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1.
Nat Neurosci ; 23(3): 337-350, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32112058

RESUMO

Tissue repair after spinal cord injury requires the mobilization of immune and glial cells to form a protective barrier that seals the wound and facilitates debris clearing, inflammatory containment and matrix compaction. This process involves corralling, wherein phagocytic immune cells become confined to the necrotic core, which is surrounded by an astrocytic border. Here we elucidate a temporally distinct gene signature in injury-activated microglia and macrophages (IAMs) that engages axon guidance pathways. Plexin-B2 is upregulated in IAMs and is required for motor sensory recovery after spinal cord injury. Plexin-B2 deletion in myeloid cells impairs corralling, leading to diffuse tissue damage, inflammatory spillover and hampered axon regeneration. Corralling begins early and requires Plexin-B2 in both microglia and macrophages. Mechanistically, Plexin-B2 promotes microglia motility, steers IAMs away from colliding cells and facilitates matrix compaction. Our data therefore establish Plexin-B2 as an important link that integrates biochemical cues and physical interactions of IAMs with the injury microenvironment during wound healing.


Assuntos
Macrófagos/fisiologia , Microglia/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Traumatismos da Medula Espinal/patologia , Cicatrização/fisiologia , Animais , Axônios/fisiologia , Microambiente Celular , Locomoção/fisiologia , Camundongos , Regeneração Nervosa/genética , Regeneração Nervosa/fisiologia , Vias Neurais/fisiologia , Fagocitose , Recuperação de Função Fisiológica , Sensação/fisiologia , Traumatismos da Medula Espinal/metabolismo
2.
Proc Natl Acad Sci U S A ; 117(6): 3254-3260, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-32001507

RESUMO

The giant Mauthner (M) cell is the largest neuron known in the vertebrate brain. It has enabled major breakthroughs in neuroscience but its ultimate function remains surprisingly unclear: An actual survival value of M cell-mediated escapes has never been supported experimentally and ablating the cell repeatedly failed to eliminate all rapid escapes, suggesting that escapes can equally well be driven by smaller neurons. Here we applied techniques to simultaneously measure escape performance and the state of the giant M axon over an extended period following ablation of its soma. We discovered that the axon survives remarkably long and remains still fully capable of driving rapid escape behavior. By unilaterally removing one of the two M axons and comparing escapes in the same individual that could or could not recruit an M axon, we show that the giant M axon is essential for rapid escapes and that its loss means that rapid escapes are also lost forever. This allowed us to directly test the survival value of the M cell-mediated escapes and to show that the absence of this giant neuron directly affects survival in encounters with a natural predator. These findings not only offer a surprising solution to an old puzzle but demonstrate that even complex brains can trust vital functions to individual neurons. Our findings suggest that mechanisms must have evolved in parallel with the unique significance of these neurons to keep their axons alive and connected.


Assuntos
Reação de Fuga/fisiologia , Sistema Nervoso/crescimento & desenvolvimento , Neurônios/citologia , Neurônios/fisiologia , Animais , Axônios/fisiologia , Embrião não Mamífero/fisiologia , Larva/fisiologia , Peixe-Zebra
3.
PLoS One ; 15(1): e0227910, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31990956

RESUMO

In the study of the human connectome, the vertices and the edges of the network of the human brain are analyzed: the vertices of the graphs are the anatomically identified gray matter areas of the subjects; this set is exactly the same for all the subjects. The edges of the graphs correspond to the axonal fibers, connecting these areas. In the biological applications of graph theory, it happens very rarely that scientists examine numerous large graphs on the very same, labeled vertex set. Exactly this is the case in the study of the connectomes. Because of the particularity of these sets of graphs, novel, robust methods need to be developed for their analysis. Here we introduce the new method of the Frequent Network Neighborhood Mapping for the connectome, which serves as a robust identification of the neighborhoods of given vertices of special interest in the graph. We apply the novel method for mapping the neighborhoods of the human hippocampus and discover strong statistical asymmetries between the connectomes of the sexes, computed from the Human Connectome Project. We analyze 413 braingraphs, each with 463 nodes. We show that the hippocampi of men have much more significantly frequent neighbor sets than women; therefore, in a sense, the connections of the hippocampi are more regularly distributed in men and more varied in women. Our results are in contrast to the volumetric studies of the human hippocampus, where it was shown that the relative volume of the hippocampus is the same in men and women.


Assuntos
Axônios/fisiologia , Conectoma , Hipocampo/diagnóstico por imagem , Vias Neurais/fisiologia , Adulto , Mapeamento Encefálico , Feminino , Substância Cinzenta/diagnóstico por imagem , Substância Cinzenta/fisiologia , Hipocampo/fisiologia , Humanos , Masculino , Modelos Neurológicos , Vias Neurais/diagnóstico por imagem , Caracteres Sexuais , Lobo Temporal/diagnóstico por imagem , Lobo Temporal/fisiologia
4.
Nat Commun ; 11(1): 169, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924785

RESUMO

Leukocyte common antigen-related receptor protein tyrosine phosphatases (LAR-RPTPs) are cell adhesion molecules involved in mediating neuronal development. The binding of LAR-RPTPs to extracellular ligands induces local clustering of LAR-RPTPs to regulate axon growth and synaptogenesis. LAR-RPTPs interact with synaptic liprin-α proteins via the two cytoplasmic phosphatase domains, D1 and D2. Here we solve the crystal structure of LAR_D1D2 in complex with the SAM repeats of liprin-α3, uncovering a conserved two-site binding mode. Cellular analysis shows that liprin-αs robustly promote clustering of LAR in cells by both the liprin-α/LAR interaction and the oligomerization of liprin-α. Structural analysis reveals a unique homophilic interaction of LAR via the catalytically active D1 domains. Disruption of the D1/D1 interaction diminishes the liprin-α-promoted LAR clustering and increases tyrosine dephosphorylation, demonstrating that the phosphatase activity of LAR is negatively regulated by forming clusters. Additionally, we find that the binding of LAR to liprin-α allosterically regulates the liprin-α/liprin-ß interaction.


Assuntos
Neurogênese/fisiologia , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/química , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/metabolismo , Animais , Axônios/fisiologia , Sítios de Ligação , Células COS , Adesão Celular/fisiologia , Chlorocebus aethiops , Análise por Conglomerados , Cristalografia por Raios X , Ligantes , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Proteínas Tirosina Fosfatases Classe 4 Semelhantes a Receptores/genética , Sinapses/metabolismo
5.
Nat Commun ; 11(1): 133, 2020 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-31919407

RESUMO

Neurons are subjected to strain due to body movement and their location within organs and tissues. However, how they withstand these forces over the lifetime of an organism is still poorly understood. Here, focusing on touch receptor neuron-epidermis interactions using Caenorhabditis elegans as a model system, we show that UNC-70/ß-spectrin and TBC-10, a conserved GTPase-activating protein, function non-cell-autonomously within the epidermis to dynamically maintain attachment of the axon. We reveal that, in response to strain, UNC-70/ß-spectrin and TBC-10 stabilize trans-epidermal hemidesmosome attachment structures which otherwise become lost, causing axonal breakage and degeneration. Furthermore, we show that TBC-10 regulates axonal attachment and maintenance by inactivating RAB-35, and reveal functional conservation of these molecules with their vertebrate orthologs. Finally, we demonstrate that ß-spectrin functions in this context non-cell-autonomously. We propose a model in which mechanically resistant epidermal attachment structures are maintained by UNC-70/ß-spectrin and TBC-10 during movement, preventing axonal detachment and degeneration.


Assuntos
Axônios/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas Ativadoras de GTPase/metabolismo , Espectrina/metabolismo , Estresse Fisiológico/fisiologia , Animais , Citoesqueleto/fisiologia , Epiderme/metabolismo , Hemidesmossomos/metabolismo , Proteínas rab de Ligação ao GTP/metabolismo
6.
PLoS One ; 15(1): e0226797, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940316

RESUMO

Analysis of neuronal compartments has revealed many state-dependent changes in geometry but establishing synapse-specific mechanisms at the nanoscale has proven elusive. We co-expressed channelrhodopsin2-GFP and mAPEX2 in a subset of hippocampal CA3 neurons and used trains of light to induce late-phase long-term potentiation (L-LTP) in area CA1. L-LTP was shown to be specific to the labeled axons by severing CA3 inputs, which prevented back-propagating recruitment of unlabeled axons. Membrane-associated mAPEX2 tolerated microwave-enhanced chemical fixation and drove tyramide signal amplification to deposit Alexa Fluor dyes in the light-activated axons. Subsequent post-embedding immunogold labeling resulted in outstanding ultrastructure and clear distinctions between labeled (activated), and unlabeled axons without obscuring subcellular organelles. The gold-labeled axons in potentiated slices were reconstructed through serial section electron microscopy; presynaptic vesicles and other constituents could be quantified unambiguously. The genetic specification, reliable physiology, and compatibility with established methods for ultrastructural preservation make this an ideal approach to link synapse ultrastructure and function in intact circuits.


Assuntos
Axônios/efeitos da radiação , Axônios/ultraestrutura , Luz , Potenciação de Longa Duração/efeitos da radiação , Optogenética , Animais , Axônios/metabolismo , Axônios/fisiologia , Ratos , Sinapses/metabolismo , Sinapses/efeitos da radiação
7.
Genes Dev ; 34(3-4): 194-208, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31919191

RESUMO

Promoting axon regeneration in the central and peripheral nervous system is of clinical importance in neural injury and neurodegenerative diseases. Both pro- and antiregeneration factors are being identified. We previously reported that the Rtca mediated RNA repair/splicing pathway restricts axon regeneration by inhibiting the nonconventional splicing of Xbp1 mRNA under cellular stress. However, the downstream effectors remain unknown. Here, through transcriptome profiling, we show that the tubulin polymerization-promoting protein (TPPP) ringmaker/ringer is dramatically increased in Rtca-deficient Drosophila sensory neurons, which is dependent on Xbp1. Ringer is expressed in sensory neurons before and after injury, and is cell-autonomously required for axon regeneration. While loss of ringer abolishes the regeneration enhancement in Rtca mutants, its overexpression is sufficient to promote regeneration both in the peripheral and central nervous system. Ringer maintains microtubule stability/dynamics with the microtubule-associated protein futsch/MAP1B, which is also required for axon regeneration. Furthermore, ringer lies downstream from and is negatively regulated by the microtubule-associated deacetylase HDAC6, which functions as a regeneration inhibitor. Taken together, our findings suggest that ringer acts as a hub for microtubule regulators that relays cellular status information, such as cellular stress, to the integrity of microtubules in order to instruct neuroregeneration.


Assuntos
Anilidas/metabolismo , Axônios/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila/fisiologia , Ácidos Hidroxâmicos/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Regeneração/genética , Animais , Proteínas de Drosophila/genética , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Microtúbulos/genética , Ligação Proteica , Processamento de RNA/genética , Células Receptoras Sensoriais/fisiologia
8.
Adv Exp Med Biol ; 1190: 43-51, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760637

RESUMO

Oligodendrocyte form myelin around the axons to regulate the conduction velocity. Myelinated axons are composed of white matter to act as cables to connect distinct brain regions. Recent human MRI studies showed that the signal from white matter change in the people with special skills such as taxi driver, piano player, and juggling. The change of the white matter suggested that (1) The plasticity of myelination depends on neuronal activity (activity-dependent myelination) and (2) White matter plasticity is essential for brain functions. In this session, we discussed that how the un-electrical components, oligodendrocytes, and its precursor cells receive the signal from electrically active neurons and differentiate, proliferate, and myelinate the axons to modulate the activity of neuronal circuits, ultimately affect on their behaviors. In this review, we highlight the physiological functions of oligodendrocyte and their neuronal activity-dependent functions and thus show new insight for their contribution to brain functions.


Assuntos
Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Substância Branca/fisiologia , Axônios/fisiologia , Humanos , Neurônios/fisiologia
9.
Adv Exp Med Biol ; 1190: 53-62, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760638

RESUMO

While oligodendrocytes have been thought to be homogenous, a number of reports have indicated evidences of the heterogeneity of oligodendrocytes and their precursor cells, OPCs. Almost a century ago, Del Río Hortega found three and four types of oligodendrocytes with regions where they exist and their morphologies, respectively. Interfascicular oligodendrocytes are one of the three regional dependent types and are the most typical oligodendendroglial cells that myelinate axonal fibers in the white matter tracts. In the other two, perineuronal oligodendrocyes function as reserve cells for remyelination and regulate neuronal excitability, whereas perivascular oligodendrocytes may play a role in metabolic support of axons. Among the four morphological categories, type I and II oligodendrocytes form many myelin sheaths on small-diameter axons and specific signal is required for the myelination of small-diameter axons. Type III and IV oligodendrocytes myelinate a few number of axons/or one axon, whose diameters are large. A recent comprehensive gene expression analysis with single-cell RNA sequencing identifies six different populations in mature oligodendrocytes and only one population in OPCs. However, OPCs are not uniformed developmentally and regionally. Further, the capacity of OPC differentiation depends on the environments and conditions of the tissues. Taken together, oligodendrocytes and OPCs are diverse as the other cell types in the CNS. The orchestration of these cells with their specialized functions is critical for proper functioning of the CNS.


Assuntos
Sistema Nervoso Central/fisiologia , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia , Axônios/fisiologia , Diferenciação Celular , Humanos , Neurônios/fisiologia , Substância Branca/fisiologia
10.
Adv Exp Med Biol ; 1190: 65-83, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760639

RESUMO

Propagation of action potentials along axons is optimized through interactions between neurons and myelinating glial cells. Myelination drives division of the axons into distinct molecular domains including nodes of Ranvier. The high density of voltage-gated sodium channels at nodes generates action potentials allowing for rapid and efficient saltatory nerve conduction. At paranodes flanking both sides of the nodes, myelinating glial cells interact with axons, forming junctions that are essential for node formation and maintenance. Recent studies indicate that the disruption of these specialized axonal domains is involved in the pathophysiology of various neurological diseases. Loss of paranodal axoglial junctions due to genetic mutations or autoimmune attack against the paranodal proteins leads to nerve conduction failure and neurological symptoms. Breakdown of nodal and paranodal proteins by calpains, the calcium-dependent cysteine proteases, may be a common mechanism involved in various nervous system diseases and injuries. This chapter reviews recent progress in neurobiology and pathophysiology of specialized axonal domains along myelinated nerve fibers.


Assuntos
Axônios/fisiologia , Fibras Nervosas Mielinizadas/fisiologia , Condução Nervosa , Axônios/patologia , Humanos , Fibras Nervosas Mielinizadas/patologia , Neuroglia/patologia , Neuroglia/fisiologia
11.
Adv Exp Med Biol ; 1190: 85-106, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760640

RESUMO

Nerve conduction in myelinated axons is a fascinating subject due to the intricate structure and complex properties of the axon and its relation to the equally complex Schwann cells surrounding it. This chapter first deals with normal functional aspects of voltage-gated ion channels in the axon and Schwann cell membranes as well as their related proteins. Next, the pathophysiological alterations that are induced by experimental studies to mimic and study neuropathic disorders in humans are discussed. Finally, a link is made with human neuropathies associated with antibodies against gangliosides, and the putative mechanisms of axonal degeneration in demyelinating neuropathies are discussed. Although this chapter is relevant to understand symptoms in human neuropathies, the reader is referred to Franssen and Straver (Muscle Nerve 49:4-20, 2014) for a review of translational and clinical studies in human patients.


Assuntos
Doenças Desmielinizantes/fisiopatologia , Bainha de Mielina/fisiologia , Condução Nervosa , Axônios/fisiologia , Humanos , Células de Schwann/fisiologia
12.
Adv Exp Med Biol ; 1190: 107-122, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760641

RESUMO

Enriched Na+ channel clustering allows for rapid saltatory conduction at a specialized structure in myelinated axons, the node of Ranvier, where cations are exchanged across the axon membrane. In the extracellular matrix (ECM), highly negatively charged molecules accumulate and wrap around the nodal gaps creating an ECM dome, called the perinodal ECM. The perinodal ECM has different molecular compositions in the central nervous system (CNS) and peripheral nervous system (PNS). Chondroitin sulfate proteoglycans are abundant in the ECM at the CNS nodes, whereas heparan sulfate proteoglycans are abundant at the PNS nodes. The proteoglycans have glycosaminoglycan chains on their core proteins, which makes them electrostatically negative. They associate with other ECM molecules and form a huge stable ECM complex at the nodal gaps. The polyanionic molecular complexes have high affinity to cations and potentially contribute to preventing cation diffusion at the nodes.In this chapter, we describe the molecular composition of the perinodal ECM in the CNS and PNS, and discuss their physiological role at the node of Ranvier.


Assuntos
Sistema Nervoso Central/fisiologia , Matriz Extracelular/fisiologia , Sistema Nervoso Periférico/fisiologia , Nós Neurofibrosos/fisiologia , Axônios/fisiologia , Sulfatos de Condroitina/fisiologia , Glicosaminoglicanos/fisiologia , Heparitina Sulfato/fisiologia , Humanos , Proteoglicanas/fisiologia
13.
Adv Exp Med Biol ; 1190: 123-144, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760642

RESUMO

Oligodendrocytes enable saltatory conduction by forming a myelin sheath around axons, dramatically boosts action potential conduction velocity. In addition to this canonical function of oligodendrocytes, it is now known that oligodendrocytes can respond to neuronal activity and regulate axonal conduction. Importantly, white matter plasticity, including adaptive responses by oligodendrocytes, has been shown to be involved in learning and memory. In this chapter, the role of oligodendrocytes in axonal conduction and axonal excitability will be reviewed. Focus will be paid to the mechanisms through which oligodendrocytes, including perineuronal oligodendrocytes, facilitate and suppress axonal conduction.


Assuntos
Axônios/fisiologia , Condução Nervosa , Oligodendroglia/fisiologia , Humanos , Bainha de Mielina/fisiologia , Substância Branca/fisiologia
14.
Adv Exp Med Biol ; 1190: 145-163, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760643

RESUMO

Mitochondria play essential roles in neurons and abnormal functions of mitochondria have been implicated in neurological disorders including myelin diseases. Since mitochondrial functions are regulated and maintained by their dynamic behavior involving localization, transport, and fusion/fission, modulation of mitochondrial dynamics would be involved in physiology and pathology of myelinated axons. In fact, the integration of multimodal imaging in vivo and in vitro revealed that mitochondrial localization and transport are differentially regulated in nodal and internodal regions in response to the changes of metabolic demand in myelinated axons. In addition, the mitochondrial behavior in axons is modulated as adaptive responses to demyelination irrespective of the cause of myelin loss, and the behavioral modulation is partly through interactions with cytoskeletons and closely associated with the pathophysiology of demyelinating diseases. Furthermore, the behavior and functions of axonal mitochondria are modulated in congenital myelin disorders involving impaired interactions between axons and myelin-forming cells, and, together with the inflammatory environment, implicated in axonal degeneration and disease phenotypes. Further studies on the regulatory mechanisms of the mitochondrial dynamics in myelinated axons would provide deeper insights into axo-glial interactions mediated through myelin ensheathment, and effective manipulations of the dynamics may lead to novel therapeutic strategies protecting axonal and neuronal functions and survival in primary diseases of myelin.


Assuntos
Axônios/fisiologia , Doenças Desmielinizantes/fisiopatologia , Dinâmica Mitocondrial , Bainha de Mielina/fisiologia , Axônios/patologia , Humanos , Bainha de Mielina/patologia , Neurônios/patologia , Neurônios/fisiologia
15.
Adv Exp Med Biol ; 1190: 165-179, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31760644

RESUMO

Myelin is heavily enriched in lipids (comprising approximately 70% of its dry weight), and the amount of cholesterol and glycolipids is higher than in any other cell membrane. Galactocerebroside (GalC) and its sulfated form, sulfatide, comprise the major glycolipid components of myelin. Their functional significance has been extensively studied using membrane models, cell culture, and in vivo experiments in which either GalC/sulfatide or sulfatide is deficient. From these studies, GalC and sulfatide have been distinctly localized within oligodendrocytes and their specific function in myelin has been elucidated. Here, the function of sulfatide in axo-glial interactions in myelin-forming cells as well as within myelin and its potential mechanisms of action are discussed.


Assuntos
Axônios/fisiologia , Bainha de Mielina/química , Neuroglia/fisiologia , Sulfoglicoesfingolipídeos/química , Humanos , Bainha de Mielina/fisiologia , Oligodendroglia/fisiologia
16.
Nat Rev Neurol ; 15(12): 732-745, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31728042

RESUMO

Over the past decade, we have witnessed a flourishing of novel strategies to enhance neuroplasticity and promote axon regeneration following spinal cord injury, and results from preclinical studies suggest that some of these strategies have the potential for clinical translation. Spinal cord injury leads to the disruption of neural circuitry and connectivity, resulting in permanent neurological disability. Recovery of function relies on augmenting neuroplasticity to potentiate sprouting and regeneration of spared and injured axons, to increase the strength of residual connections and to promote the formation of new connections and circuits. Neuroplasticity can be fostered by exploiting four main biological properties: neuronal intrinsic signalling, the neuronal extrinsic environment, the capacity to reconnect the severed spinal cord via neural stem cell grafts, and modulation of neuronal activity. In this Review, we discuss experimental evidence from rodents, nonhuman primates and patients regarding interventions that target each of these four properties. We then highlight the strengths and challenges of individual and combinatorial approaches with respect to clinical translation. We conclude by considering future developments and providing views on how to bridge the gap between preclinical studies and clinical translation.


Assuntos
Regeneração Nervosa/fisiologia , Plasticidade Neuronal/fisiologia , Recuperação de Função Fisiológica/fisiologia , Traumatismos da Medula Espinal/metabolismo , Pesquisa Médica Translacional/métodos , Animais , Axônios/fisiologia , Humanos , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/genética
17.
Yakugaku Zasshi ; 139(11): 1385-1390, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31685734

RESUMO

In neurodegenerative diseases, such as Alzheimer's disease (AD) and spinal cord injury (SCI), inhibited axonal regeneration lead to irreversible functional impairment. Although many agents that eliminate axonal growth impediments have been clinically investigated, none induced functional recovery. I hypothesized that the removal of impediments alone was not enough and that promoting axonal growth and neuronal network reconstruction were needed for recovery from neurodegenerative diseases. To promote axonal growth, I have focused on neurons and microglia. In vitro models of AD and SCI were developed by culturing neurons in the presence of amyloid ß (Aß) and chondroitin sulfate proteoglycan, respectively. These were then used to identify several extracts of herbal medicines and their constituents that promoted axonal growth. Oral administration of these extracts and their constituents improved memory and motor function in in vivo mouse models of AD and SCI, respectively. The bioactive compounds in these extracts were identified by analyzing brain and spinal cord samples from the mice. Their protein targets were identified using the drug affinity responsive target stability method. Analysis of early events in the axons after culture with Aß revealed that the inhibition of endocytosis was sufficient to prevent the axonal atrophy and memory deficits caused by Aß. The compounds that increased M2 microglia were observed to promote axonal normalization and growth; they were also found to recover memory and motor function in mice models of AD and SCI, respectively. The above results indicate that axonal growth plays important roles in the recovery from AD and SCI.


Assuntos
Axônios/fisiologia , Medicina Herbária , Regeneração Nervosa , Doenças Neurodegenerativas/tratamento farmacológico , Extratos Vegetais/farmacologia , Administração Oral , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/metabolismo , Animais , Encéfalo/metabolismo , Modelos Animais de Doenças , Endocitose/efeitos dos fármacos , Microglia/efeitos dos fármacos , Microglia/fisiologia , Regeneração Nervosa/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Extratos Vegetais/metabolismo , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/tratamento farmacológico , Estimulação Química
18.
Nat Commun ; 10(1): 4549, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31591398

RESUMO

Interhemispheric axons of the corpus callosum (CC) facilitate the higher order functions of the cerebral cortex. According to current views, callosal and non-callosal fates are determined early after a neuron's birth, and certain populations, such as cortical layer (L) 4 excitatory neurons of the primary somatosensory (S1) barrel, project only ipsilaterally. Using a novel axonal-retrotracing strategy and GFP-targeted visualization of Rorb+ neurons, we instead demonstrate that L4 neurons develop transient interhemispheric axons. Locally restricted L4 connectivity emerges when exuberant contralateral axons are refined in an area- and layer-specific manner during postnatal development. Surgical and genetic interventions of sensory circuits demonstrate that refinement rates depend on distinct inputs from sensory-specific thalamic nuclei. Reductions in input-dependent refinement result in mature functional interhemispheric hyperconnectivity, demonstrating the plasticity and bona fide callosal potential of L4 neurons. Thus, L4 neurons discard alternative interhemispheric circuits as instructed by thalamic input. This may ensure optimal wiring.


Assuntos
Axônios/fisiologia , Corpo Caloso/fisiologia , Vias Neurais/fisiologia , Neurônios/fisiologia , Córtex Somatossensorial/fisiologia , Animais , Animais Recém-Nascidos , Axônios/metabolismo , Corpo Caloso/citologia , Corpo Caloso/metabolismo , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Microscopia Confocal , Neurônios/metabolismo , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Córtex Somatossensorial/citologia , Córtex Somatossensorial/metabolismo , Tálamo/citologia , Tálamo/metabolismo , Tálamo/fisiologia
19.
Nat Neurosci ; 22(11): 1913-1924, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31591560

RESUMO

Axonal injury results in regenerative success or failure, depending on whether the axon lies in the peripheral or the CNS, respectively. The present study addresses whether epigenetic signatures in dorsal root ganglia discriminate between regenerative and non-regenerative axonal injury. Chromatin immunoprecipitation for the histone 3 (H3) post-translational modifications H3K9ac, H3K27ac and H3K27me3; an assay for transposase-accessible chromatin; and RNA sequencing were performed in dorsal root ganglia after sciatic nerve or dorsal column axotomy. Distinct histone acetylation and chromatin accessibility signatures correlated with gene expression after peripheral, but not central, axonal injury. DNA-footprinting analyses revealed new transcriptional regulators associated with regenerative ability. Machine-learning algorithms inferred the direction of most of the gene expression changes. Neuronal conditional deletion of the chromatin remodeler CCCTC-binding factor impaired nerve regeneration, implicating chromatin organization in the regenerative competence. Altogether, the present study offers the first epigenomic map providing insight into the transcriptional response to injury and the differential regenerative ability of sensory neurons.


Assuntos
Axônios/fisiologia , Epigenômica , Gânglios Espinais/fisiologia , Regeneração Nervosa/fisiologia , Células Receptoras Sensoriais/fisiologia , Acetilação , Algoritmos , Animais , Fator de Ligação a CCCTC/genética , Cromatina/metabolismo , Feminino , Gânglios Espinais/lesões , Expressão Gênica , Histonas/metabolismo , Aprendizado de Máquina , Masculino , Camundongos , Camundongos Transgênicos , Nervo Isquiático/lesões , Análise de Sequência de RNA
20.
Elife ; 82019 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-31577226

RESUMO

EphA/ephrin signaling regulates axon growth and guidance of neurons, but whether this process occurs also independently of ephrins is unclear. We show that presenilin-1 (PS1)/γ-secretase is required for axon growth in the developing mouse brain. PS1/γ-secretase mediates axon growth by inhibiting RhoA signaling and cleaving EphA3 independently of ligand to generate an intracellular domain (ICD) fragment that reverses axon defects in PS1/γ-secretase- and EphA3-deficient hippocampal neurons. Proteomic analysis revealed that EphA3 ICD binds to non-muscle myosin IIA (NMIIA) and increases its phosphorylation (Ser1943), which promotes NMIIA filament disassembly and cytoskeleton rearrangement. PS1/γ-secretase-deficient neurons show decreased phosphorylated NMIIA and NMIIA/actin colocalization. Moreover, pharmacological NMII inhibition reverses axon retraction in PS-deficient neurons suggesting that NMIIA mediates PS/EphA3-dependent axon elongation. In conclusion, PS/γ-secretase-dependent EphA3 cleavage mediates axon growth by regulating filament assembly through RhoA signaling and NMIIA, suggesting opposite roles of EphA3 on inhibiting (ligand-dependent) and promoting (receptor processing) axon growth in developing neurons.


Assuntos
Axônios/fisiologia , Miosina não Muscular Tipo IIA/metabolismo , Presenilina-1/metabolismo , Receptor EphA3/metabolismo , Animais , Células Cultivadas , Humanos , Camundongos , Transdução de Sinais , Proteína rhoA de Ligação ao GTP/metabolismo
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