scholarly journals Ermin deficiency as an inside-out model of inflammatory dysmyelination

2020 ◽  
Author(s):  
Amin Ziaei ◽  
Marta Garcia-Miralles ◽  
Carola I. Radulescu ◽  
Harwin Sidik ◽  
Aymeric Silvin ◽  
...  
Keyword(s):  
White Matter ◽  
Critical Role ◽  
Neurological Deficits ◽  
Actin Binding ◽  
New Paradigm ◽  
Conduction Loss ◽  
Myelin Sheaths ◽  
Multiple Sclerosis Patients ◽  
Inside Out

ABSTRACTErmin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here we show that Ermin is essential for myelin sheath integrity and normal saltatory conduction. Loss of Ermin in mice caused de-compacted and fragmented myelin sheaths and led to slower conduction along with progressive neurological deficits. RNA sequencing of the corpus callosum, the largest white matter structure in the CNS, pointed to inflammatory activation in aged Ermin-deficient mice, which was corroborated by increased levels of microgliosis and astrogliosis. The inflammatory milieu and myelin abnormalities were further associated with increased susceptibility to immune-mediated demyelination insult in Ermin knockout mice. Supporting a possible role of Ermin deficiency in inflammatory white matter disorders, a rare inactivating mutation in the ERMN gene was identified in multiple sclerosis patients. Our findings demonstrate a critical role for Ermin in maintaining myelin integrity. Given its near exclusive expression in myelinating oligodendrocytes, Ermin deficiency represents a compelling “inside-out” model of inflammatory dysmyelination and may offer a new paradigm for the development of myelin stability-targeted therapies.

scholarly journals Neuron-class specific responses govern adaptive remodeling of myelination in the neocortex

2020 ◽  
Author(s):  
Sung Min Yang ◽  
Katrin Michel ◽  
Vahbiz Jokhi ◽  
Elly Nedivi ◽  
Paola Arlotta
Keyword(s):  
Critical Role ◽  
Sensory Experience ◽  
Monocular Deprivation ◽  
Fine Tuning ◽  
Initial Increase ◽  
Projection Neurons ◽  
Myelin Sheaths ◽  
Adaptive Circuit ◽  
Callosal Projection

AbstractMyelination plasticity plays a critical role in neurological function, including learning and memory. However, it is unknown whether this plasticity is enacted through uniform changes across all neuronal subtypes, or whether myelin dynamics vary between neuronal classes to enable fine-tuning of adaptive circuit responses. We performed in vivo two-photon imaging to investigate the dynamics of myelin sheaths along single axons of both excitatory callosal projection neurons and inhibitory parvalbumin+ interneurons in layer 2/3 of adult mouse visual cortex. We find that both neuron types show dynamic, homeostatic myelin remodeling under normal vision. However, monocular deprivation results in experience-dependent adaptive myelin remodeling only in parvalbumin+ interneurons, but not in callosal projection neurons. Monocular deprivation induces an initial increase in elongation events in myelin segments of parvalbumin+ interneurons, followed by a contraction phase affecting a separate cohort of segments. Sensory experience does not alter the generation rate of new myelinating oligodendrocytes, but can recruit pre-existing oligodendrocytes to generate new myelin sheaths. Parvalbumin+ interneurons also show a concomitant increase in axonal branch tip dynamics independent from myelination events. These findings suggest that adaptive myelination is part of a coordinated suite of circuit reconfiguration processes, and demonstrate that distinct classes of neocortical neurons individualize adaptive remodeling of their myelination profiles to diversify circuit tuning in response to sensory experience.

scholarly journals In Vivo Characterization of Cortical and White Matter Microstructural Pathology in Growth Hormone-Secreting Pituitary Adenoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Taoyang Yuan ◽  
Jianyou Ying ◽  
Chuzhong Li ◽  
Lu Jin ◽  
Jie Kang ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Pituitary Adenoma ◽  
White Matter ◽  
Diffusion Tensor ◽  
Critical Role ◽  
Mean Diffusivity ◽  
Occipital Cortex ◽  
Test Surface ◽  
Neuropsychological Dysfunction

BackgroundThe growth hormone (GH) and insulin-like-growth factor 1 (IGF-1) axis has long been recognized for its critical role in brain growth, development. This study was designed to investigate microstructural pathology in the cortex and white matter in growth hormone-secreting pituitary adenoma, which characterized by excessive secretion of GH and IGF-1.Methods29 patients with growth hormone-secreting pituitary adenoma (acromegaly) and 31 patients with non-functional pituitary adenoma as controls were recruited and assessed using neuropsychological test, surface-based morphometry, T1/T2-weighted myelin-sensitive magnetic resonance imaging, neurite orientation dispersion and density imaging, and diffusion tensor imaging.ResultsCompared to controls, we found 1) acromegaly had significantly increased cortical thickness throughout the bilateral cortex (pFDR < 0.05). 2) T1/T2-weighted ratio in the cortex were decreased in the bilateral occipital cortex and pre/postcentral central gyri but increased in the bilateral fusiform, insular, and superior temporal gyri in acromegaly (pFDR < 0.05). 3) T1/T2-weighted ratio were decreased in most bundles, and only a few areas showed increases in acromegaly (pFDR < 0.05). 4) Neurite density index (NDI) was significantly lower throughout the cortex and bundles in acromegaly (pTFCE < 0.05). 5) lower fractional anisotropy (FA) and higher mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) in extensive bundles in acromegaly (pTFCE < 0.05). 6) microstructural pathology in the cortex and white matter were associated with neuropsychological dysfunction in acromegaly.ConclusionsOur findings suggested that long-term persistent and excess serum GH/IGF-1 levels alter the microstructure in the cortex and white matter in acromegaly, which may be responsible for neuropsychological dysfunction.

In vivo gradients of thalamic damage in paediatric multiple sclerosis: a window into pathology

Brain ◽  
2020 ◽  
Author(s):  
Ermelinda De Meo ◽  
Loredana Storelli ◽  
Lucia Moiola ◽  
Angelo Ghezzi ◽  
Pierangelo Veggiotti ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Magnetic Resonance ◽  
Fractional Anisotropy ◽  
Mean Diffusivity ◽  
White Matter Lesions ◽  
Healthy Controls ◽  
Paediatric Multiple Sclerosis ◽  
Multiple Sclerosis Patients

Abstract The thalamus represents one of the first structures affected by neurodegenerative processes in multiple sclerosis. A greater thalamic volume reduction over time, on its CSF side, has been described in paediatric multiple sclerosis patients. However, its determinants and the underlying pathological changes, likely occurring before this phenomenon becomes measurable, have never been explored. Using a multiparametric magnetic resonance approach, we quantified, in vivo, the different processes that can involve the thalamus in terms of focal lesions, microstructural damage and atrophy in paediatric multiple sclerosis patients and their distribution according to the distance from CSF/thalamus interface and thalamus/white matter interface. In 70 paediatric multiple sclerosis patients and 26 age- and sex-matched healthy controls, we tested for differences in thalamic volume and quantitative MRI metrics—including fractional anisotropy, mean diffusivity and T1/T2-weighted ratio—in the whole thalamus and in thalamic white matter, globally and within concentric bands originating from CSF/thalamus interface. In paediatric multiple sclerosis patients, the relationship of thalamic abnormalities with cortical thickness and white matter lesions was also investigated. Compared to healthy controls, patients had significantly increased fractional anisotropy in whole thalamus (f2 = 0.145; P = 0.03), reduced fractional anisotropy (f2 = 0.219; P = 0.006) and increased mean diffusivity (f2 = 0.178; P = 0.009) in thalamic white matter and a trend towards a reduced thalamic volume (f2 = 0.027; P = 0.058). By segmenting the whole thalamus and thalamic white matter into concentric bands, in paediatric multiple sclerosis we detected significant fractional anisotropy abnormalities in bands nearest to CSF (f2 = 0.208; P = 0.002) and in those closest to white matter (f2 range = 0.183–0.369; P range = 0.010–0.046), while we found significant mean diffusivity (f2 range = 0.101–0.369; P range = 0.018–0.042) and T1/T2-weighted ratio (f2 = 0.773; P = 0.001) abnormalities in thalamic bands closest to CSF. The increase in fractional anisotropy and decrease in mean diffusivity detected at the CSF/thalamus interface correlated with cortical thickness reduction (r range = −0.27–0.34; P range = 0.004–0.028), whereas the increase in fractional anisotropy detected at the thalamus/white matter interface correlated with white matter lesion volumes (r range = 0.24–0.27; P range = 0.006–0.050). Globally, our results support the hypothesis of heterogeneous pathological processes, including retrograde degeneration from white matter lesions and CSF-mediated damage, leading to thalamic microstructural abnormalities, likely preceding macroscopic tissue loss. Assessing thalamic microstructural changes using a multiparametric magnetic resonance approach may represent a target to monitor the efficacy of neuroprotective strategies early in the disease course.

Abstract WP103: ABCA1/HDL Signaling Pathway Mediates White Matter Remodeling and Improves Functional Outcome After Stroke

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Rongwen Li ◽  
Michael Chopp ◽  
Jieli Chen ◽  
Alex Zacharek ◽  
fengjie Wang ◽  
...  
Keyword(s):  
White Matter ◽  
Functional Outcome ◽  
Critical Role ◽  
Conditioned Media ◽  
Neurological Deficits ◽  
Control Treatment ◽  
Axonal Outgrowth ◽  
Lesion Volume ◽  
Ischemic Lesion

The ATP-binding cassette transporter A1 (ABCA1) plays a critical role in the formation of brain HDL cholesterol, mainly from astrocytes. Specific brain ABCA1 deficient (ABCA1 -B/-B ) mice exhibit reduced HDL levels in brain tissue and cerebrospinal fluid, as well as increases in white matter (WM) damage and neurological deficits after stroke. We tested the hypothesis, that treatment of stroke in ABCA1 -B/-B mice with intraventricularly infused HDL increases WM remodeling in the ischemic brain and attenuates ABCA1 -B/-B induced deficits after stroke. Method: Adult male ABCA1 -B/-B mice were subjected to permanent right distal middle cerebral artery occlusion (dMCAo), and were intraventricularly infused with PBS or recombinant human HDL3 (rhHDL3, 25μg in 100μl PBS) by transplanting a micro-osmotic pump (D1002, 0.25 μl/h for 14 days, Alzet) into the right lateral ventricle starting 24h after dMCAo. Animals were sacrificed 21 days after dMCAo. In vitro primary cortical neuron (PCN) culture derived from C57BL/6 and ABCA1 -B/-B embryos and axonal outgrowth measurements were also employed. Results: 1) There were no ischemic lesion volume changes between the two groups. 2) rhHDL3-infused ABCA1 -B/-B stroke mice exhibited significantly increased WM-remodeling identified by increased level of myelin basic protein, increased densities of myelin and axons, increased number of oligodendrocytes and oligodendrocyte progenitor cells in the ischemic boundary zone, as well as improved functional outcome compared with PBS-infused ABCA1 -B/-B stroke mice (p<0.05, n=8/group). 3) HDL (40 or 80μg/ml) treatment in ABCA1 -B/-B -PCNs significantly increased axonal outgrowth compared to non-treatment control. Treatment of C57BL/6-PCNs with astrocyte-conditioned media derived from ABCA1 -B/-B embryos significantly decreased axonal outgrowth compared to treatment with astrocyte-conditioned media derived from ABCA1 floxed-control embryos. However, ABCA1 -B/-B -astrocyte-conditioned media combination with HDL treatment significantly increased C57BL/6-PCN axonal outgrowth compared to treatment with ABCA1 -B/-B -astrocyte-conditioned media alone. Conclusion: ABCA1/HDL pathway may contribute to WM-remodeling as well as functional recovery after stroke.

scholarly journals Ontogeny of the VIP+ interneuron sensory-motor circuit prior to active whisking

2020 ◽  
Author(s):  
Cristiana Vagnoni ◽  
Liad J. Baruchin ◽  
Filippo Ghezzi ◽  
Sara Ratti ◽  
Zoltán Molnár ◽  
...  
Keyword(s):  
Long Range ◽  
Critical Role ◽  
Pyramidal Cells ◽  
Cortical Circuits ◽  
Motor Processing ◽  
Efferent Connections ◽  
Sensory Motor ◽  
Sensory Evoked ◽  
Inside Out

ABSTRACTDevelopment of the cortical circuits for sensory-motor processing require the coordinated integration of both columnar and long-range synaptic connections. To understand how this occurs at the level of individual neurons we have explored the timeline over which vasoactive intestinal peptide (VIP)-expressing interneurons integrate into mouse somatosensory cortex. We find a distinction in emergent long-range anterior-motor and columnar glutamatergic inputs onto layer (L)2 and L3 VIP+ interneurons respectively. In parallel, VIP+ interneurons form efferent connections onto both pyramidal cells and interneurons in the immediate column in an inside-out manner. Cell-autonomous deletion of the fate-determinant transcription factor, Prox1, spares long-range anterior-motor inputs onto VIP+ interneurons, but leads to deficits in local connectivity. This imbalance in the somatosensory circuit results in altered spontaneous and sensory-evoked cortical activity in vivo. This identifies a critical role for VIP+ interneurons, and more broadly interneuron heterogeneity, in formative circuits of neocortex.

scholarly journals Testing Pathological Variation of White Matter Tract in Adult Rats after Severe Spinal Cord Injury with MRI

2018 ◽  
Vol 2018 ◽  
pp. 1-13 ◽  
Author(s):  
Wei Song ◽  
Guiyun Song ◽  
Can Zhao ◽  
Xiaoguang Li ◽  
Xiaojiao Pei ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Motor Function ◽  
Critical Role ◽  
White Matter Tract ◽  
Noninvasive Technique ◽  
Function Recovery ◽  
Cord Injury

The purpose of this study was to assess the pathological variation in white matter tracts in the adult severe thoracic contusion spinal cord injury (SCI) rat models combined with in vivo magnetic resonance imaging (MRI), as well as the effect of spared white matter (WM) quantity on hindlimb motor function recovery. 7.0T MRI was conducted for all experimental animals before SCI and 1, 3, 7, and 14 days after SCI. The variation in the white matter tract in different regions of the spinal cord after SCI was examined by luxol fast blue (LFB) staining, NF200 immunochemistry, and diffusion tensor imaging (DTI) parameters, including fraction anisotropy, mean diffusivity, axial diffusion, and radial diffusivity. Meanwhile, Basso-Beattie-Bresnahan (BBB) open-field scoring was performed to evaluate the behavior of the paraplegic hind limbs. The quantitative analysis showed that spared white matter measures assessed by LFB and MRI had a close correlation (R2 = 0.8508). The percentage of spared white matter area was closely correlated with BBB score (R2 = 0.8460). After SCI, spared white matter in the spinal cord, especially the ventral column WM, played a critical role in motor function restoration. The results suggest that the first three days provides a key time window for SCI protection and treatment; spared white matter, especially in the ventral column, plays a key role in motor function recovery in rats. Additionally, DTI may be an important noninvasive technique to diagnose acute SCI degree as well as a tool to evaluate functional prognosis. During the transition from nerve protection toward clinical treatment after SCI, in vivo DTI may serve as an emerging noninvasive technique to diagnose acute SCI degree and predict the degree of spontaneous functional recovery after SCI.

Clobetasol Attenuates White Matter Injury by Promoting Oligodendrocyte Precursor Cell Differentiation

2020 ◽  
Vol 55 (4) ◽  
pp. 188-196
Author(s):  
Xuewen Su ◽  
Haifeng Yuan ◽  
Yuxin Bai ◽  
Junlong Chen ◽  
Mingze Sui ◽  
...  
Keyword(s):  
White Matter ◽  
Rat Model ◽  
Myelin Sheath ◽  
White Matter Injury ◽  
Neurological Deficits ◽  
Treatment Groups ◽  
Myelin Sheaths ◽  
Neurobehavioral Function ◽  
Sheath Formation ◽  
Oligodendrocyte Precursor

<b><i>Introduction:</i></b> White matter injury (WMI) is the most common brain injury in preterm infants and can result in life-long neurological deficits. The main cause of WMI is damage to the oligodendrocyte precursor cells (OPC) in the brain that results in delayed myelin sheath formation, or the destruction of existing myelin sheaths. OPC undergo highly regulated and strictly timed developmental changes that result in their transformation to mature oligodendrocytes capable of myelin production. <b><i>Objective:</i></b> Studies have shown that clobetasol strongly promotes differentiation of OPC into myelin sheaths. Therefore, we hypothesized that clobetasol may be a therapeutic option for the treatment of preterm WMI. <b><i>Methods:</i></b> We induced a WMI rat model and observed white matter damage under an optical microscope. Rats subjected to WMI were injected intraperitoneally with clobetasol (2 or 5 mg/kg daily) from day 1 to day 5 in the early treatment groups, or from day 6 to day 10 in the late treatment groups. After 17 days, the rats were sacrificed and the expression of myelin basic protein (MBP) was visualized using immunofluorescence. In addition, we evaluated myelin sheath formation using electron microscopy. The rats were also subjected to the suspension test, ramp test, and open field test to evaluate neurobehavioral functions. <b><i>Results:</i></b> A rat model of WMI was successfully induced. It was found that clobetasol significantly induced MBP expression and myelin sheath formation and improved neurobehavioral function in the rats subjected to WMI. <b><i>Conclusions:</i></b> Our results indicate that clobetasol attenuates WMI by promoting OPC differentiation, and it may be an effective therapeutic agent for the treatment of preterm WMI.

scholarly journals RACK1 plays a critical role in mast cell secretion and calcium mobilization by modulating F-actin dynamics

2021 ◽  
Author(s):  
Edismauro G. Freitas Filho ◽  
Elaine Z. M. da Silva ◽  
Hwei Ling Ong ◽  
William D. Swaim ◽  
Indu S. Ambudkar ◽  
...  
Keyword(s):  
Secretory Granules ◽  
Critical Role ◽  
Calcium Mobilization ◽  
Actin Dynamics ◽  
Actin Binding ◽  
Cell Secretion ◽  
Antigen Stimulation ◽  
Cortical Regions

Although RACK1 is known to act as a signaling hub in immune cells, its presence and role in mast cells (MCs) is undetermined. MC activation via antigen stimulation results in mediator release and is preceded by cytoskeleton reorganization and calcium mobilization. In this study RACK1 was distributed throughout the MC cytoplasm both in vivo and in vitro. After RACK1 knockdown (KD), MCs cells were rounded, and the cortical F-actin was fragmented. Following antigen stimulation, in RACK1 KD MCs there was a reduction in cortical F-actin, an increase in monomeric G-actin, and a failure to organize F-actin. RACK1 KD also increased and accelerated degranulation. CD63+-secretory granules were localized in F-actin-free cortical regions in non-stimulated RACK1 KD MCs. Additionally, RACK1 KD increased antigen-stimulated Ca2+ mobilization, but attenuated antigen-stimulated depletion of ER Ca2+-stores and thapsigargin-induced Ca2+ entry. Following MC activation there was also an increase in interaction of RACK1 with Orai1 Ca2+-channels, β-actin and the actin binding proteins vinculin and MyoVa. These results show that RACK1 is a critical regulator of actin dynamics affecting mediator secretion, and calcium signaling in MCs.

Abstract TP344: Stat6 Signaling in Microglia/macrophage is Critical for Functional Recovery After Intracerebral Hemorrhage

Stroke ◽  
2017 ◽  
Vol 48 (suppl_1) ◽  
Author(s):  
Jing Xu ◽  
Wei Cai ◽  
Kai Zhang ◽  
Huan Liu ◽  
Yejie Shi ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Medical Condition ◽  
Critical Role ◽  
White Matter Injury ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Spatial Learning And Memory ◽  
Secondary Brain Injury ◽  
Male Adult

Objective: Intracerebral hemorrhage (ICH) is a devastating medical condition that remains a leading cause of death and long term disability in the US. Hematoma triggers a cascade of signaling events resulting in secondary brain injury and severe neurological deficits. Microglia and macrophage are activated within minutes after ICH, which may influence stroke outcome by clearing the hematoma and regulating neuro-inflammation. However, the molecular mechanism underlying the functional regulation of microglia and macrophages in ICH is poorly understood. The current study was designed to test the role of signal transducers and activators of transcription 6 (STAT6) in microglia/macrophage functions in a mouse model of ICH. Methods: Male adult WT and STAT6 KO mice were subjected to intrastriatal collagenase (0.075U) injection. Spatial and temporal profiles of STAT6 activation after ICH were determined by double-label immunostaining of phospho-STAT6 and cell markers. Neurobehavioral performances were assessed using rotarod, foot fault and water maze tests up to day 21 after ICH. Gray and white matter injury was examined quantitatively on sections stained with antibodies against MAP2/NeuN and MBP, respectively. Microglial phagocytosis of fluorescent labeled-red blood cells was evaluated in vitro by immunofluorescence and flow cytometry. Results: Robustly enhanced expression of phospho-STAT6 was found predominantly in Iba1 + cells, starting at day 1, peaking at day 5, and lasting for at least 14 d after ICH. STAT6 KO mice exhibited exacerbated sensorimotor and spatial learning and memory deficits compared to WT mice ( P <0.05). STAT6 KO mice also showed larger neuronal tissue loss and more severe white matter injury ( P <0.01). Hematoma resolving was slower in STAT6 KO mice than WT mice ( P =0.03). In cultures, primary microglia derived from STAT6 KO mice had 52.6% reduction of phagocytic activity compared to WT microglia ( P =0.006). Conclusions: STAT6 is activated in microglia/macrophage after ICH and plays a critical role in ameliorating gray and white matter injury and facilitating post-stroke neurological recovery. STAT6-afforded neuroprotection against ICH may be attributable, at least in part, to the enhanced hematoma clearance by phagocytes.

Metalloprotease-disintegrin ADAM 12 interacts with α-actinin-1

2001 ◽  
Vol 357 (2) ◽  
pp. 353-361 ◽  
Author(s):  
Yi CAO ◽  
Qing KANG ◽  
Anna ZOLKIEWSKA
Keyword(s):  
Cell Adhesion ◽  
Fluorescent Protein ◽  
Critical Role ◽  
Cytoplasmic Domain ◽  
C2c12 Cells ◽  
Actin Binding ◽  
Myoblast Differentiation ◽  
Adam 12

ADAM 12, a member of the ADAM family of proteins (containing ADisintegrin And Metalloprotease domain), has been implicated in differentiation and fusion of myoblasts. While the extracellular domain of ADAM 12 contains an active metalloprotease and a region involved in cell adhesion, the function of the cytoplasmic tail of ADAM 12 has been less clear. Here we show that the cytoplasmic domain of ADAM 12 interacts in vitro and in vivo with α-actinin-1, an actin-binding and cross-linking protein. Green fluorescent protein fused to ADAM 12 cytoplasmic domain co-localizes with α-actinin-1-containing actin stress fibres in C2C12 cells. The interaction between ADAM 12 and α-actinin-1 is direct and involves the 58-amino acid C-terminal fragment of ADAM 12 and the 27kDa N-terminal domain of α-actinin-1. Consistently, expression of the 27kDa fragment of α-actinin-1 in C2C12 cells using a mitochondrial targeting system results in recruitment of the co-expressed ADAM 12 cytoplasmic domain to the mitochondrial surface. Moreover, α-actinin-1 co-purifies with a transmembrane, His6-tagged form of ADAM 12 expressed in C2C12 myoblasts, indicating that the transmembrane ADAM 12 forms a complex with α-actinin-1 in vivo. These results indicate that the actin cytoskeleton may play a critical role in ADAM 12-mediated cell–cell adhesion or cell signalling during myoblast differentiation and fusion.

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