pinecone/core-2020-05-10-deduplication huggingface dataset:
Heterogeneity and phenotypic plasticity of glial cells in the mammalian enteric nervous system

Enteric glial cells are vital for the autonomic control of gastrointestinal homeostasis by the enteric nervous system. Several different functions have been assigned to enteric glial cells but whether these are performed by specialized subtypes with a distinctive phenotype and function remains elusive. We used Mosaic Analysis with Double Markers and inducible lineage tracing to characterize the morphology and dynamic molecular marker expression of enteric GLIA in the myenteric plexus. Functional analysis in individually identified enteric glia was performed by Ca(2+) imaging. Our experiments have identified four morphologically distinct subpopulations of enteric glia in the gastrointestinal tract of adult mice. Marker expression analysis showed that the majority of glia in the myenteric plexus co-express glial fibrillary acidic protein (GFAP), S100β, and Sox10. However, a considerable fraction (up to 80%) of glia outside the myenteric ganglia, did not label for these markers. Lineage tracing experiments suggest that these alternative combinations of markers reflect dynamic gene regulation rather than lineage restrictions. At the functional level, the three myenteric glia subtypes can be distinguished by their differential response to adenosine triphosphate. Together, our studies reveal extensive heterogeneity and phenotypic plasticity of enteric glial cells and set a framework for further investigations aimed at deciphering their role in digestive function and disease. GLIA 2014 Main points: Enteric glia can be discriminated on the basis of morphology and location but also display distinct molecular and functional characteristics. The diversity among enteric glia reflects dynamic gene regulation rather than lineage restrictions.status: publishe
The EIIIA domain from astrocyte-derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination

Central nervous system remyelination by oligodendrocyte progenitor cells (OPCs) ultimately fails in the majority of multiple sclerosis (MS) lesions. Remyelination benefits from transient expression of factors that promote migration and proliferation of OPCs, which may include fibronectin (Fn). Fn is present in demyelinated lesions in two major forms; plasma Fn (pFn), deposited following blood-brain barrier disruption, and cellular Fn, synthesized by resident glial cells and containing alternatively spliced domains EIIIA and EIIIB. Here, we investigated the distinctive roles that astrocyte-derived Fn (aFn) and pFn play in remyelination. We used an inducible Cre-lox recombination strategy to selectively remove pFn, aFn or both from mice, and examined the impact on remyelination of toxin-induced demyelinated lesions of spinal cord white matter. This approach revealed that astrocytes are a major source of Fn in demyelinated lesions. Furthermore, following aFn conditional knockout, the number of OPCs recruited to the demyelinated lesion decreased significantly, whereas OPC numbers were unaltered following pFn conditional knockout. However, remyelination completed normally following conditional knockout of aFn and pFn. Both the EIIIA and EIIIB domains of aFn were expressed following demyelination, and in vitro assays demonstrated that the EIIIA domain of aFn mediates proliferation of OPCs, but not migration. Therefore, although the EIIIA domain from aFn mediates OPC proliferation, aFn is not essential for successful remyelination. Since previous findings indicated that astrocyte-derived Fn aggregates in chronic MS lesions inhibit remyelination, aFn removal may benefit therapeutic strategies to promote remyelination in MS.JMJS is recipient of a Junior Scientific Masterclass MD/PhD fellowship from the University Medical Center Groningen. This work was supported by grants from the Netherlands Organization of Scientific Research (NWO, WB, VIDI and Aspasia), the Dutch MS Research
Foundation (‘Stichting MS Research’, WB, JMJS, DH), the UK MS Society (CZ, RJMF), and the Research School of Behavioral and Cognitive Neurosciences (BCN, JMJS). Parts of this study were performed at the UMCG Microscopy and Imaging Center (UMIC), which is supported by NWO grants 40-00506-98-9021 and 175-010-2009-023.This is the final version of the article. It was first published by Wiley at http://dx.doi.org/10.1002/glia.2274
Identification of a chronic non-neurodegenerative microglia activation state in a mouse model of peroxisomal β-oxidation deficiency

The functional diversity and molecular adaptations of reactive microglia in the chronically inflamed central nervous system (CNS) are poorly understood. We previously showed that mice lacking multifunctional protein 2 (MFP2), a pivotal enzyme in peroxisomal β-oxidation, persistently accumulate reactive myeloid cells in the gray matter of the CNS. Here, we show that the increased numbers of myeloid cells solely derive from the proliferation of resident microglia and not from infiltrating monocytes. We defined the signature of Mfp2(-/-) microglia by gene expression profiling after acute isolation, which was validated by quantitative polymerase reaction (qPCR), immunohistochemical, and flow cytometric analysis. The features of Mfp2(-/-) microglia were compared with those from SOD1(G93A) mice, an amyotrophic lateral sclerosis model. In contrast to the neurodegenerative milieu of SOD1(G93A) spinal cord, neurons were intact in Mfp2(-/-) brain and Mfp2(-/-) microglia lacked signs of phagocytic and neurotoxic activity. The chronically reactive state of Mfp2(-/-) microglia was accompanied by the downregulation of markers that specify the unique microglial signature in homeostatic conditions. In contrast, mammalian target of rapamycin (mTOR) and downstream glycolytic and protein translation pathways were induced, indicative of metabolic adaptations. Mfp2(-/-) microglia were immunologically activated but not polarized to a pro- or anti-inflammatory phenotype. A peripheral lipopolysaccharide challenge provoked an exaggerated inflammatory response in Mfp2(-/-) brain, consistent with a primed state. Taken together, we demonstrate that chronic activation of resident microglia does not necessarily lead to phagocytosis nor overt neurotoxicity. GLIA 2015.status: publishe
Activation of mitochondrial transient receptor potential vanilloid 1 channel contributes to microglial migration.

Article first published online: 23 MAY 2015Microglia, the resident immune cells in the brain, survey the environment of the healthy brain. Microglial migration is essential for many physiological and pathophysiological processes. Although microglia express some members of the transient receptor potential (TRP) channel family, there is little knowledge regarding the physiological roles of TRP channels in microglia. Here, we explored the role of TRP vanilloid 1 (TRPV1), a channel opened by capsaicin, heat, protons, and endovanilloids, in microglia. We found that application of capsaicin induced concentration-dependent migration in microglia derived from wild-type mice but not in those derived from TRPV1 knockout (TRPV1-KO) mice. Capsaicin-induced microglial migration was significantly inhibited by co-application of the TRPV1 blocker SB366791 and the Ca(2+) chelator BAPTA-AM. Using RT-PCR and immunocytochemistry, we validated that TRPV1 was expressed in microglia. Electrophysiological recording, intracellular Ca(2+) imaging, and immunocytochemistry indicated that TRPV1 was localized primarily in intracellular organelles. Treatment with capsaicin induced an increase in intramitochondrial Ca(2+) concentrations and mitochondrial depolarization. Furthermore, microglia derived from TRPV1-KO mice showed delayed Ca(2+) efflux compared with microglia derived from wild-type mice. Capsaicin-induced microglial migration was inhibited by membrane-permeable antioxidants and MAPK inhibitors, suggesting that mitochondrial TRPV1 activation induced Ca(2+) -dependent production of ROS followed by MAPK activation, which correlated with an augmented migration of microglia. Moreover, a mixture of three endovanilloids augmented microglial migration via TRPV1 activation. Together, these results indicate that mitochondrial TRPV1 plays an important role in inducing microglial migration. Activation of TRPV1 triggers an increase in intramitochondrial Ca(2+) concentration and following depolarization of mitochondria, which results in mtROS production, MAPK activation, and enhancement of chemotactic activity in microglia
Thyroid hormone activation of retinoic acid synthesis in hypothalamic tanycytes

yesThyroid hormone (TH) is essential for adult brain function and its actions include several key roles in the hypothalamus.
Although TH controls gene expression via specific TH receptors of the nuclear receptor class, surprisingly few genes have
been demonstrated to be directly regulated by TH in the hypothalamus, or the adult brain as a whole. This study explored
the rapid induction by TH of retinaldehyde dehydrogenase 1 (Raldh1), encoding a retinoic acid (RA)-synthesizing enzyme, as a
gene specifically expressed in hypothalamic tanycytes, cells that mediate a number of actions of TH in the hypothalamus. The
resulting increase in RA may then regulate gene expression via the RA receptors, also of the nuclear receptor class. In vivo
exposure of the rat to TH led to a significant and rapid increase in hypothalamic Raldh1 within 4 hours. That this may lead to
an in vivo increase in RA is suggested by the later induction by TH of the RA-responsive gene Cyp26b1. To explore the
actions of RA in the hypothalamus as a potential mediator of TH control of gene regulation, an ex vivo hypothalamic rat slice
culture method was developed in which the Raldh1-expressing tanycytes were maintained. These slice cultures confirmed that
TH did not act on genes regulating energy balance but could induce Raldh1. RA has the potential to upregulate expression
of genes involved in growth and appetite, Ghrh and Agrp. This regulation is acutely sensitive to epigenetic changes, as has
been shown for TH action in vivo. These results indicate that sequential triggering of two nuclear receptor signalling systems
has the capability to mediate some of the functions of TH in the hypothalamus.gol
Sodium signaling and astrocyte energy metabolism.

The Na(+) gradient across the plasma membrane is constantly exploited by astrocytes as a secondary energy source to regulate the intracellular and extracellular milieu, and discard waste products. One of the most prominent roles of astrocytes in the brain is the Na(+) -dependent clearance of glutamate released by neurons during synaptic transmission. The intracellular Na(+) load collectively generated by these processes converges at the Na,K-ATPase pump, responsible for Na(+) extrusion from the cell, which is achieved at the expense of cellular ATP. These processes represent pivotal mechanisms enabling astrocytes to increase the local availability of metabolic substrates in response to neuronal activity. This review presents basic principles linking the intracellular handling of Na(+) following activity-related transmembrane fluxes in astrocytes and the energy metabolic pathways involved. We propose a role of Na(+) as an energy currency and as a mediator of metabolic signals in the context of neuron-glia interactions. We further discuss the possible impact of the astrocytic syncytium for the distribution and coordination of the metabolic response, and the compartmentation of these processes in cellular microdomains and subcellular organelles. Finally, we illustrate future avenues of investigation into signaling mechanisms aimed at bridging the gap between Na(+) and the metabolic machinery. GLIA 2016;64:1667-1676
Astrocytes are key but indirect contributors to the development of the symptomatology and pathophysiology of Huntington's disease.

Huntington's disease (HD) is a fatal neurodegenerative disease in which an early and selective vulnerability of striatal Spiny Projection Neurons is observed. However, several studies have highlighted the implication of glial cells, and in particular astrocytes, in the pathophysiological mechanisms of this disease. A better understanding of the respective contributions of neurons and astrocytes in HD is needed and would be important for the development of new therapeutic approaches. Today, no comparable in vivo models expressing the mutant HTT selectively in astrocytes or in neurons are available. In this study, we developed comparable cell-type specific mouse models expressing a fragment of Huntingtin specifically in neurons, astrocytes, or in both cell populations of the adult mouse basal ganglia circuit. This approach allowed us to characterize behavioral alterations occurring as soon as 4 weeks postinjection. Interestingly, less severe but significant behavioral alterations were also observed in the two cell-type specific models. We further showed that astrocytes are less affected by mHTT compared to neurons, in particular concerning mHTT aggregation. Additionally, a more indirect contribution of astrocytes compared to neurons was observed in several pathophysiological mechanisms such as astrogliosis and neuronal dysfunction. Finally, we showed that direct and indirect transcriptional alterations within the glial glutamatergic clearing system are caused by astrocytic and neuronal expression of mHTT, respectively. We anticipate that our study will help to better understand the contributions of astrocytes to HD and guide future therapeutic efforts. GLIA 2016;64:1841-1856
IL-4 drives microglia and macrophages toward a phenotype conducive for tissue repair and functional recovery after spinal cord injury

Macrophages and microglia play a key role in the maintenance of nervous system homeostasis. However, upon different challenges, they can adopt several phenotypes, which may lead to divergent effects on tissue repair. After spinal cord injury (SCI), microglia and macrophages show predominantly pro-inflammatory activation and contribute to tissue damage. However, the factors that hamper their conversion to an anti-inflammatory state after SCI, or to other protective phenotypes, are poorly understood. Here, we show that IL-4 protein levels are undetectable in the spinal cord after contusion injury, which likely favors microglia and macrophages to remain in a pro-inflammatory state. We also demonstrate that a single delayed intraspinal injection of IL-4, 48 hours after SCI, induces increased expression of M2 marker in microglia and macrophages. We also show that delayed injection of IL-4 leads to the appearance of resolution-phase macrophages, and that IL-4 enhances resolution of inflammation after SCI. Interestingly, we provide clear evidence that delayed administration of IL-4 markedly improves functional outcomes and reduces tissue damage after contusion injury. It is possible that these improvements are mediated by the presence of macrophages with M2 markers and resolution-phase macrophages. These data suggest that therapies aimed at increasing IL-4 levels could be valuable for the treatment of acute SCI, for which there are currently no effective treatments
Identification of a conserved and acute neurodegeneration-specific microglial transcriptome in the zebrafish

Microglia are brain resident macrophages important for brain development, connectivity, homeostasis and disease. However, it is still largely unclear how microglia functions and their identity are regulated at the molecular level. Although recent transcriptomic studies have identified genes specifically expressed in microglia, the function of most of these genes in microglia is still unknown. Here, we performed RNA sequencing on microglia acutely isolated from healthy and neurodegenerative zebrafish brains. We found that a large fraction of the mouse microglial signature is conserved in the zebrafish, corroborating the use of zebrafish to help understand microglial genetics in mammals in addition to studying basic microglia biology. Second, our transcriptome analysis of microglia following neuronal ablation suggested primarily a proliferative response of microglia, which we confirmed by immunohistochemistry and in vivo imaging. Together with the recent improvements in genome editing technology in zebrafish, these data offer opportunities to facilitate functional genetic research on microglia in vivo in the healthy as well as in the diseased brain. GLIA 2016;65:138–149
Astrocytic signaling supports hippocampal-prefrontal theta synchronization and cognitive function

Astrocytic signaling supports hippocampal-prefrontal theta synchronization and cognitive functionAstrocytes interact with neurons at the cellular level through modulation of synaptic formation, maturation, and function, but the impact of such interaction into behavior remains unclear. Here, we studied the dominant negative SNARE (dnSNARE) mouse model to dissect the role of astrocyte-derived signaling in corticolimbic circuits, with implications for cognitive processing. We found that the blockade of gliotransmitter release in astrocytes triggers a critical desynchronization of neural theta oscillations between dorsal hippocampus and prefrontal cortex. Moreover, we found a strong cognitive impairment in tasks depending on this network. Importantly, the supplementation with D-serine completely restores hippocampal-prefrontal theta synchronization and rescues the spatial memory and long-term memory of dnSNARE mice. We provide here novel evidence of long distance network modulation by astrocytes, with direct implications to cognitive function.Foundation for Science and Technology
(FCT) project (PTDC/SAU-NSC/118194/
2010) to V.M.S., S.G.G., G.T., M.M., J.S.R.,
J.S.C., J.F.O. and fellowships (SFRH/BD/
89714/2012 to V.M.S., SFRH/BPD/97281/
2013 to J.F.O., SFRH/BD/101298/2014 to
S.G.G., IF/00328/2015 to JFO, IF/01079/
2014 to LP); Marie Curie Fellowship FP7-
PEOPLE-2010-IEF 273936 and BIAL
Foundation Grants 207/14 to J.F.O. and
427/14 to LP; Northern Portugal Regional
Operational Programme (NORTE 2020),
under the Portugal 2020 Partnership
Agreement, through the European Regional
Development Fund (FEDER) (NORTE-01-
0145-FEDER-000013); FEDER funds,
through the Competitiveness Factors
Operational Programme (COMPETE), and
National funds, through the FCT (POCI-01-
0145-FEDER-007038)info:eu-repo/semantics/publishedVersio
Cell therapy for spinal cord injury with Olfactory Ensheathing Glia Cells (OECs)

This is the peer reviewed version of the following article: Gómez RM, Sánchez MY, Portela-Lomba M, et al. Cell therapy for spinal cord injury with olfactoryensheathing glia cells (OECs). Glia. 2018;00:1–35
 which has been published in final form at GLIA 13 January (2018) http://doi.org/10.1002/glia.23282. © 2018 Wiley Periodicals This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.The prospects of achieving regeneration in the central nervous system (CNS) have changed, asmost recent findings indicate that several species, including humans, can produce neurons in adult-hood. Studies targeting this property may be considered as potential therapeutic strategies torespond to injury or the effects of demyelinating diseases in the CNS. While CNS trauma mayinterrupt the axonal tracts that connect neurons with their targets, some neurons remain alive, asseen in optic nerve and spinal cord (SC) injuries (SCIs). The devastating consequences of SCIs aredue to the immediate and significant disruption of the ascending and descending spinal pathways,which result in varying degrees of motor and sensory impairment. Recent therapeutic studies forSCI have focused on cell transplantation in animal models, using cells capable of inducing axonregeneration like Schwann cells (SchCs), astrocytes, genetically modified fibroblasts and olfactoryensheathing glia cells (OECs). Nevertheless, and despite the improvements in such cell-based ther-apeutic strategies, there is still little information regarding the mechanisms underlying the successof transplantation and regarding any secondary effects. Therefore, further studies are needed to clarify these issues. In this review, we highlight the properties of OECs that make them suitable toachieve neuroplasticity/neuroregeneration in SCI. OECs can interact with the glial scar, stimulateangiogenesis, axon outgrowth and remyelination, improving functional outcomes following lesion.Furthermore, we present evidence of the utility of cell therapy with OECs to treat SCI, both fromanimal models and clinical studies performed on SCI patients, providing promising results for future treatments
High conductance anion channel in Schwann cell vesicles from rat spinal roots

Potassium uptake, possibly together with chloride, is one of the presumed functions of Schwann cells in the peripheral nervous system. However, the presence of chloride channels has not been demonstrated in adult Schwann cells. We present here a new method which allows single channel recordings to be made from Schwann cells in situ without enzymatic treatment. Isolated rat spinal roots were split mechanically into several bundles. Within about 30 min after this procedure small belb-like vesicles (20-30 m in diameter) with a clean surface appeared at the edges of the fibre bundles. Immunofluorescence microscopy with a surface marker for Schwann cell membranes (monoclonal antibody O4) revealed that the vesicles originate from Schwann cells. In standard patch clamp recordings with symmetrical bath and pipette solutions (excised inside-out configuration) an anion channel with the following characteristics was mainly observed: (1) single channel slope conductance of 337 ± 5 pS in 125 mM KCl and 209 ± 6 pS in 125 mM K+ methylsulphate; (2) ion permeability ratio: PCl/PK/Pgluconate = 1/0.12/0.06; (3) linear current-voltage relationship (range ± 60 mV) and (4) voltage- and time-dependent inactivation (the channel was most active at potentials ± 20mV). Pharmacologically, the channel was completely blocked with zinc (1 mM) and barium (10 mM). A similar anion channel, showing characteristics 1 - (4), has been described in cultured Schwann cells of newborn rats (Gray et al., 1984). We now demonstrate that this channel is also present in adult Schwann cells in situ.