RESUMEN
The myelination of axons has evolved to enable fast and efficient transduction of electrical signals in the vertebrate nervous system. Acting as an electric insulator, the myelin sheath is a multilamellar membrane structure around axonal segments generated by the spiral wrapping and subsequent compaction of oligodendroglial plasma membranes. These oligodendrocytes are metabolically active and remain functionally connected to the subjacent axon via cytoplasmic-rich myelinic channels for movement of metabolites and macromolecules to and from the internodal periaxonal space under the myelin sheath. Increasing evidence indicates that oligodendrocyte numbers, specifically in the forebrain, and myelin as a dynamic cellular compartment can both respond to physiological demands, collectively referred to as adaptive myelination. This review summarizes our current understanding of how myelin is generated, how its function is dynamically regulated, and how oligodendrocytes support the long-term integrity of myelinated axons.
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In a recent study, Kim et al. utilized gamma entrainment using sensory stimuli (GENUS) to rescue cognitive impairment and glial dysregulation associated with cisplatin and methotrexate chemotherapy, specifically when applied both throughout and after chemotherapy administration. GENUS provides a time-dependent, non-invasive method for treating chemobrain, with broader implications for resolving neurodegenerative neuroinflammation.
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Cisplatino , Humanos , Cisplatino/efectos adversos , Metotrexato/efectos adversos , Estimulación Luminosa , Animales , Factores de Tiempo , Disfunción Cognitiva/inducido químicamente , Antineoplásicos/efectos adversos , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Estimulación AcústicaRESUMEN
SUMMARY: The field of cancer neuroscience has begun to define the contributions of nerves to cancer initiation and progression; here, we highlight the future directions of basic and translational cancer neuroscience for malignancies arising outside of the central nervous system.
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Neoplasias , Neurociencias , Humanos , Sistema Nervioso Central , Predicción , ProteómicaRESUMEN
Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.
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Factores de Transcripción ARNTL , Esclerosis Múltiple , Ratones , Animales , Factores de Transcripción ARNTL/genética , Privación de Sueño/metabolismo , Ratones Noqueados , Oligodendroglía/metabolismo , Vaina de Mielina/metabolismo , Esclerosis Múltiple/metabolismo , Sueño/genética , Diferenciación CelularRESUMEN
Sheehan and Nadarajah et al.1 identified that Bmal1 loss from astrocytes induces the expression of BAG3, a macroautophagy chaperone enriched in Alzheimer's disease patients and in disease-associated astrocytes, enhancing the phagocytosis of misfolded proteins and preventing tau and alpha-synuclein pathologies.
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Enfermedad de Alzheimer , Astrocitos , Humanos , Astrocitos/metabolismo , Enfermedad de Alzheimer/metabolismo , Fagocitosis , Proteínas tau/metabolismo , alfa-Sinucleína/metabolismo , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismoRESUMEN
A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https://neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.
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Fatiga , Motivación , Humanos , BiologíaRESUMEN
High-grade gliomas are malignant brain tumors that are characteristically hard to treat because of their nature; they grow quickly and invasively through the brain tissue and develop chemoradiation resistance in adults. There is also a distinct lack of targeted treatment options in the pediatric population for this tumor type to date. Several approaches to overcome therapeutic resistance have been explored, including targeted therapy to growth pathways (ie. EGFR and VEGF inhibitors), epigenetic modulators, and immunotherapies such as Chimeric Antigen Receptor T-cell and vaccine therapies. One new promising approach relies on the timing of chemotherapy administration based on intrinsic circadian rhythms. Recent work in glioblastoma has demonstrated temporal variations in chemosensitivity and, thus, improved survival based on treatment time of day. This may be due to intrinsic rhythms of the glioma cells, permeability of the blood brain barrier to chemotherapy agents, the tumor immune microenvironment, or another unknown mechanism. We review the literature to discuss chronotherapeutic approaches to high-grade glioma treatment, circadian regulation of the immune system and tumor microenvironment in gliomas. We further discuss how these two areas may be combined to temporally regulate and/or improve the effectiveness of immunotherapies.
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The molecular mechanisms that maintain circadian rhythms in mammalian as well as non-mammalian systems are well documented in neuronal populations but comparatively understudied in glia. Glia are highly dynamic in form and function, and the circadian clock provides broad dynamic ranges for the maintenance of this homeostasis, thus glia are key to understanding the role of circadian biology in brain function. Here, we highlight the implications of the molecular circadian clock on the homeodynamic nature of glia, underscoring the current gap in understanding the role of the circadian system in oligodendroglia lineage cells and subsequent myelination. Through this perspective, we will focus on the intersection of circadian and glial biology and how it interfaces with global circadian rhythm maintenance associated with normative and aberrant brain function.
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Relojes Circadianos , Ritmo Circadiano , Ritmo Circadiano/fisiología , Neuroglía/fisiología , Neuronas/fisiología , HomeostasisRESUMEN
It has recently emerged that microglia, the tissue-resident macrophages of the central nervous system, play significant non-innate immune roles to support the development, maintenance, homeostasis and repair of the brain. Apart from being highly specialized brain phagocytes, microglia modulate the development and functions of neurons and glial cells through both direct and indirect interactions. Thus, recognizing the elements that influence the homeostasis and heterogeneity of microglia in normal brain development is crucial to understanding the mechanisms that lead to early disease pathogenesis of neurodevelopmental disorders. In this Review, we discuss recent studies that have elucidated the physiological development of microglia and summarize our knowledge of their non-innate immune functions in brain development and tissue repair.
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Sistema Nervioso Central , Microglía , Encéfalo/fisiología , Sistema Nervioso Central/patología , Homeostasis , Microglía/patología , NeuroglíaRESUMEN
Neurons have recently emerged as essential cellular constituents of the tumour microenvironment, and their activity has been shown to increase the growth of a diverse number of solid tumours1. Although the role of neurons in tumour progression has previously been demonstrated2, the importance of neuronal activity to tumour initiation is less clear-particularly in the setting of cancer predisposition syndromes. Fifteen per cent of individuals with the neurofibromatosis 1 (NF1) cancer predisposition syndrome (in which tumours arise in close association with nerves) develop low-grade neoplasms of the optic pathway (known as optic pathway gliomas (OPGs)) during early childhood3,4, raising the possibility that postnatal light-induced activity of the optic nerve drives tumour initiation. Here we use an authenticated mouse model of OPG driven by mutations in the neurofibromatosis 1 tumour suppressor gene (Nf1)5 to demonstrate that stimulation of optic nerve activity increases optic glioma growth, and that decreasing visual experience via light deprivation prevents tumour formation and maintenance. We show that the initiation of Nf1-driven OPGs (Nf1-OPGs) depends on visual experience during a developmental period in which Nf1-mutant mice are susceptible to tumorigenesis. Germline Nf1 mutation in retinal neurons results in aberrantly increased shedding of neuroligin 3 (NLGN3) within the optic nerve in response to retinal neuronal activity. Moreover, genetic Nlgn3 loss or pharmacological inhibition of NLGN3 shedding blocks the formation and progression of Nf1-OPGs. Collectively, our studies establish an obligate role for neuronal activity in the development of some types of brain tumours, elucidate a therapeutic strategy to reduce OPG incidence or mitigate tumour progression, and underscore the role of Nf1mutation-mediated dysregulation of neuronal signalling pathways in mouse models of the NF1 cancer predisposition syndrome.
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Transformación Celular Neoplásica/genética , Genes de Neurofibromatosis 1 , Mutación , Neurofibromina 1/genética , Neuronas/metabolismo , Glioma del Nervio Óptico/genética , Glioma del Nervio Óptico/patología , Animales , Astrocitoma/genética , Astrocitoma/patología , Moléculas de Adhesión Celular Neuronal/deficiencia , Moléculas de Adhesión Celular Neuronal/genética , Moléculas de Adhesión Celular Neuronal/metabolismo , Transformación Celular Neoplásica/efectos de la radiación , Femenino , Mutación de Línea Germinal , Humanos , Masculino , Proteínas de la Membrana/deficiencia , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Proteínas del Tejido Nervioso/deficiencia , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Neuronas/efectos de la radiación , Nervio Óptico/citología , Nervio Óptico/efectos de la radiación , Estimulación Luminosa , Retina/citología , Retina/efectos de la radiaciónRESUMEN
Millions of cancer survivors experience a persistent neurological syndrome that includes deficits in memory, attention, information processing, and mental health. Cancer therapy-related cognitive impairment can cause mild to severe disruptions to quality of life for these cancer survivors. Understanding the cellular and molecular underpinnings of this disorder will facilitate new therapeutic strategies aimed at ameliorating these long-lasting impairments. Accumulating evidence suggests that a range of cancer therapies induce persistent activation of the brain's resident immune cells, microglia. Cancer therapy-induced microglial activation disrupts numerous mechanisms of neuroplasticity, and emerging findings suggest that this impairment in plasticity is central to cancer therapy-related cognitive impairment. This review explores reactive microglial dysregulation of neural circuit structure and function following cancer therapy.
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Disfunción Cognitiva , Neoplasias , Cognición , Disfunción Cognitiva/etiología , Humanos , Microglía , Neoplasias/terapia , Plasticidad Neuronal , Calidad de VidaAsunto(s)
Neoplasias Encefálicas/complicaciones , Disfunción Cognitiva/tratamiento farmacológico , Metformina/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/radioterapia , Niño , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/patología , Femenino , Humanos , Masculino , Neuronas/efectos de los fármacos , Neuronas/patología , Radioterapia/efectos adversosRESUMEN
The COVID19 crisis has magnified the issues plaguing academic science, but it has also provided the scientific establishment with an unprecedented opportunity to reset. Shoring up the foundation of academic science will require a concerted effort between funding agencies, universities, and the public to rethink how we support scientists, with a special emphasis on early career researchers.
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Movilidad Laboral , Investigadores/tendencias , Investigación/tendencias , Logro , Investigación Biomédica , Humanos , Investigadores/educación , Ciencia/educación , Ciencia/tendencias , UniversidadesRESUMEN
PURPOSE OF REVIEW: Modern innovations in cancer therapy have dramatically increased the number of cancer survivors. An unfortunately frequent side-effect of cancer treatment is enduring neurological impairment. Persistent deficits in attention, concentration, memory, and speed of information processing afflict a substantial fraction of cancer survivors following completion of these life-saving therapies. Here, we highlight chemotherapy-related cognitive impairment (CRCI) and discuss the current understanding of mechanisms underlying CRCI. RECENT FINDINGS: New studies emphasize the deleterious impact of chemotherapeutic agents on glial-glial and neuron-glial interactions that shape the form, function and plasticity of the central nervous system. An emerging theme in cancer therapy-related cognitive impairment is therapy-induced microglial activation and consequent dysfunction of both neural precursor cells and mature neural cell types. Recent work has highlighted the complexity of dysregulated intercellular interactions involving oligodendrocyte lineage cells, microglia, astrocytes, and neurons following exposure to traditional cancer therapies such as methotrexate. This new understanding of the mechanistic underpinnings of CRCI has elucidated potential therapeutic interventions, including colony-stimulating factor 1 receptor inhibition, TrkB agonism, and aerobic exercise. SUMMARY: Traditional cancer therapies induce lasting alterations to multiple neural cell types. Therapy-induced microglial activation is a critical component of the cause of CRCI, contributing to dysregulation of numerous processes of neural plasticity. Therapeutic targeting of microglial activation or the consequent dysregulation of neural plasticity mechanisms are emerging.
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Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/terapia , Animales , Disfunción Cognitiva/patología , Ejercicio Físico/fisiología , Humanos , Microglía/efectos de los fármacos , Microglía/patología , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/psicología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/patología , Plasticidad Neuronal/efectos de los fármacosRESUMEN
Activity-dependent myelination is thought to contribute to adaptive neurological function. However, the mechanisms by which activity regulates myelination and the extent to which myelin plasticity contributes to non-motor cognitive functions remain incompletely understood. Using a mouse model of chemotherapy-related cognitive impairment (CRCI), we recently demonstrated that methotrexate (MTX) chemotherapy induces complex glial dysfunction for which microglial activation is central. Here, we demonstrate that remote MTX exposure blocks activity-regulated myelination. MTX decreases cortical Bdnf expression, which is restored by microglial depletion. Bdnf-TrkB signaling is a required component of activity-dependent myelination. Oligodendrocyte precursor cell (OPC)-specific TrkB deletion in chemotherapy-naive mice results in impaired cognitive behavioral performance. A small-molecule TrkB agonist rescues both myelination and cognitive impairment after MTX chemotherapy. This rescue after MTX depends on intact TrkB expression in OPCs. Taken together, these findings demonstrate a molecular mechanism required for adaptive myelination that is aberrant in CRCI due to microglial activation.
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Trastornos del Conocimiento/tratamiento farmacológico , Trastornos del Conocimiento/patología , Inmunosupresores/uso terapéutico , Metotrexato/uso terapéutico , Vaina de Mielina/metabolismo , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Channelrhodopsins/genética , Channelrhodopsins/metabolismo , Trastornos del Conocimiento/genética , Modelos Animales de Enfermedad , Humanos , Proteínas Luminiscentes/genética , Proteínas Luminiscentes/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Vaina de Mielina/patología , Vaina de Mielina/ultraestructura , Células Precursoras de Oligodendrocitos/efectos de los fármacos , Compuestos Orgánicos/uso terapéutico , Proteínas Tirosina Quinasas/genética , Proteínas Tirosina Quinasas/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Urea/análogos & derivados , Urea/metabolismoRESUMEN
Chemotherapy results in a frequent yet poorly understood syndrome of long-term neurological deficits. Neural precursor cell dysfunction and white matter dysfunction are thought to contribute to this debilitating syndrome. Here, we demonstrate persistent depletion of oligodendrocyte lineage cells in humans who received chemotherapy. Developing a mouse model of methotrexate chemotherapy-induced neurological dysfunction, we find a similar depletion of white matter OPCs, increased but incomplete OPC differentiation, and a persistent deficit in myelination. OPCs from chemotherapy-naive mice similarly exhibit increased differentiation when transplanted into the microenvironment of previously methotrexate-exposed brains, indicating an underlying microenvironmental perturbation. Methotrexate results in persistent activation of microglia and subsequent astrocyte activation that is dependent on inflammatory microglia. Microglial depletion normalizes oligodendroglial lineage dynamics, myelin microstructure, and cognitive behavior after methotrexate chemotherapy. These findings indicate that methotrexate chemotherapy exposure is associated with persistent tri-glial dysregulation and identify inflammatory microglia as a therapeutic target to abrogate chemotherapy-related cognitive impairment. VIDEO ABSTRACT.
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Disfunción Cognitiva/inducido químicamente , Metotrexato/efectos adversos , Oligodendroglía/efectos de los fármacos , Animales , Encéfalo/metabolismo , Diferenciación Celular , Linaje de la Célula , Disfunción Cognitiva/metabolismo , Modelos Animales de Enfermedad , Quimioterapia , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos , Humanos , Metotrexato/farmacología , Ratones , Microglía/metabolismo , Vaina de Mielina/metabolismo , Fibras Nerviosas Mielínicas , Neurogénesis/fisiología , Neuroglía/metabolismo , Neuronas/efectos de los fármacos , Oligodendroglía/metabolismo , Sustancia Blanca/metabolismoRESUMEN
Human central nervous system myelin development extends well into the fourth decade of life, and this protracted period underscores the potential for experience to modulate myelination. The concept of myelin plasticity implies adaptability in myelin structure and function in response to experiences during development and beyond. Mounting evidence supports this concept of neuronal activity-regulated changes in myelin-forming cells, including oligodendrocyte precursor cell proliferation, oligodendrogenesis and modulation of myelin microstructure. In healthy individuals, myelin plasticity in associative white matter structures of the brain is implicated in learning and motor function in both rodents and humans. Activity-dependent changes in myelin-forming cells may influence the function of neural networks that depend on the convergence of numerous neural signals on both a temporal and spatial scale. However, dysregulation of myelin plasticity can disadvantageously alter myelin microstructure and result in aberrant circuit function or contribute to pathological cell proliferation. Emerging roles for myelin plasticity in normal neurological function and in disease are discussed. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 123-135, 2018.
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Vaina de Mielina/fisiología , Plasticidad Neuronal/fisiología , Animales , Epilepsia/fisiopatología , Humanos , Trastornos Mentales/fisiopatología , Esclerosis Múltiple/fisiopatología , Neoplasias/fisiopatologíaRESUMEN
Myelin sheaths, specialized segments of oligodendrocyte (OL) plasma membranes in the central nervous system (CNS), facilitate fast, saltatory conduction of action potentials down axons. Changes to the fine structure of myelin in a neural circuit, including sheath thickness and internode length (length of myelin segments between nodes of Ranvier), are expected to affect conduction velocity of action potentials. Myelination of the mammalian CNS occurs in a stereotyped, progressive pattern and continues well into adulthood in humans. Recent evidence from zebrafish, rodents, non-human primates, and humans suggests that myelination may be sensitive to experiences during development and adulthood, and that varying levels of neuronal activity may underlie these experience-dependent changes in myelin and myelin-forming cells. Several cellular, molecular, and epigenetic mechanisms have been investigated as contributors to myelin plasticity. A deeper understanding of myelin plasticity and its underlying mechanisms may provide insights into diseases involving myelin damage or dysregulation. This article is part of the Special Issue entitled 'Oligodendrocytes in Health and Disease'.
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Sistema Nervioso Central/citología , Sistema Nervioso Central/fisiología , Vaina de Mielina/fisiología , Plasticidad Neuronal/fisiología , Animales , Diferenciación Celular/fisiología , Humanos , Oligodendroglía/fisiologíaRESUMEN
Active neurons exert a mitogenic effect on normal neural precursor and oligodendroglial precursor cells, the putative cellular origins of high-grade glioma (HGG). By using optogenetic control of cortical neuronal activity in a patient-derived pediatric glioblastoma xenograft model, we demonstrate that active neurons similarly promote HGG proliferation and growth in vivo. Conditioned medium from optogenetically stimulated cortical slices promoted proliferation of pediatric and adult patient-derived HGG cultures, indicating secretion of activity-regulated mitogen(s). The synaptic protein neuroligin-3 (NLGN3) was identified as the leading candidate mitogen, and soluble NLGN3 was sufficient and necessary to promote robust HGG cell proliferation. NLGN3 induced PI3K-mTOR pathway activity and feedforward expression of NLGN3 in glioma cells. NLGN3 expression levels in human HGG negatively correlated with patient overall survival. These findings indicate the important role of active neurons in the brain tumor microenvironment and identify secreted NLGN3 as an unexpected mechanism promoting neuronal activity-regulated cancer growth.
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Neoplasias Encefálicas/patología , Moléculas de Adhesión Celular Neuronal/metabolismo , Proliferación Celular , Glioma/patología , Proteínas de la Membrana/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Adolescente , Secuencia de Aminoácidos , Animales , Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Xenoinjertos , Humanos , Masculino , Ratones , Datos de Secuencia Molecular , Trasplante de Neoplasias , Neuronas/metabolismoRESUMEN
Myelination of the central nervous system requires the generation of functionally mature oligodendrocytes from oligodendrocyte precursor cells (OPCs). Electrically active neurons may influence OPC function and selectively instruct myelination of an active neural circuit. In this work, we use optogenetic stimulation of the premotor cortex in awake, behaving mice to demonstrate that neuronal activity elicits a mitogenic response of neural progenitor cells and OPCs, promotes oligodendrogenesis, and increases myelination within the deep layers of the premotor cortex and subcortical white matter. We further show that this neuronal activity-regulated oligodendrogenesis and myelination is associated with improved motor function of the corresponding limb. Oligodendrogenesis and myelination appear necessary for the observed functional improvement, as epigenetic blockade of oligodendrocyte differentiation and myelin changes prevents the activity-regulated behavioral improvement.