaller head sizes with larger head:body ratios indicating a head sparing IUGR effect. IUGR fetuses at embryonic day 19 (E19) had reduced nestin (progenitors), β-III tubulin (immature neurons), Glial fibrillary acidic protein (astrocytes), and O4 (oligodendrocytes) cell lineages via immunofluorescence quantification and a 30% reduction in cortical thickness. No difference was found in Bcl-2 or Bax (apoptosis) between controls and IUGR, though qualitatively, immunoreactivity of doublecortin (migration) and Ki67 (proliferation) was decreased. In the interest of examining a potential therapeutic peptide, we next investigated a novel pro-survival peptide, mouse Humanin (mHN). Ontogeny examination revealed highest mHN expression at E19, diminishing by postnatal day 15 (P15), and nearly absent in adult (3months). Subanalysis by sex at E19yielded higher mHN expression among males during fetal life, without significant difference between sexes postnatally. Furthermore, femaleIUGR mice at E19had a greater increase in cortical mHN versus the male fetus over their respective controls. We conclude that maternal dietary restriction-associated IUGR interferes with neural progenitors differentiating into the various cellular components populating the cerebral cortex, and reduces cerebral cortical size. mHN expression is developmental stage and sex specific, with IUGR, particularly in the females, adaptively increasing its expression toward mediating a pro-survival approach against nutritional adversity.

Human tau pathology transmits glial tau aggregates in the absence of neuronal tau.

Tauopathies are characterized by abnormal accumulation of tau protein in neurons and glia. In Alzheimer's disease (AD), tau aggregates in neurons, while in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), tau also aggregates in astrocytes and oligodendrocytes. We previously demonstrated that human CBD and PSP tauopathy lysates (CBD-tau and PSP-tau) contain distinct tau strains that propagate neuronal and glial tau aggregates in nontransgenic (nonTg) mouse brain. Yet the mechanism of glial tau transmission is unknown. Here, we developed a novel mouse model to knock down tau in neurons to test for glial tau transmission. While oligodendroglial tau pathology propagated across the mouse brain in the absence of neuronal tau pathology, astrocytic tau pathology did not. Oligodendroglial tau aggregates propagated along white matter tracts independently of neuronal axons, and resulted in oligodendrocyte cell loss. Thus, glial tau pathology has significant functional consequences independent of neuronal tau pathology.

Benzothiazole-Based LRRK2 Inhibitors as Wnt Enhancers and Promoters of Oligodendrocytic Fate.

Leucine rich repeat kinase 2 (LRRK2) is an enigmatic enzyme and a relevant target for Parkinson's disease (PD). However, despite the significant amount of research done in the past decade, the precise function of LRRK2 remains largely unknown. Moreover, the therapeutic potential of its inhibitors is in its infancy with the first clinical trial having just started. In the present work, the molecular mechanism of LRRK2 in the control of neurogenesis or gliogenesis was investigated. We designed and synthesized novel benzothiazole-based LRRK2 inhibitors and showed that they can modulate the Wnt/β-catenin signaling pathway. Furthermore, compounds 5 and 14 were able to promote neural progenitors proliferation and drive their differentiation toward neuronal and oligodendrocytic cell fates. These results suggest potential new avenues for the application of LRRK2 inhibitors in demyelinating diseases in which oligodendrocyte cell-death is one of the pathological features.

Reducing Th2 inflammation through neutralizing IL-4 antibody rescues myelination in IUGR rat brain

BackgroundIntrauterine growth restriction (IUGR) is a common complication of pregnancy and is associated with significant neurological deficits in infants, including white matter damage. Previous work using an animal model of IUGR has demonstrated that IUGR rats exhibit neurobehavioral deficits and developmental delays in oligodendrocyte maturation and myelination, but the mechanisms which cause this delay are unknown. Inflammation may be an important etiological factor in IUGR and has been recognized as playing a fundamental role in the pathogenesis of myelin disorders, including cerebral palsy.MethodsTo create the model, the uterine arteries of pregnant rats were ligated at embryonic day 15. Rats delivered spontaneously. Cytokine and chemokine expression was evaluated at one prenatal and three postnatal time points, and myelin protein expression and oligodendrocyte cell numbers were evaluated by several methods at postnatal day 14. IL-4 was identified as a potential inhibitor of myelination, and rat pups were injected with IL-4 function blocking antibody from postnatal days 1–5 and myelination was assessed.ResultsHere, we show a novel mechanism of white matter injury. IUGR induces an exaggerated Th2 response in the developing rat brain, including upregulation of several Th2 cytokines. Of these, IL-4 is significantly increased during the period corresponding to robust developmental myelination. We show that neutralizing IL-4 antibody therapy given in the newborn period ameliorates inflammation and restores myelin protein expression and oligodendrocyte cell number in the IUGR brain to control levels, demonstrating a novel role for Th2 responses and IL-4 in IUGR and white matter injury. In addition, IL-4 directly affects oligodendrocytes in vitro decreasing differentiation.ConclusionsIn this study, we have identified inflammation as a factor in the decrease in myelin seen in an animal model of IUGR. IL-4, an inflammatory protein often thought to be protective in the adult, is specifically increased, and treatment of these animals to prevent this increase ameliorates white matter damage. Our results suggest that the immune system plays a role in IUGR that is different in the perinatal period than in the adult and preventing this exaggerated Th2 response may be a potential therapeutic target.

Sox17 Regulates a Program of Oligodendrocyte Progenitor Cell Expansion and Differentiation during Development and Repair

Sox17, a SoxF family member transiently upregulated during postnatal oligodendrocyte (OL) development, promotes OL cell differentiation, but its function in white matter development and pathology invivo is unknown. Our analysis of oligodendroglial- and OL-progenitor-cell-targeted ablation invivo using a floxed Sox17 mouse establishes a dependence of postnatal oligodendrogenesis on Sox17 and reveals Notch signaling as a mediator of Sox17 function. Following Sox17 ablation, reduced numbers of Olig2-expressing cells and mature OLs led to developmental hypomyelination and motor dysfunction. After demyelination, Sox17 deficiency inhibited OL regeneration. OL decline was unexpectedly preceded by transiently increased differentiation and a reduction of OL progenitor cells. Evidence of a dual role for Sox17 in progenitor cell expansion by Notch and differentiation involving TCF7L2 expression were found. A program of progenitor expansion and differentiation promoted by Sox17 through Notch thus contributes to OL production and determines the outcome of white matter repair.

Oligodendrocyte Neurofascin Independently Regulates Both Myelin Targeting and Sheath Growth in the CNS.

SummarySelection of the correct targets for myelination and regulation of myelin sheath growth are essential for central nervous system (CNS) formation and function. Through a genetic screen in zebrafish and complementary analyses in mice, we find that loss of oligodendrocyte Neurofascin leads to mistargeting of myelin to cell bodies, without affecting targeting to axons. In addition, loss of Neurofascin reduces CNS myelination by impairing myelin sheath growth. Time-lapse imaging reveals that the distinct myelinating processes of individual oligodendrocytes can engage in target selection and sheath growth at the same time and that Neurofascin concomitantly regulates targeting and growth. Disruption to Caspr, the neuronal binding partner of oligodendrocyte Neurofascin, also impairs myelin sheath growth, likely reflecting its association in an adhesion complex at the axon-glial interface with Neurofascin. Caspr does not, however, affect myelin targeting, further indicating that Neurofascin independently regulates distinct aspects of CNS myelination by individual oligodendrocytes in vivo.

Oxytocin induced labor causes region and sex-specific transient oligodendrocyte cell death in neonatal mouse brain.

Previous reports showed associations between oxytocin induced labor and mental disorders in offspring. However, those reports are restricted in epidemiological analyses and its mechanism remains unclear. In this study, we hypothesized that induced labor directly causes brain damage in newborns and results in the development of mental disorders. Therefore we aimed to investigate this hypothesis with animal model. The animal model of induced labor was established by subcutaneous oxytocin administration to term-pregnant C57BL/6J mice. We investigated the neonatal brain damage with evaluating immediate early gene expression (c-Fos, c-Jun and JunB) by quantitative polymerase reaction and TdT-mediated dUTP nick end labeling staining. To investigate the injured brain cell types, we performed double-immunostaining with TdT-mediated dUTP nick end labeling staining and each brain component specific protein, such as Oligo2, NeuN, GFAP and Iba1. Brain damage during induced labor led to cell death in specific brain regions, which are implicated in mental disorders, in only male offspring at P0. Furthermore, oligodendrocyte precursors were selectively vulnerable compared to the other cell types. This oligodendrocyte-specific impairment during the perinatal period led to an increased numbers of Olig2-positive cells at P5. Expression levels of oxytocin and Oxtr in the fetal brain were not affected by the oxytocin administered to mothers during induced labor. Oligodendrocyte cell death in specific brain regions, which was unrelated to the oxytocin itself, was caused by induced labor in only male offspring. This may be an underlying mechanism explaining the human epidemiological data suggesting an association between induced labor and mental disorders.

A Systems-Based Map of Human Brain Cell-Type Enriched Genes and Malignancy-Associated Endothelial Changes

Changes in the endothelium of the cerebral vasculature can contribute to inflammatory, thrombotic, and malignant disorders. The importance of defining cell-type-specific genes and their modification in disease is increasingly recognized. Here, we develop a bioinformatics-based approach to identify normal brain cell-enriched genes, using bulk RNA sequencing (RNA-seq) data from 238 normal human cortex samples from 2 independent cohorts. We compare endothelial cell-enriched gene profiles with astrocyte, oligodendrocyte, neuron, and microglial cell profiles. Endothelial changes in malignant disease are explored using RNA-seq data from 516 lower-grade gliomas and 401 glioblastomas. Lower-grade gliomas appear to be an "endothelial intermediate" between normal brain and glioblastoma. We apply our method for the prediction of glioblastoma-specific endothelial biomarkers, providing potential diagnostic or therapeutic targets. In summary, we provide a roadmap of endothelial cell identity in normal and malignant brain, using a method developed to resolve bulk RNA-seq into constituent cell-type-enriched profiles.

Enhanced mitochondrial autophagy (mitophagy) in oligodendrocytes might play a role in white matter pathology in schizophrenia

Disrupted white matter integrity is a typical feature of brain pathologic alterations in schizophrenia, which includes impaired myelination, decreased oligodendrocyte densities, distortion of their spatial distribution and deviations from normal oligodendrocyte cell morphology. While most genes expressed “in the remaining” oligodendrocytes are downregulated in schizophrenia, only a few are upregulated. To the latter group belong prohibitin 2 and DISC 1, which were recently identified as mitochondria-located mitophagy receptors. Their overexpression, together with greatly reduced numbers and densities of oligodendroglial mitochondria and the structurally “normal appearance of the remaining mitochondria” in these cells as reported by Uranova’s group (Uranova et al., 2001, 2004, 2018), point to enhanced mitophagy in oligodendrocytes in schizophrenia, which is possibly even cell protective by preventing apoptosis. Since massive loss of white matter oligodendrocytes is a characteristic feature of schizophrenia, we assume that increased mitophagy is a late event in the development and/or further progression of white matter pathologic changes. Moreover, altered oligodendroglial mitophagy might in part result from antipsychotic treatment. Further studies are clearly needed to substantiate our hypothesis on enhanced mitochondrial autophagy in schizophrenia, whereby the “drug-naïve state” and the possible influence of antipsychotic treatment could be elegantly simulated using animal models of the disease.

VDAC1 is essential for neurite maintenance and the inhibition of its oligomerization protects spinal cord from demyelination and facilitates locomotor function recovery after spinal cord injury

During the progression of the neurodegenerative process, mitochondria participates in several intercellular signaling pathways. Voltage-dependent anion-selective channel 1 (VDAC1) is a mitochondrial porin involved in the cellular metabolism and apoptosis intrinsic pathway in many neuropathological processes. In spinal cord injury (SCI), after the primary cell death, a secondary response that comprises the release of pro-inflammatory molecules triggers apoptosis, inflammation, and demyelination, often leading to the loss of motor functions. Here, we investigated the functional role of VDAC1 in the neurodegeneration triggered by SCI. We first determined that in vitro targeted ablation of VDAC1 by specific morpholino antisense nucleotides (MOs) clearly promotes neurite retraction, whereas a pharmacological blocker of VDAC1 oligomerization (4, 4′-diisothiocyanatostilbene-2, 2′-disulfonic acid, DIDS), does not cause this effect. We next determined that, after SCI, VDAC1 undergoes conformational changes, including oligomerization and N-terminal exposition, which are important steps in the triggering of apoptotic signaling. Considering this, we investigated the effects of DIDS in vivo application after SCI. Interestingly, blockade of VDAC1 oligomerization decreases the number of apoptotic cells without interfering in the neuroinflammatory response. DIDS attenuates the massive oligodendrocyte cell death, subserving undisputable motor function recovery. Taken together, our results suggest that the prevention of VDAC1 oligomerization might be beneficial for the clinical treatment of SCI.

Reappraisal of Human HOG and MO3.13 Cell Lines as a Model to Study Oligodendrocyte Functioning.

Myelination of neuronal axons is essential for proper brain functioning and requires mature myelinating oligodendrocytes (myOLs). The human OL cell lines HOG and MO3.13 have been widely used as in vitro models to study OL (dys) functioning. Here we applied a number of protocols aimed at differentiating HOG and MO3.13 cells into myOLs. However, none of the differentiation protocols led to increased expression of terminal OL differentiation or myelin-sheath formation markers. Surprisingly, the applied protocols did cause changes in the expression of markers for early OLs, neurons, astrocytes and Schwann cells. Furthermore, we noticed that mRNA expression levels in HOG and MO3.13 cells may be affected by the density of the cultured cells. Finally, HOG and MO3.13 co-cultured with human neuronal SH-SY5Y cells did not show myelin formation under several pro-OL-differentiation and pro-myelinating conditions. Together, our results illustrate the difficulty of inducing maturation of HOG and MO3.13 cells into myOLs, implying that these oligodendrocytic cell lines may not represent an appropriate model to study the (dys)functioning of human (my)OLs and OL-linked disease mechanisms.

Schema‐like learning and memory consolidation acting through myelination

Memory is a dynamic brain function that is continually processed after encoding. Although psychologic concepts of mental schema are now well established, they have rarely been considered in animal studies. We used a behavior paradigm of multiple flavor-place paired associates (PAs) and showed that memory schema facilitates fast acquisition of new PAs in a single trial. The hippocampus is necessary for the encoding of new PAs and for memory retrieval within a certain time window—24 h following new PA consolidation. Whereas the anterior cingulate cortex (ACC) plays a critical role for dynamic PA learning and consolidation during training sessions, ACC is essential in schema representation and activation. New myelin generation is essential for learning. Neural activity in the cortical regions impacts myelination by regulating oligodendrocyte (OL) proliferation, differentiation, and myelin formation. Here, we show that newly formed OL progenitor cells and mature OLs are increased following repeated PA learning and that establishment of the memory schema is associated with enhanced myelin strength in the ACC region. Furthermore, to ensure that myelination is necessary for the acquisition of paired-associate learning, ACC lysolecithin-induced demyelination revealed impaired PA learning associated with decrease in ACC θ band power and reduced spike-field coherence and phase-locking in ACC.—Hasan, M., Kanna, M. S., Jun, W., Ramkrishnan, A. S., Iqbal, Z., Lee, Y., Li, Y. Schema-like learning and memory consolidation acting through myelination.

Novel Endogenous Ligands of Aryl Hydrocarbon Receptor Mediate Neural Development and Differentiation of Neuroblastoma.

Aryl hydrocarbon receptor (AHR) signaling has been suggested to play roles in various physiological functions independent of its xenobiotic activity, including cell cycle regulation, immune response, and embryonic development. Several endogenous ligands were also identified by high-throughput screening techniques. However, the mechanism by which these molecules mediate AHR signaling in certain functions is still elusive. In this study, we investigated the possible pathway through which AHR and its endogenous ligands regulate neural development. We first identified two neuroactive steroids, 3α,5α-tetrahydrocorticosterone and 3α,5β-tetrahydrocorticosterone (5α- and 5β-THB), as novel AHR endogenous ligands through the use of an ultrasensitive dioxin-like compound bioassay and liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS). We then treated zebrafish embryos with 5α- and 5β-THB, which enhance the expression of neurogenesis marker HuC. Furthermore, 5α- and 5β-THB both enhanced the expression of myelinating glial cell markers, sex determining region Y-box 10 (Sox10), and myelin-associated proteins myelin basic protein (Mbp) and improved the mobility of zebrafish larvae via the Ahr2 pathway. These results indicated that AHR mediates zebrafish neurogenesis and gliogenesis, especially the differentiation of oligodendrocyte or Schwann cells. Additionally, we showed that these molecules may induce neuroblastoma (NB) cell differentiation suggesting therapeutic potential of 5α- and 5β-THB in NB treatment. In summary, our results reveal that 5α- and 5β-THB are endogenous ligands of AHR and have therapeutic potential for NB treatment. By the interaction with THB, AHR signaling regulates various aspects of neural development.

Inhibition of CD147 improves oligodendrogenesis and promotes white matter integrity and functional recovery in mice after ischemic stroke

White matter damage is an important contributor to long-term neurological deficit after stroke. Our previous study has shown that inhibition of CD147 ameliorates acute ischemic stroke in mice. In this study, we aimed to investigate whether inhibition of CD147 promotes white matter repair and long-term functional recovery after ischemic stroke.Male adult C57BL/6 mice were subjected to transient (1-h) middle cerebral artery occlusion (tMCAO). Anti-CD147 function–blocking antibody (αCD147) was injected intravenously once daily for 3 days beginning 4 h after onset of ischemia. Sensorimotor and cognitive functions were evaluated up to 28 days after stroke. We found that αCD147 treatment not only prevented neuronal and oligodendrocyte cell death in the acute phase, but also profoundly protected white matter integrity and reduced brain atrophy and tissue loss in the late phase, leading to improved sensorimotor and cognitive functions for at least 28 days after stroke. Mechanistically, we found that αCD147 treatment increased the number of proliferating NG2(+)/PDGFRα(+) oligodendrocyte precursor cells (OPCs) and newly generated mature APC(+)/Sox10(+) oligodendrocytes after stroke, possibly through upregulation of SDF-1/CXCR4 axis in OPCs. In conclusion, inhibition of CD147 promotes long-term functional recovery after stroke, at least in part, by enhancing oligodendrogenesis and white matter repair.