Micromotion Derived Fluid Shear Stress Mediates Peri‐Electrode Gliosis through Mechanosensitive Ion Channels

Advanced Science, Journal Year: 2023, Volume and Issue: 10(27)

Published: July 30, 2023

The development of bioelectronic neural implant technologies has advanced significantly over the past 5 years, particularly in brain-machine interfaces and electronic medicine. However, neuroelectrode-based therapies require invasive neurosurgery can subject tissues to micromotion-induced mechanical shear, leading chronic inflammation, formation a peri-electrode void deposition reactive glial scar tissue. These structures act as physical barriers, hindering electrical signal propagation reducing functionality. Although well documented, mechanisms behind initiation progression these processes are poorly understood. Herein, silico analysis gliosis is described. Subsequently, ventral mesencephalic cells exposed milliscale fluid shear stress vitro exhibited increased expression gliosis-associated proteins overexpression mechanosensitive ion channels PIEZO1 (piezo-type channel component 1) TRPA1 (transient receptor potential ankyrin 1), effects further confirmed vivo rat model gliosis. Furthermore, indicates that chemical inhibition/activation affects mediated astrocyte reactivity mitochondrial-dependent manner. Together, results suggest play major role scarring at region.

Language: Английский

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Astrocytic Glutamate Transporters and Migraine

Neurochemical Research, Journal Year: 2022, Volume and Issue: 48(4), P. 1167 - 1179

Published: Dec. 30, 2022

Language: Английский

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Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: Sept. 27, 2023

The optic nerve is an important tissue in glaucoma and the unmyelinated head region remains site of many early neurodegenerative changes. In both humans mice, astrocytes constitute major glial cell type region, they become reactive, influencing (ONH) microenvironment disease outcome. Despite recognizing their importance progression disease, reactive response poorly understood.To determine global ONH we studied transcriptional to elevation IOP induced by microbead occlusion model. To specifically isolate astrocyte mRNA vivo from complex tissues, used ribotag method genetically tag ribosomes astrocytes, restricting analysis enabling purification astrocyte-associated throughout entire cell, including fine processes, for bulk RNA-sequencing. We also assessed more distal myelinated proper (ONP) as glaucomatous changes manifest differently between two regions.Astrocytes exhibited a region-specific temporally distinct response. Surprisingly, showed very few ONP demonstrated substantially larger over course experimental period. Energy metabolism, particularly oxidative phosphorylation mitochondrial protein translation emerged highly upregulated processes with former showing additional upregulation antioxidative capacity proteolysis. Interestingly, limited neuroinflammatory response, even when challenged severe IOP. Lastly, there were greater number downregulated populations compared processes.Our findings demonstrate essential role energy metabolism elevated IOP, contrary expectations, neuroinflammation had overall role. profile supportive notion that have beneficial glaucoma. These previously uncharacterized injury reveal functional diversity heterogeneity than appreciated.

Language: Английский

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Targeting mitochondrial Ca²⁺ uptake for the treatment of amyotrophic lateral sclerosis

The Journal of Physiology, Journal Year: 2023, Volume and Issue: 602(8), P. 1519 - 1549

Published: Nov. 27, 2023

Amyotrophic lateral sclerosis (ALS) is a rare adult-onset neurodegenerative disease characterized by progressive motor neuron (MN) loss, muscle denervation and paralysis. Over the past several decades, researchers have made tremendous efforts to understand pathogenic mechanisms underpinning ALS, with much yet be resolved. ALS described as non-cell autonomous condition pathology detected in both MNs non-neuronal cells, such glial cells skeletal muscle. Studies patient animal models reveal ubiquitous abnormalities mitochondrial structure function, disturbance of intracellular calcium homeostasis various tissue types, suggesting pivotal role aberrant uptake dysfunctional signalling cascades pathogenesis. Calcium dysfunction are intricately related manifestation cell death contributing MN loss dysfunction. In this review, we discuss potential contribution signalling, particularly uptake, Functional consequences excessive possible therapeutic strategies targeting or uniporter, main channel mediating influx, also discussed.

Language: Английский

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Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes

Published: June 20, 2024

Astrocytes are considered to possess a noticeable role in brain metabolism and as partners neuron-glia cooperation contribute synthesis, bioconversions regulation of the flux substrates for neuronal metabolism. With aim investigate which extend human astrocytes metabolizing amino acids by compounds they enriching their surrounding we employed metabolomics analysis culture media 1H-NMR. In addition, compered composition with either 5 mM or 25 glucose. The quantitative 1H-NMR revealed that readely dispose from milieu glutamine, branched-chain acids, pyruvate significantly high rate, while enrich lactate, keto citrate, acetate, ketone bodies, alanine. hyperglycemia suppressed capacity release stimulating generation bodies. Our results highlight active involvement several key metabolic intermediates. observed activities provide valuable insights into roles supporting function, metabolism, intercellular interactions within brain. Understanding complex between neurons is essential elucidating homeostasis pathophysiology neurological disorders.

Language: Английский

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Hyperglycemia Stimulates the Irreversible Catabolism of Branched-Chain Amino Acids and Generation of Ketone Bodies by Cultured Human Astrocytes

Biomedicines, Journal Year: 2024, Volume and Issue: 12(8), P. 1803 - 1803

Published: Aug. 8, 2024

Astrocytes are considered to possess a noticeable role in brain metabolism and, as partners neuron-glia cooperation, contribute the synthesis, bioconversion, and regulation of flux substrates for neuronal metabolism. With aim investigating what extent human astrocytes metabolizing amino acids by which compounds they enriching their surroundings, we employed metabolomics analysis culture media 1H-NMR. In addition, compared composition with either 5 mM or 25 glucose. The quantitative 1H-NMR revealed that readily dispose from milieu glutamine, branched-chain acids, pyruvate significantly high rates, while enrich lactate, keto citrate, acetate, ketone bodies, alanine. Hyperglycemia suppressed capacity release 2-oxo stimulating generation bodies. Our results highlight active involvement several key metabolic intermediates. observed activities provide valuable insights into roles supporting function, metabolism, intercellular interactions within brain. Understanding complex between neurons is essential elucidating homeostasis pathophysiology neurological disorders. hints about putative

Language: Английский

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Aging impairs astrocytes in the human cerebral cortex

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: Nov. 1, 2022

Abstract How aging affects cellular components of the human brain active milieu remains largely unknown. We analyzed astrocytes and neurons in neocortical access tissue younger (22 - 50 years) older (51 72 adult patients who underwent glioma resection. Aging decreased amount reduced mitochondrial cytochromes but not neurons. The total protein was increased Aged showed morphological dystrophy quantified by length branches, volume fraction leaflets, shrinkage anatomical domain. Dystrophy correlated with loss gap junction coupling between input resistance. accompanied upregulation glial fibrillary acidic (GFAP) downregulation membrane-cytoskeleton linker Ezrin associated leaflets. No significant changes neuronal excitability or spontaneous inhibitory postsynaptic signaling were observed. Thus, is impaired presence malfunction astrocytes,

Language: Английский

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Distribution patterns of astrocyte populations in the human cortex

Research Square (Research Square), Journal Year: 2022, Volume and Issue: unknown

Published: June 30, 2022

Abstract Astrocytes are a major class of glial cell in the central nervous system that have diverse range types and functions thought to be based on their anatomical location, morphology cellular properties. Recent studies highlight astrocyte dysfunction contributes pathogenesis neurological conditions. However, few described pattern, distribution density astrocytes adult human cortex. This study mapped immunolabelled with cytoskeletal membrane markers frontal Distinct overlapping populations were determined. The cortex from ten normal control cases (75±9 years) was immunostained fibrillary acidic protein (GFAP), aldehyde dehydrogenase-1 L1 (ALDH1L1), connexin-43 (Cx43), aquaporin-4 (AQP4), glutamate transporter 1 (GLT-1). All labelled grey white matter, separate cortical layers, subpial perivascular regions. informative for labelling different properties compartments astrocytes. ALDH1L1 largest population astrocytes, Cx43-immunopositive found all layers. AQP4 GLT-1 distal astrocytic process end-feet same (98% GLT-1-immunopositive contained AQP4). highlights diversity cortex, providing reference map distinct which can used comparative purposes various disease, inflammatory injury states involving

Language: Английский

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Micromotion derived fluid shear stress mediates peri-electrode gliosis through mechanosensitive ion channels

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2023, Volume and Issue: unknown

Published: Jan. 13, 2023

Abstract Clinical applications for neural implant technologies are steadily advancing. Yet, despite clinical successes, neuroelectrode-based therapies require invasive neurosurgery and can subject local soft-tissues to micro-motion induced mechanical shear, leading the development of peri-implant scaring. This reactive glial tissue creates a physical barrier electrical signal propagation, loss device function. Although peri-electrode gliosis is well described contributor neuroelectrode failure, mechanistic basis behind initiation progression scarring remains poorly understood. Here, we develop an in silico model electrode-induced shear stress evaluate evolution fluid-filled void, encompassing solid viscoelastic liquid/solid interface. was subsequently used inform vitro parallel-plate flow micromotion mediated fluid stress. Ventral mesencephalic E14 rat embryonic cultures exposed physiologically relevant exhibited upregulation gliosis-associated proteins overexpression two mechanosensitive ion channel receptors, PIEZO1 TRPA1, confirmed vivo probe scar model. Finally, it shown that chemical inhibition/activation could exacerbate or attenuate astrocyte reactivity as by this mitochondrial dependant. Together, our results suggests channels play major role modulation TRPA1 through agonist/antagonist may promote chronic electrode stability . Graphical abstract Highlights Peri-electrode void Oscillatory replicates Astrocyte upregulated at region response pharmaceutical activation diminishes stress-induced inhibition exacerbates reduces functions

Language: Английский

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Cell morphology: Astrocyte structure at the nanoscale

Current Biology, Journal Year: 2023, Volume and Issue: 33(5), P. R200 - R202

Published: March 1, 2023

Language: Английский

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