Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination
ABSTRACT Although commonly considered a disease of white matter, gray matter demyelination is increasingly recognized as an important component of multiple sclerosis (MS) pathogenesis, particularly in the secondary progressive disease phase. Extent of damage to gray matter is strongly correlated to decline in memory and cognitive dysfunction in MS patients. Aging likewise occurs with cognitive decline from myelin loss, and age-associated failure to remyelinate significantly contributes to MS progression. However, recent evidence demonstrates that parabiotic exposure of aged animals to a youthful systemic milieu can promote oligodendrocyte precursor cell (OPC) differentiation and improve remyelination. In the current study, we focus on this potential for stimulating remyelination, and show it involves serum exosomes that increase OPCs and their differentiation into mature myelin-producing cells-both under control conditions and after acute demyelination. Environmental enrichment (EE) of aging animals produced exosomes that mimicked this promyelinating effect. Additionally, stimulating OPC differentiation via exosomes derived from environmentally enriched animals is unlikely to deplete progenitors, as EE itself promotes proliferation of neural stem cells. We found that both young and EE serum-derived exosomes were enriched in miR-219, which is necessary and sufficient for production of myelinating oligodendrocytes by reducing the expression of inhibitory regulators of differentiation. Accordingly, protein transcript levels of these miR-219 target mRNAs decreased following exosome application to slice cultures. Finally, nasal administration of exosomes to aging rats also enhanced myelination. Thus, peripheral circulating cells in young or environmentally enriched animals produce exosomes that may be a useful therapy for remyelination. GLIA 2014;62:284-299.
- SourceAvailable from: Dong Ho Woo
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- "Astrocytes in cell culture release leukemia inhibitory factor (LIF) in response to ATP released from axons firing action potentials , which promotes myelination by mature oligodendrocytes (Ishibashi et al., 2006). Recent evidence for other mechanisms of activity-dependent myelination is emerging, for example, via exosome signaling (Frü hbeis et al., 2013; Pusic and Kraig, 2014) and blood oxygen tension (Yuen et al., 2014). "
ABSTRACT: If "the connectome" represents a complete map of anatomical and functional connectivity in the brain, it should also include glia. Glia define and regulate both the brain's anatomical and functional connectivity over a broad range of length scales, spanning the whole brain to subcellular domains of synaptic interactions. This Perspective article examines glial interactions with the neuronal connectome (including long-range networks, local circuits, and individual synaptic connections) and highlights opportunities for future research. Our understanding of the structure and function of the neuronal connectome would be incomplete without an understanding of how all types of glia contribute to neuronal connectivity and function, from single synapses to circuits. Copyright © 2015 Elsevier Inc. All rights reserved.Neuron 04/2015; 86(2):374-386. DOI:10.1016/j.neuron.2015.01.014 · 15.05 Impact Factor
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- "In prior experiments, injection electrodes were raised immediately after SD induction and moved into a microscope slide with depression wells (ThermoFisher Scientific) filled with light 3-In-ONE oil (WD-40 Company, San Diego, CA). KCl injections were then repeated into oil and volumes calculated from diameter measured using a compound microscope fitted with an optical micrometer within an eye piece (Pusic et al., 2014a; Grinberg and Kraig, 2013). Here, we increased this nL volume by 2–3 fold to reliably evoke six SDs. "
ABSTRACT: Multiple sclerosis and migraine with aura are clinically correlated and both show imaging changes suggestive of myelin disruption. Furthermore, cortical myelin loss in the cuprizone animal model of multiple sclerosis enhances susceptibility to spreading depression, the likely underlying cause of migraine with aura. Since multiple sclerosis pathology involves inflammatory T cell lymphocyte production of interferon-gamma and a resulting increase in oxidative stress, we tested the hypothesis that spreading depression disrupts myelin through similar signaling pathways. Rat hippocampal slice cultures were initially used to explore myelin loss in spreading depression, since they contain T cells, and allow for controlled tissue microenvironment. These experiments were then translated to the in vivo condition in neocortex. Spreading depression in slice cultures induced significant loss of myelin integrity and myelin basic protein one day later, with gradual recovery by seven days. Myelin basic protein loss was abrogated by T cell depletion, neutralization of interferon-gamma, and pharmacological inhibition of neutral sphingomyelinase-2. Conversely, one day after exposure to interferon-gamma, significant reductions in spreading depression threshold, increases in oxidative stress, and reduced levels of glutathione, an endogenous neutral sphingomyelinase-2 inhibitor, emerged. Similarly, spreading depression triggered significant T cell accumulation, sphingomyelinase activation, increased oxidative stress, and reduction of gray and white matter myelin in vivo. Myelin disruption is involved in spreading depression, thereby providing pathophysiological links between multiple sclerosis and migraine with aura. Myelin disruption may promote spreading depression by enhancing aberrant excitability. Thus, preservation of myelin integrity may provide novel therapeutic targets for migraine with aura. Copyright © 2014. Published by Elsevier Inc.Experimental Neurology 12/2014; 264. DOI:10.1016/j.expneurol.2014.12.001 · 4.70 Impact Factor
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- "Cultures that lacked evidence of stratum pyramidale neuronal death were considered viable, and thus suitable for subsequent experimental use. We used hippocampal slice cultures maintained in vitro for 21 to 35 days to model SD in vivo, since culture in this window of time closely parallel the in vivo counterpart (for review see Kunkler et al., 2005 and Pusic et al., 2014). Specifically, the neurovascular unit (Kovacs et al., 2011), multisynaptic electrical activity (Kunkler and Kraig, 1998), pyramidal neuron vitality (Hulse et al., 2008), responsive astrocytes and microglia (Grinberg et al., 2011; Ransohoff and Perry, 2009) and cytokine signaling (Kunkler et al., 2004) resemble that seen in vivo. "
ABSTRACT: Microglia play an important role in fine-tuning neuronal activity. In part, this involves their production of tumor necrosis factor-alpha (TNFα), which increases neuronal excitability. Excessive synaptic activity is necessary to initiate spreading depression (SD). Increased microglial production of proinflammatory cytokines promotes initiation of SD, which, when recurrent, may play a role in conversion of episodic to high frequency and chronic migraine. Previous work shows that this potentiation of SD occurs through increased microglial production of TNFα and reactive oxygen species, both of which are associated with an M1-skewed microglial population. Hence, we explored the role of microglia and their M1 polarization in SD initiation. Selective ablation of microglia from rat hippocampal slice cultures confirmed that microglia are essential for initiation of SD. Application of minocycline to dampen M1 signaling led to increased SD threshold. In addition, we found that SD threshold was increased in rats exposed to environmental enrichment. These rats had increased neocortical levels of interleukin-11 (IL-11), which decreases TNFα signaling and polarized microglia to an M2a-dominant phenotype. M2a microglia reduce proinflammatory signaling and increase production of anti-inflammatory cytokines, and therefore may protect against SD. Nasal administration of IL-11 to mimic effects of environmental enrichment likewise increased M2a polarization and increased SD threshold, an effect also seen in vitro. Similarly, application of conditioned medium from M2a polarized primary microglia to slice cultures also increased SD threshold. Thus, microglia and their polarization state play an essential role in SD initiation, and perhaps by extension migraine with aura and migraine. GLIA 2014Glia 07/2014; 62(7). DOI:10.1002/glia.22672 · 6.03 Impact Factor