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Research Interests: Neuroscience and Biology
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Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease and neuropsychiatric... more
Disruption or loss of oligodendrocytes (OLs) and myelin has devastating effects on CNS function and integrity, which occur in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular pathways. Here, we have used a combined systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, next generation pharmacogenomic analysis identified the PI3K/Akt modulator LY294002 as the most highly ranked small molecule with both pro- and anti-oligodendroglial concentration-dependent effects. We validated these in silico findings using multidisciplinary approaches to reveal a profoundly bipartite effect of LY294002 on the generation of OPCs and their differentiation into myelinating oligodendrocytes in both postnatal and adult contexts. Finally, we employed transcriptional profiling and signalling pathway activity assays to determine cell-specific mechanisms of action of LY294002 on oligodendrocytes and resolve optimal in vivo conditions required to promote myelin repair. These results demonstrate the power of multidisciplinary strategies in determining the therapeutic potential of small molecules in neurodegenerative disorders.
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Glial cells are the most numerous cells in the human brain but for many years have attracted little scientific attention. Neurophysiologists concentrated their research efforts instead, on neurones and neuronal networks because it was... more
Glial cells are the most numerous cells in the human brain but for many years have attracted little scientific attention. Neurophysiologists concentrated their research efforts instead, on neurones and neuronal networks because it was thought that they were the key elements responsible for higher brain function. Recent advances, however, indicate this isn't exactly the case. Not only are astroglial cells the stem elements from which neurones are born, but they also control the development, functional activity and death of neuronal circuits. These ground-breaking developments have revolutionized our understanding of the human brain and the complex interrelationship of glial and neuronal networks in health and disease.
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Research Interests: Neuroscience, Physiology, Biology, Medicine, Signalling, and 4 moreMedical Physiology, Oligodendrocyte, Myelin, and MRC
Research Interests: Neuroscience, Psychology, Cognitive Science, Biology, Membrane Proteins, and 15 moreMedicine, Gene expression, Brain, Optic Nerve, Animals, Polymerase Chain Reaction, Astrocyte, Membrane transport proteins, White matter, Rats, Rat, Neurosciences, Gamma-Aminobutyric Acid, Visual Pathway, and Reverse transcription polymerase chain reaction
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Research Interests: Cognitive Science, Biology, Cell Cycle, Cell Biology, Medicine, and 15 moreNeural stem cell, Cell Differentiation, Humans, Cerebellum, Mice, Animals, Astrocyte, Glial Cell, Neurons, Astrocytes, Green Fluorescent Protein, Glial Fibrillary Acidic Protein, Biological markers, Cellular and Molecular Neuroscience, and Neurosciences
Research Interests: Neuroscience, Genomics, Neurogenesis, Biology, Medicine, and 15 moreSignal Transduction, Transcriptome, Biological Sciences, Neural stem cell, Computer Simulation, Mice, Animals, Gene Regulatory Networks, Nerve Regeneration, Neural Stem Cells, Subventricular Zone, Neurosciences, Gene Expression Regulation, Forebrain, and Medical and Health Sciences
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Classic studies recognize two functionally segregated macroglial cell types in the central nervous system (CNS), namely astrocytes and oligodendrocytes. A third macroglial cell type has now been identified by its specific expression of... more
Classic studies recognize two functionally segregated macroglial cell types in the central nervous system (CNS), namely astrocytes and oligodendrocytes. A third macroglial cell type has now been identified by its specific expression of the NG2 chondroitin sulphate proteoglycan (NG2-glia). These NG2-glia exist abundantly in both grey and white matter of the mature CNS and are almost as numerous as astrocytes. It is well established that NG2-glia give rise to oligodendrocytes. However, the majority of NG2-glia in the adult CNS proliferate very slowly and are non-motile. Both astrocytes and NG2-glia display a stellate morphology and express ion channels and receptors to neurotransmitters used by neurons. Both types of glia make intimate contacts with neurons in grey and white matter, and their functional differences and similarities are only beginning to be unravelled. Recent observations emphasize the need to examine the relationship between astrocytes and NG2-glia, and address the question of whether they represent overlapping or two distinct glial cell populations. To be of any relevance, this classification must relate to specific functions in the neural network. At present, the balance of evidence is that NG2-glia and astrocytes are functionally segregated populations.
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Background. Stroke is a leading cause of death and disability worldwide. A major factor in brain damage following ischemia is excitotoxicity caused by elevated levels of the neurotransmitter glutamate. In the brain, glutamate homeostasis... more
Background. Stroke is a leading cause of death and disability worldwide. A major factor in brain damage following ischemia is excitotoxicity caused by elevated levels of the neurotransmitter glutamate. In the brain, glutamate homeostasis is a primary function of astrocytes. Amburana cearensis has long been used in folk medicine and seed extract obtained with dichloromethane (EDAC) have previously been shown to exhibit cytoprotective activity in vitro. The aim of the present study was to analyse the activity of EDAC in hippocampal brain slices. Methods. We prepared a dichloromethane extract (EDAC) from A. cearensis seeds and characterized the chemical constituents by 1H and 13C-NMR. Hippocampal slices from P6-8 or P90 Wistar rats were used for cell viability assay or glutamate uptake test. Hippocampal slices from P10-12 transgenic mice SOX10-EGFP and GFAP-EGFP and immunofluorescence for GS, GLAST and GLT1 were used to study oligodendrocytes and astrocytes. Results. Astrocytes play a ...
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Research Interests: Biomedical Engineering, Fluorescence Microscopy, Biology, Calcium, Axon, and 15 moreAnatomy, Glutamate, Female, Animals, Astrocyte, Calcium Signaling, Astrocytes, Glial Fibrillary Acidic Protein, Biological markers, Action Potentials, Axons, Antigens, Adenosine Triphosphate, astrogliosis, and Glial scar
The factors regulating astroglial resting membrane potential (RMP) are unresolved. Here, we have examined developmental, morphological, and intracellular factors that may regulate the RMP in astrocytes of isolated intact optic nerves of... more
The factors regulating astroglial resting membrane potential (RMP) are unresolved. Here, we have examined developmental, morphological, and intracellular factors that may regulate the RMP in astrocytes of isolated intact optic nerves of rats and mice aged postnatal day (P3) to adult. The astroglial RMP ranged from -25 to -85 mV, independent of age and morphological phenotype. There was a developmental negative shift in the astroglial RMP from a non-Gaussian distribution in perinatal nerves, to a bimodal distribution of RMPs after P15, with peaks at -52 and -74 mV in adults. Blockade of Kir with 100 microM BaCl(2) significantly depolarized the RMP to -30 mV; the RMP was unaffected by TEA or agents that modulated ATP-sensitive potassium channels. Raising intracellular cyclic AMP (cAMP) with dbcAMP or forskolin induced a significant hyperpolarization by approximately 15 mV, whereas inhibition of cAMP-dependent protein kinase (PKA) depolarized the astroglial RMP to -40 mV. The hyperpolarizing action of dbcAMP was blocked by 100 microM BaCl(2). The effects of BaCl(2) indicate that the developmental negative shift in the RMP and the cAMP-mediated hyperpolarization were dependent on Kir. This study provides evidence that the heterogeneous RMP of mature astrocytes is regulated by cAMP and PKA signaling.
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NG2‐glia are an abundant population of cells in the adult CNS that make up a novel glial cell type. Here, we have examined calcium signals in NG2‐glia identified by expression of the fluorescent protein DsRed under the control of the NG2... more
NG2‐glia are an abundant population of cells in the adult CNS that make up a novel glial cell type. Here, we have examined calcium signals in NG2‐glia identified by expression of the fluorescent protein DsRed under the control of the NG2 promoter in the white matter of the mouse optic nerve. We focused on mice aged postnatal day (P)12–16, after the main period of oligodendrocyte generation. Using fluo‐4 and fura‐2 calcium imaging in isolated intact nerves, we show that glutamate and ATP evoke Ca2+ signals in NG2‐glia in situ, acting on AMPA‐type glutamate receptors and P2Y1 and P2X7 purine receptors; NMDA evoked a weak Ca2+ signal in a small proportion of NG2‐glia. We show that axonal action potentials and mechanical stimulation of astrocytes effect the release of glutamate and ATP to act on NG2‐glia; ATP alone evokes robust Ca2+ signals, whereas glutamate did not unless AMPA receptor desensitization was blocked with cyclothiazide. We identify the precise contacts that NG2‐glia form with axons at nodes of Ranvier, and the intricate bipartite sheaths formed between the processes of NG2‐glia and astrocytes. In addition, we provide evidence that NG2‐glia express synaptophysin, indicating they have mechanisms for transmitting as well as receiving signals. This study places NG2‐glia within a neuron‐glial network, and identifies roles for glutamate and ATP in communication with astrocytes as well as axons. © 2009 Wiley‐Liss, Inc.
Research Interests: Biology, Calcium, Cell Biology, Axon, Glutamate, and 15 moreCerebral Cortex, Female, Animals, Astrocyte, Calcium Signaling, Astrocytes, ATP, Glial Fibrillary Acidic Protein, Glia, Cellular and Molecular Neuroscience, Axons, Antigens, Adenosine Triphosphate, Adenosine Diphosphate, and Electric stimulation
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Research Interests: Cognitive Science, Migration, Flow Cytometry, Biology, Developmental neuroscience, and 13 moreCell Migration, Cancer Research, Medicine, Extracellular Matrix, Glioma, Progenitor Cells, Human Brain, Glioblastoma Multiforme, Growth Factor, Neurosciences, Low Grade Glioma, Differential expression, and Basic Fibroblast Growth Factor
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Agathisflavone, purified from Cenostigma pyramidale (Tul.) has been shown to be neuroprotective in in vitro models of glutamate-induced excitotoxicity and inflammatory damage. However, the potential role of microglial regulation by... more
Agathisflavone, purified from Cenostigma pyramidale (Tul.) has been shown to be neuroprotective in in vitro models of glutamate-induced excitotoxicity and inflammatory damage. However, the potential role of microglial regulation by agathisflavone in these neuroprotective effects is unclear. Here we investigated the effects of agathisflavone in microglia submitted to inflammatory stimulus in view of elucidating mechanisms of neuroprotection. Microglia isolated from cortices of newborn Wistar rats were exposed to Escherichia coli lipopolysaccharide (LPS, 1 µg/mL) and treated or not with agathisflavone (1 µM). Neuronal PC12 cells were exposed to a conditioned medium from microglia (MCM) treated or not with agathisflavone. We observed that LPS induced microglia to assume an activated inflammatory state (increased CD68, more rounded/amoeboid phenotype). However, most microglia exposed to LPS and agathisflavone, presented an anti-inflammatory profile (increased CD206 and branched-phenotyp...
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<p>Gene list generated to obtain the drug profiles for AR-A014418 (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2000698#pbio.2000698.s011" target="_blank">S6 Table</a>)... more
<p>Gene list generated to obtain the drug profiles for AR-A014418 (<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2000698#pbio.2000698.s011" target="_blank">S6 Table</a>) was utilized to compile the CMAP “AR-A014418” target-gene list, and genes prospectively up-regulated are presented as a heatmap in <b>(A)</b> showing enrichment in earlier postnatal dorsal subventricular zone (dSVZ) cells. aEPs, adult ependymas; aNPs, adult neuronal precursors; GM, grey matter; astros, astrocytes; mOLs, mature/myelinating oligodendrocytes; aNSCs, adult neural stem cells (NSCs); dNSCs, dorsal NSCs; dTAPs, dorsal transient amplifying progenitors (TAPs); lNSCs, lateral NSCs; lTAPs, lateral TAPs. <b>(B)</b> Prospectively up-regulated or down-regulated genes analyzed by Genego Metacore for GO Pathway Maps and Process Networks, and lists are ranked according to significance (false discovery rate [FDR] <1%)/numbers of genes present in each of the categories. <b>(C, D)</b> Short path network to visualize highly connected signaling-to-transcriptional nodes were performed for up- and down-regulated ARA-014418 target genes. Internal clusters were grouped by selecting the “link GO objects” in GeneGo Metacore. Highlighted blue objects are directly within data and remaining objects are within the background (or basal) data.</p
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Ongoing research continues to add new elements to the emerging picture of involvement of astrocyte energy metabolism in the pathophysiology of major psychiatric disorders, including schizophrenia, mood disorders, and addictions. This... more
Ongoing research continues to add new elements to the emerging picture of involvement of astrocyte energy metabolism in the pathophysiology of major psychiatric disorders, including schizophrenia, mood disorders, and addictions. This review outlines what is known about the energy metabolism in astrocytes, the most numerous cell type in the brain, and summarizes the recent work on how specific perturbations of astrocyte bioenergetics may contribute to the neuropsychiatric conditions. The role of astrocyte energy metabolism in mental health and disease is reviewed on the organism, organ, and cell level. Data arising from genomic, metabolomic, in vitro, and neurobehavioral studies is critically analyzed to suggest future directions in research and possible metabolism-focused therapeutic interventions.
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The subventricular zone (SVZ) is the largest and most active germinal zone in the adult forebrain. Neural stem cells (NSCs) of the SVZ generate olfactory interneurons throughout life and retain the intrinsic ability to generate... more
The subventricular zone (SVZ) is the largest and most active germinal zone in the adult forebrain. Neural stem cells (NSCs) of the SVZ generate olfactory interneurons throughout life and retain the intrinsic ability to generate oligodendrocytes (OLs), the myelinating cells of the central nervous system. OLs and myelin are targets in demyelinating diseases such as multiple sclerosis (MS). Remyelination is dependent on the ability of oligodendrocyte progenitor cells (OPCs) to proliferate, migrate, and terminally differentiate into myelinating OLs. During aging, there is a gradual decrease in the regenerative capacity of OPCs, and the consequent loss of OLs and myelin is a contributing factor in cognitive decline and the failure of remyelination in MS and other pathologies with aging contexts, including Alzheimer’s disease (AD) and stroke. The age-related decrease in oligodendrogenesis has not been fully characterised but is known to reflect changes in intrinsic and environmental facto...
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<p>Small molecules are ranked according to the largest numbers of “target” or “perturbed” genes. For the full list, please refer to corresponding <a... more
<p>Small molecules are ranked according to the largest numbers of “target” or “perturbed” genes. For the full list, please refer to corresponding <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2000698#pbio.2000698.s006" target="_blank">S1</a>–<a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.2000698#pbio.2000698.s009" target="_blank">S4</a> Tables.</p
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Oligodendrocytes are the myelin forming cells of the central nervous system (CNS) and are generated from oligodendrocyte progenitor cells (OPCs). Disruption or loss of oligodendrocytes and myelin has devastating effects on CNS function... more
Oligodendrocytes are the myelin forming cells of the central nervous system (CNS) and are generated from oligodendrocyte progenitor cells (OPCs). Disruption or loss of oligodendrocytes and myelin has devastating effects on CNS function and integrity, which occurs in diverse neurological disorders, including Multiple Sclerosis (MS), Alzheimer’s disease (AD) and neuropsychiatric disorders. Hence, there is a need to develop new therapies that promote oligodendrocyte regeneration and myelin repair. A promising approach is drug repurposing, but most agents have potentially contrasting biological actions depending on the cellular context and their dose-dependent effects on intracellular regulatory pathways. Here, we have used a combined drug connectivity systems biology and neurobiological approach to identify compounds that exert positive and negative effects on oligodendroglia, depending on concentration. Notably, LY294002, a potent inhibitor of PI3K/Akt signalling, was the most highly ...
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Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life‐long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning.... more
Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life‐long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning. OPCs are known to contact synapses and it is proposed that neuronal synaptic activity in turn regulates their behavior. To examine this in the adult, we performed unilateral injection of the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of adult mice. We confirm BoNT/A cleaves SNAP‐25 in the CA1 are of the hippocampus, which has been proven to block neurotransmission. Notably, BoNT/A significantly decreased OPC density and caused their shrinkage, as determined by immunolabeling for the OPC marker NG2. Furthermore, BoNT/A resulted in an overall decrease in the number of OPC processes, as well as a decrease in their lengths and branching frequency. These data indicate that synaptic activity is important for maintaining adult O...
Research Interests: Neuroscience and Medicine
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SummaryBrain aging is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain... more
SummaryBrain aging is characterised by a decline in neuronal function and associated cognitive deficits. There is increasing evidence that myelin disruption is an important factor that contributes to the age-related loss of brain plasticity and repair responses. In the brain, myelin is produced by oligodendrocytes, which are generated throughout life by oligodendrocyte progenitor cells (OPCs). Currently, a leading hypothesis points to aging as a major reason for the ultimate breakdown of remyelination in Multiple Sclerosis (MS). However, an incomplete understanding of the cellular and molecular processes underlying brain aging hinders the development of regenerative strategies. Here, our combined systems biology and neurobiological approach demonstrates that oligodendroglial and myelin genes are amongst the most altered in the aging mouse cortex. This was underscored by the identification of causal links between signaling pathways and their downstream transcriptional networks that d...
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Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life-long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning.... more
Oligodendrocyte progenitor cells (OPCs) are responsible for generating oligodendrocytes, the myelinating cells of the CNS. Life-long myelination is promoted by neuronal activity and is essential for neural network plasticity and learning. OPCs are known to contact synapses and it is proposed that neuronal synaptic activity in turn regulates OPC proliferation and differentiation. To examine this in the adult, we performed unilateral injection of the synaptic blocker botulinum neurotoxin A (BoNT/A) into the hippocampus of adult mice. We confirm BoNT/A cleaves SNAP-25 in the CA1 are of the hippocampus, which has been proven to block neurotransmission. Notably, synaptic silencing by BoNT/A significantly decreased OPC density and caused their shrinkage, as determined by immunolabelling for the OPC marker NG2. Inhibition of synaptic activity resulted in an overall decrease in the number of OPC processes, as well as a decrease in their lengths and branching frequency. These data indicate t...
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Adult NG2-glia are stellate cells with multiple branching processes which contact nodes of Ranvier, indicating an unresolved role in axon-glial signalling at nodes. We have previously shown that ATP and glutamate evoke raised cytosolic... more
Adult NG2-glia are stellate cells with multiple branching processes which contact nodes of Ranvier, indicating an unresolved role in axon-glial signalling at nodes. We have previously shown that ATP and glutamate evoke raised cytosolic calcium ([Ca2+]i) in optic nerve glia. There is evidence that NG2-glia express glutamate receptors but whether glutamate evokes raised [Ca2+]i, or whether NG2-glia express functional purinoceptors had not previously been determined. Here, we have examined the effects of purinoceptor and glutamate receptor activation, in vitro in optic nerve explants from juvenile rats postnatal day (P) 6 and in situ in isolated optic nerves from mature rats (P26), using fura-2 calcium imaging. Wistar rats were humanely killed with CO2 narcosis and optic nerves were dissected free. For in vitro experiments, the nerves were cut into small pieces and placed in DMEM culture medium for 15 d. Whole nerve experiments involved the careful splitting of the optic nerve pia with a glass microelectrode to allow the calcium dye to reach the cells and maintaining the nerve alive for short periods in a brain slice chamber. At the end of the calcium recovery immunofluorescence labelling was performed to identify NG2-glia. Application of 1 mm ATP or glutamate evoked a large and rapid increase in [Ca2+]i in NG2-glia in vitro and in situ. The glutamate-evoked increase in [Ca2+]i had a significantly longer latency and recovery time, compared with ATP responses in the same cell. ATP and glutamate evoked an increase in [Ca2+]i in concentration dependent manners, with the half maximum effect at 50 µm for ATP and 100 µm for glutamate. This study demonstrates the presence of purinoceptors and glutamate receptors in NG2-glia, supporting a role for these neurotransmitters in neuronal signalling to Ca2+ dependent processes with NG2-glia. Supported by the Anatomical Society of Great Britain and Ireland.