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1.
Phys Rev Lett ; 126(11): 118101, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33798338

RESUMO

During the development of the nervous system, neurons extend bundles of axons that grow and meet other neurons to form the neuronal network. Robust guidance mechanisms are needed for these bundles to migrate and reach their functional target. Directional information depends on external cues such as chemical or mechanical gradients. Unlike chemotaxis that has been extensively studied, the role and mechanism of durotaxis, the directed response to variations in substrate rigidity, remain unclear. We model bundle migration and guidance by rigidity gradients by using the theory of morphoelastic rods. We show that, at a rigidity interface, the motion of axon bundles follows a simple behavior analogous to optic ray theory and obeys Snell's law for refraction and reflection. We use this powerful analogy to demonstrate that axons can be guided by the equivalent of optical lenses and fibers created by regions of different stiffnesses.


Assuntos
Orientação de Axônios/fisiologia , Modelos Neurológicos , Rede Nervosa/crescimento & desenvolvimento , Animais , Axônios/fisiologia , Fenômenos Biomecânicos , Rede Nervosa/fisiologia , Neurônios/fisiologia , Xenopus
2.
Nat Commun ; 12(1): 391, 2021 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-33452250

RESUMO

Spinal cord injury (SCI) often causes severe and permanent disabilities due to the regenerative failure of severed axons. Here we report significant locomotor recovery of both hindlimbs after a complete spinal cord crush. This is achieved by the unilateral transduction of cortical motoneurons with an AAV expressing hyper-IL-6 (hIL-6), a potent designer cytokine stimulating JAK/STAT3 signaling and axon regeneration. We find collaterals of these AAV-transduced motoneurons projecting to serotonergic neurons in both sides of the raphe nuclei. Hence, the transduction of cortical neurons facilitates the axonal transport and release of hIL-6 at innervated neurons in the brain stem. Therefore, this transneuronal delivery of hIL-6 promotes the regeneration of corticospinal and raphespinal fibers after injury, with the latter being essential for hIL-6-induced functional recovery. Thus, transneuronal delivery enables regenerative stimulation of neurons in the deep brain stem that are otherwise challenging to access, yet highly relevant for functional recovery after SCI.


Assuntos
Terapia Genética/métodos , Interleucina-6/genética , Locomoção/fisiologia , Regeneração Nervosa/fisiologia , Traumatismos da Medula Espinal/terapia , Animais , Axônios/fisiologia , Córtex Cerebral/citologia , Córtex Cerebral/fisiologia , Dependovirus/genética , Modelos Animais de Doenças , Feminino , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Janus Quinases/metabolismo , Masculino , Camundongos , Camundongos Knockout , Microinjeções , Neurônios Motores/fisiologia , PTEN Fosfo-Hidrolase/genética , Núcleos da Rafe/citologia , Núcleos da Rafe/fisiologia , Recuperação de Função Fisiológica , Fator de Transcrição STAT3/metabolismo , Neurônios Serotoninérgicos/fisiologia , Índice de Gravidade de Doença , Transdução de Sinais , Medula Espinal/citologia , Medula Espinal/fisiopatologia , Traumatismos da Medula Espinal/diagnóstico , Traumatismos da Medula Espinal/fisiopatologia , Transdução Genética
3.
Biochem Biophys Res Commun ; 534: 121-127, 2021 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-33321289

RESUMO

The intrinsic capacity of axonal growth is varied among the neurons form different tissues or different developmental stages. In this study, we established an in vitro model to compare the axonal growth of neurons from embryonic 18 days, post-natal 1 day and post-natal 3 days rat. The E18 neurons showed powerful ability of neuritogenensis and axon outgrowth and the ability decreased rapidly along with development. The transcriptome profile of these neurons revealed a set of genes positively correlated with the capacity of neurite outgrowth. Glucose-dependent insulinotropic polypeptide receptor (GIPR) is identified as a gene to promote neurite outgrowth, which was approved by siRNA knock down assay in E18 neuron. Glucose-dependent insulinotropic polypeptide (GIP), a ligand of GIPR secreted from enteroendocrine K cells, is well-known for its role in nutrient sensing and intake. To verify the effect of GIP-GIPR signal on neurite outgrowth, we administrated GIP to stimulate the E18 neurons, the results showed that GIP significantly improved extension of axon. We further revealed that GIP increased Rac1/Cdc42 phosphorylation in Akt dependent manner. In summary, our study established an in vitro model to screen the genes involved in neurite outgrowth, and we provided mechanical insight on the GIP-GIPR axis to promote axonal outgrowth.


Assuntos
Polipeptídeo Inibidor Gástrico/metabolismo , Crescimento Neuronal/fisiologia , Neurônios/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores dos Hormônios Gastrointestinais/metabolismo , Animais , Animais Recém-Nascidos , Axônios/fisiologia , Células Cultivadas , Córtex Cerebral/citologia , Córtex Cerebral/embriologia , Córtex Cerebral/crescimento & desenvolvimento , Feminino , Polipeptídeo Inibidor Gástrico/genética , Regulação da Expressão Gênica no Desenvolvimento , Neurônios/citologia , Ratos Sprague-Dawley , Receptores dos Hormônios Gastrointestinais/genética
4.
J Neurosci ; 41(7): 1443-1454, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33334866

RESUMO

Renshaw cells mediate recurrent inhibition between motoneurons within the spinal cord. The function of this circuit is not clear; we previously suggested based on computational modeling that it may cancel oscillations in muscle activity around 10 Hz, thereby reducing physiological tremor. Such tremor is especially problematic for dexterous hand movements, yet knowledge of recurrent inhibitory function is sparse for the control of the primate upper limb, where no direct measurements have been made to date. In this study, we made intracellular penetrations into 89 motoneurons in the cervical enlargement of four terminally anesthetized female macaque monkeys, and recorded recurrent IPSPs in response to antidromic stimulation of motor axons. Recurrent inhibition was strongest to motoneurons innervating shoulder muscles and elbow extensors, weak to wrist and digit extensors, and almost absent to the intrinsic muscles of the hand. Recurrent inhibitory connections often spanned joints, for example from motoneurons innervating wrist and digit muscles to those controlling the shoulder and elbow. Wrist and digit flexor motoneurons sometimes inhibited the corresponding extensors, and vice versa. This complex connectivity presumably reflects the flexible usage of the primate upper limb. Using trains of stimuli to motor nerves timed as a Poisson process and coherence analysis, we also examined the temporal properties of recurrent inhibition. The recurrent feedback loop effectively carried frequencies up to 100 Hz, with a coherence peak around 20 Hz. The coherence phase validated predictions from our previous computational model, supporting the idea that recurrent inhibition may function to reduce tremor.SIGNIFICANCE STATEMENT We present the first direct measurements of recurrent inhibition in primate upper limb motoneurons, revealing that it is more flexibly organized than previous observations in cat. Recurrent inhibitory connections were relatively common between motoneurons controlling muscles that act at different joints, and between flexors and extensors. As in the cat, connections were minimal for motoneurons innervating the most distal intrinsic hand muscles. Empirical data are consistent with previous modeling: temporal properties of the recurrent inhibitory feedback loop are compatible with a role in reducing physiological tremor by suppressing oscillations around 10 Hz.


Assuntos
Inibição Neural/fisiologia , Extremidade Superior/fisiologia , Animais , Axônios/fisiologia , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores/fisiologia , Retroalimentação Fisiológica , Feminino , Macaca mulatta , Neurônios Motores/fisiologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Neurônios/fisiologia , Células de Renshaw/fisiologia , Medula Espinal/citologia , Medula Espinal/fisiologia , Extremidade Superior/inervação
5.
J Neurosci ; 41(7): 1582-1596, 2021 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-33372061

RESUMO

During rapid eye movement (REM) sleep, anti-gravity muscle tone and bodily movements are mostly absent, because somatic motoneurons are inhibited by descending inhibitory pathways. Recent studies showed that glycine/GABA neurons in the ventromedial medulla (VMM; GlyVMM neurons) play an important role in generating muscle atonia during REM sleep (REM-atonia). However, how these REM-atonia-inducing neurons interconnect with other neuronal populations has been unknown. In the present study, we first identified a specific subpopulation of GlyVMM neurons that play an important role in induction of REM-atonia by virus vector-mediated tracing in male mice in which glycinergic neurons expressed Cre recombinase. We found these neurons receive direct synaptic input from neurons in several brain stem regions, including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD; GluSLD neurons). Silencing this circuit by specifically expressing tetanus toxin light chain (TeTNLC) resulted in REM sleep without atonia. This manipulation also caused a marked decrease in time spent in cataplexy-like episodes (CLEs) when applied to narcoleptic orexin-ataxin-3 mice. We also showed that GlyVMM neurons play an important role in maintenance of sleep. This present study identified a population of glycinergic neurons in the VMM that are commonly involved in REM-atonia and cataplexy.SIGNIFICANCE STATEMENT We identified a population of glycinergic neurons in the ventral medulla that plays an important role in inducing muscle atonia during rapid eye movement (REM) sleep. It sends axonal projections almost exclusively to motoneurons in the spinal cord and brain stem except to those that innervate extraocular muscles, while other glycinergic neurons in the same region also send projections to other regions including monoaminergic nuclei. Furthermore, these neurons receive direct inputs from several brainstem regions including glutamatergic neurons in the sublaterodorsal tegmental nucleus (SLD). Genetic silencing of this pathway resulted in REM sleep without atonia and a decrease of cataplexy when applied to narcoleptic mice. This work identified a neural population involved in generating muscle atonia during REM sleep and cataplexy.


Assuntos
Cataplexia/fisiopatologia , Glicina/fisiologia , Bulbo/fisiologia , Músculo Esquelético/fisiologia , Neurônios/fisiologia , Sono REM/fisiologia , Animais , Ataxina-3/genética , Axônios/fisiologia , Cataplexia/genética , Eletroencefalografia , Masculino , Bulbo/fisiopatologia , Camundongos , Camundongos Endogâmicos C57BL , Tono Muscular/fisiologia , Músculo Esquelético/fisiopatologia , Narcolepsia/genética , Narcolepsia/fisiopatologia , Orexinas/genética , Toxina Tetânica/farmacologia
6.
PLoS Comput Biol ; 16(12): e1007937, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33378395

RESUMO

The Golgi cells are the main inhibitory interneurons of the cerebellar granular layer. Although recent works have highlighted the complexity of their dendritic organization and synaptic inputs, the mechanisms through which these neurons integrate complex input patterns remained unknown. Here we have used 8 detailed morphological reconstructions to develop multicompartmental models of Golgi cells, in which Na, Ca, and K channels were distributed along dendrites, soma, axonal initial segment and axon. The models faithfully reproduced a rich pattern of electrophysiological and pharmacological properties and predicted the operating mechanisms of these neurons. Basal dendrites turned out to be more tightly electrically coupled to the axon initial segment than apical dendrites. During synaptic transmission, parallel fibers caused slow Ca-dependent depolarizations in apical dendrites that boosted the axon initial segment encoder and Na-spike backpropagation into basal dendrites, while inhibitory synapses effectively shunted backpropagating currents. This oriented dendritic processing set up a coincidence detector controlling voltage-dependent NMDA receptor unblock in basal dendrites, which, by regulating local calcium influx, may provide the basis for spike-timing dependent plasticity anticipated by theory.


Assuntos
Células Cerebelares de Golgi , Dendritos , Plasticidade Neuronal/fisiologia , Animais , Axônios/metabolismo , Axônios/fisiologia , Células Cerebelares de Golgi/citologia , Células Cerebelares de Golgi/metabolismo , Células Cerebelares de Golgi/fisiologia , Dendritos/metabolismo , Dendritos/fisiologia , Feminino , Canais Iônicos/metabolismo , Canais Iônicos/fisiologia , Masculino , Camundongos , Modelos Neurológicos , Transmissão Sináptica/fisiologia
7.
Elife ; 92020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33345773

RESUMO

Spinal commissural axon navigation across the midline in the floor plate requires repulsive forces from local Slit repellents. The long-held view is that Slits push growth cones forward and prevent them from turning back once they became sensitized to these cues after midline crossing. We analyzed with fluorescent reporters Slits distribution and FP glia morphology. We observed clusters of Slit-N and Slit-C fragments decorating a complex architecture of glial basal process ramifications. We found that PC2 proprotein convertase activity contributes to this pattern of ligands. Next, we studied Slit-C acting via PlexinA1 receptor shared with another FP repellent, the Semaphorin3B, through generation of a mouse model baring PlexinA1Y1815F mutation abrogating SlitC but not Sema3B responsiveness, manipulations in the chicken embryo, and ex vivo live imaging. This revealed a guidance mechanism by which SlitC constantly limits growth cone exploration, imposing ordered and forward-directed progression through aligned corridors formed by FP basal ramifications.


Assuntos
Interneurônios Comissurais/fisiologia , Medula Espinal/crescimento & desenvolvimento , Animais , Axônios/fisiologia , Western Blotting , Embrião de Galinha , Cones de Crescimento/fisiologia , Camundongos , Microscopia de Fluorescência , Tubo Neural/embriologia , Tubo Neural/crescimento & desenvolvimento , Medula Espinal/embriologia
8.
Elife ; 92020 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-33345774

RESUMO

Different regions of the striatum regulate different types of behavior. However, how dopamine signals differ across striatal regions and how dopamine regulates different behaviors remain unclear. Here, we compared dopamine axon activity in the ventral, dorsomedial, and dorsolateral striatum, while mice performed a perceptual and value-based decision task. Surprisingly, dopamine axon activity was similar across all three areas. At a glance, the activity multiplexed different variables such as stimulus-associated values, confidence, and reward feedback at different phases of the task. Our modeling demonstrates, however, that these modulations can be inclusively explained by moment-by-moment changes in the expected reward, that is the temporal difference error. A major difference between areas was the overall activity level of reward responses: reward responses in dorsolateral striatum were positively shifted, lacking inhibitory responses to negative prediction errors. The differences in dopamine signals put specific constraints on the properties of behaviors controlled by dopamine in these regions.


Assuntos
Axônios/fisiologia , Corpo Estriado/fisiologia , Tomada de Decisões/fisiologia , Neurônios Dopaminérgicos/fisiologia , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Odorantes , Reforço Psicológico , Recompensa , Olfato
9.
PLoS Biol ; 18(12): e3000621, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33351792

RESUMO

Neurons extend long axons that require maintenance and are susceptible to degeneration. Long-term integrity of axons depends on intrinsic mechanisms including axonal transport and extrinsic support from adjacent glial cells. The mechanisms of support provided by myelinating oligodendrocytes to underlying axons are only partly understood. Oligodendrocytes release extracellular vesicles (EVs) with properties of exosomes, which upon delivery to neurons improve neuronal viability in vitro. Here, we show that oligodendroglial exosome secretion is impaired in 2 mouse mutants exhibiting secondary axonal degeneration due to oligodendrocyte-specific gene defects. Wild-type oligodendroglial exosomes support neurons by improving the metabolic state and promoting axonal transport in nutrient-deprived neurons. Mutant oligodendrocytes release fewer exosomes, which share a common signature of underrepresented proteins. Notably, mutant exosomes lack the ability to support nutrient-deprived neurons and to promote axonal transport. Together, these findings indicate that glia-to-neuron exosome transfer promotes neuronal long-term maintenance by facilitating axonal transport, providing a novel mechanistic link between myelin diseases and secondary loss of axonal integrity.


Assuntos
Transporte Axonal/fisiologia , Neurônios/metabolismo , Oligodendroglia/metabolismo , Animais , Transporte Axonal/genética , Axônios/fisiologia , Exossomos/metabolismo , Exossomos/fisiologia , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/fisiologia , Feminino , Células HEK293 , Humanos , Manutenção , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Bainha de Mielina/metabolismo , Neuroglia , Neurônios/fisiologia , Oligodendroglia/fisiologia , Transdução de Sinais/fisiologia
10.
Proc Natl Acad Sci U S A ; 117(52): 33649-33659, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33376224

RESUMO

Axonal conduction velocity, which ensures efficient function of the brain network, is related to axon diameter. Noninvasive, in vivo axon diameter estimates can be made with diffusion magnetic resonance imaging, but the technique requires three-dimensional (3D) validation. Here, high-resolution, 3D synchrotron X-ray nano-holotomography images of white matter samples from the corpus callosum of a monkey brain reveal that blood vessels, cells, and vacuoles affect axonal diameter and trajectory. Within single axons, we find that the variation in diameter and conduction velocity correlates with the mean diameter, contesting the value of precise diameter determination in larger axons. These complex 3D axon morphologies drive previously reported 2D trends in axon diameter and g-ratio. Furthermore, we find that these morphologies bias the estimates of axon diameter with diffusion magnetic resonance imaging and, ultimately, impact the investigation and formulation of the axon structure-function relationship.


Assuntos
Axônios/fisiologia , Animais , Feminino , Haplorrinos , Imageamento Tridimensional , Imagem por Ressonância Magnética , Bainha de Mielina/metabolismo , Relação Estrutura-Atividade , Vacúolos/metabolismo , Substância Branca/anatomia & histologia
11.
Nat Commun ; 11(1): 5614, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154382

RESUMO

Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin's endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.


Assuntos
Axônios/fisiologia , Sistema Nervoso Central/fisiologia , Retículo Endoplasmático/metabolismo , Regeneração Nervosa , Proteínas de Transporte Vesicular/metabolismo , Animais , Axônios/metabolismo , Células Cultivadas , Retículo Endoplasmático/genética , Endossomos/metabolismo , Feminino , Humanos , Integrinas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mutação , Regeneração Nervosa/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/fisiologia , Fármacos Neuroprotetores/administração & dosagem , Traumatismos do Nervo Óptico/tratamento farmacológico , Traumatismos do Nervo Óptico/metabolismo , Traumatismos do Nervo Óptico/patologia , Fosforilação , Domínios Proteicos , Ratos , Ratos Sprague-Dawley , Retina/efeitos dos fármacos , Retina/fisiologia , Proteínas de Transporte Vesicular/administração & dosagem , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genética
12.
Science ; 370(6512)2020 10 02.
Artigo em Inglês | MEDLINE | ID: mdl-33004487

RESUMO

Injuries to the central nervous system (CNS) are inefficiently repaired. Resident neural stem cells manifest a limited contribution to cell replacement. We have uncovered a latent potential in neural stem cells to replace large numbers of lost oligodendrocytes in the injured mouse spinal cord. Integrating multimodal single-cell analysis, we found that neural stem cells are in a permissive chromatin state that enables the unfolding of a normally latent gene expression program for oligodendrogenesis after injury. Ectopic expression of the transcription factor OLIG2 unveiled abundant stem cell-derived oligodendrogenesis, which followed the natural progression of oligodendrocyte differentiation, contributed to axon remyelination, and stimulated functional recovery of axon conduction. Recruitment of resident stem cells may thus serve as an alternative to cell transplantation after CNS injury.


Assuntos
Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Oligodendroglia/fisiologia , Regeneração da Medula Espinal/fisiologia , Animais , Astrócitos/fisiologia , Axônios/fisiologia , Linhagem da Célula , Epêndima/citologia , Epêndima/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Neurogênese/genética , Fator de Transcrição 2 de Oligodendrócitos/metabolismo , Oligodendroglia/citologia , Recuperação de Função Fisiológica/genética , Recuperação de Função Fisiológica/fisiologia , Remielinização/genética , Remielinização/fisiologia , Análise de Célula Única , Traumatismos da Medula Espinal/fisiopatologia , Regeneração da Medula Espinal/genética
13.
J Vis Exp ; (163)2020 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-32955495

RESUMO

Retinal ganglion cell (RGC) axons converge at the optic nerve head to convey visual information from the retina to the brain. Pathologies such as glaucoma, trauma, and ischemic optic neuropathies injure RGC axons, disrupt transmission of visual stimuli, and cause vision loss. Animal models simulating RGC axon injury include optic nerve crush and transection paradigms. Each of these models has inherent advantages and disadvantages. An optic nerve crush is generally less severe than a transection and can be used to assay axon regeneration across the lesion site. However, differences in crush force and duration can affect tissue responses, resulting in variable reproducibility and lesion completeness. With optic nerve transection, there is a severe and reproducible injury that completely lesions all axons. However, transecting the optic nerve dramatically alters the blood brain barrier by violating the optic nerve sheath, exposing the optic nerve to the peripheral environment. Moreover, regeneration beyond a transection site cannot be assessed without reapposing the cut nerve ends. Furthermore, distinct degenerative changes and cellular pathways are activated by either a crush or transection injury. The method described here incorporates the advantages of both optic nerve crush and transection models while mitigating the disadvantages. Hydrostatic pressure delivered into the optic nerve by microinjection completely transects the optic nerve while maintaining the integrity of the optic nerve sheath. The transected optic nerve ends are reapposed to allow for axon regeneration assays. A potential limitation of this method is the inability to visualize the complete transection, a potential source of variability. However, visual confirmation that the visible portion of the optic nerve has been transected is indicative of a complete optic nerve transection with 90-95% success. This method could be applied to assess axon regeneration promoting strategies in a transection model or investigate interventions that target the axonal compartments.


Assuntos
Axônios/fisiologia , Modelos Animais de Doenças , Traumatismos do Nervo Óptico/patologia , Células Ganglionares da Retina/patologia , Animais , Axônios/patologia , Pressão Hidrostática/efeitos adversos , Bainha de Mielina/fisiologia , Compressão Nervosa , Regeneração Nervosa/fisiologia , Traumatismos do Nervo Óptico/etiologia , Ratos , Reprodutibilidade dos Testes
14.
Nat Commun ; 11(1): 4891, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32994417

RESUMO

Peripheral sensory neurons regenerate their axon after nerve injury to enable functional recovery. Intrinsic mechanisms operating in sensory neurons are known to regulate nerve repair, but whether satellite glial cells (SGC), which completely envelop the neuronal soma, contribute to nerve regeneration remains unexplored. Using a single cell RNAseq approach, we reveal that SGC are distinct from Schwann cells and share similarities with astrocytes. Nerve injury elicits changes in the expression of genes related to fatty acid synthesis and peroxisome proliferator-activated receptor (PPARα) signaling. Conditional deletion of fatty acid synthase (Fasn) in SGC impairs axon regeneration. The PPARα agonist fenofibrate rescues the impaired axon regeneration in mice lacking Fasn in SGC. These results indicate that PPARα activity downstream of FASN in SGC contributes to promote axon regeneration in adult peripheral nerves and highlight that the sensory neuron and its surrounding glial coat form a functional unit that orchestrates nerve repair.


Assuntos
Regeneração Nervosa , Neuroglia/citologia , Células Receptoras Sensoriais/citologia , Animais , Axônios/fisiologia , Proliferação de Células , Ácido Graxo Sintases/genética , Ácido Graxo Sintases/metabolismo , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neuroglia/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Traumatismos dos Nervos Periféricos/genética , Traumatismos dos Nervos Periféricos/metabolismo , Traumatismos dos Nervos Periféricos/fisiopatologia , Nervos Periféricos/crescimento & desenvolvimento , Nervos Periféricos/metabolismo , Nervos Periféricos/fisiopatologia , Células Receptoras Sensoriais/metabolismo , Transdução de Sinais
15.
Zhejiang Da Xue Xue Bao Yi Xue Ban ; 49(4): 500-507, 2020 Aug 25.
Artigo em Chinês | MEDLINE | ID: mdl-32985164

RESUMO

Different from neurons in the peripheral nervous system, mature neurons in the mammalian central nervous system often fail to regenerate after injury. Recent studies have found that calcium transduction, injury signaling, mitochondrial transportation, cytoskeletal remodeling and protein synthesis play essential roles in axon regeneration. Firstly, axon injury increases the intracellular concentration of calcium, and initiates the injury signaling pathways including cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) and dual leucine kinase (DLK), which are found to promote axon regeneration in multiple animal injury models. The second step for axonal regrowth is to rebuild growth cones. Overexpressing proteins that promote dynamics of microtubules and actin filaments is beneficial for the reassembly of cytoskeletons and initiation of new growth cones. Thirdly, mitochondria, the power factory for cells, also play important roles in growth cone formation and axonal extension. The last but not the least important step is the regulation of gene transcription and protein translation to sustain the regrowth of axons. This review summarizes important findings revealing the functions and mechanisms of these biological progresses.


Assuntos
Axônios , Regeneração Nervosa , Neurologia , Pesquisa , Animais , Axônios/fisiologia , Cones de Crescimento/fisiologia , Modelos Animais , Regeneração Nervosa/fisiologia , Neurologia/tendências , Pesquisa/tendências
16.
Nat Commun ; 11(1): 4491, 2020 09 08.
Artigo em Inglês | MEDLINE | ID: mdl-32901033

RESUMO

The functionality of the nervous system requires transmission of information along axons with high speed and precision. Conductance velocity depends on axonal diameter whereas signaling precision requires a block of electrical crosstalk between axons, known as ephaptic coupling. Here, we use the peripheral nervous system of Drosophila larvae to determine how glia regulates axonal properties. We show that wrapping glial differentiation depends on gap junctions and FGF-signaling. Abnormal glial differentiation affects axonal diameter and conductance velocity and causes mild behavioral phenotypes that can be rescued by a sphingosine-rich diet. Ablation of wrapping glia does not further impair axonal diameter and conductance velocity but causes a prominent locomotion phenotype that cannot be rescued by sphingosine. Moreover, optogenetically evoked locomotor patterns do not depend on conductance speed but require the presence of wrapping glial processes. In conclusion, our data indicate that wrapping glia modulates both speed and precision of neuronal signaling.


Assuntos
Drosophila melanogaster/fisiologia , Animais , Animais Geneticamente Modificados , Axônios/fisiologia , Diferenciação Celular , Proteínas de Drosophila/genética , Proteínas de Drosophila/fisiologia , Drosophila melanogaster/citologia , Drosophila melanogaster/genética , Larva/citologia , Larva/fisiologia , Locomoção/fisiologia , Modelos Neurológicos , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/fisiologia , Neuroglia/citologia , Neuroglia/fisiologia , Optogenética , Sistema Nervoso Periférico/citologia , Sistema Nervoso Periférico/fisiologia , Fenótipo , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Transdução de Sinais
17.
PLoS One ; 15(8): e0237440, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32790784

RESUMO

We have previously described a novel temporal encoding mechanism in the somatosensory system, where mechanical pulses grouped into periodic bursts create a perceived tactile frequency based on the duration of the silent gap between bursts, rather than the mean rate or the periodicity. This coding strategy may offer new opportunities for transmitting information to the brain using various sensory neural prostheses and haptic interfaces. However, it was not known whether the same coding mechanisms apply when using electrical stimulation, which recruits a different spectrum of afferents. Here, we demonstrate that the predictions of the burst gap coding model for frequency perception apply to burst stimuli delivered with electrical pulses, re-emphasising the importance of the temporal structure of spike patterns in neural processing and perception of tactile stimuli. Reciprocally, the electrical stimulation data confirm that the results observed with mechanical stimulation do indeed depend on neural processing mechanisms in the central nervous system, and are not due to skin mechanical factors and resulting patterns of afferent activation.


Assuntos
Estimulação Elétrica , Percepção do Tato/fisiologia , Potenciais de Ação , Adulto , Axônios/fisiologia , Feminino , Humanos , Masculino , Células Receptoras Sensoriais/fisiologia , Adulto Jovem
18.
PLoS Comput Biol ; 16(7): e1008087, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32701953

RESUMO

The dynamics and the sharp onset of action potential (AP) generation have recently been the subject of intense experimental and theoretical investigations. According to the resistive coupling theory, an electrotonic interplay between the site of AP initiation in the axon and the somato-dendritic load determines the AP waveform. This phenomenon not only alters the shape of APs recorded at the soma, but also determines the dynamics of excitability across a variety of time scales. Supporting this statement, here we generalize a previous numerical study and extend it to the quantification of the input-output gain of the neuronal dynamical response. We consider three classes of multicompartmental mathematical models, ranging from ball-and-stick simplified descriptions of neuronal excitability to 3D-reconstructed biophysical models of excitatory neurons of rodent and human cortical tissue. For each model, we demonstrate that increasing the distance between the axonal site of AP initiation and the soma markedly increases the bandwidth of neuronal response properties. We finally consider the Liquid State Machine paradigm, exploring the impact of altering the site of AP initiation at the level of a neuronal population, and demonstrate that an optimal distance exists to boost the computational performance of the network in a simple classification task.


Assuntos
Potenciais de Ação , Segmento Inicial do Axônio/fisiologia , Axônios/fisiologia , Neurônios/fisiologia , Algoritmos , Animais , Córtex Cerebral/patologia , Biologia Computacional , Simulação por Computador , Dendritos/fisiologia , Humanos , Imageamento Tridimensional , Modelos Lineares , Aprendizado de Máquina , Modelos Neurológicos , Neocórtex/fisiologia , Canais de Potássio/fisiologia , Ratos
19.
PLoS Comput Biol ; 16(7): e1008057, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32716930

RESUMO

Action potentials are a key component of neuronal communication and their precise timing is critical for processes like learning, memory, and complex behaviors. Action potentials propagate through long axons to their postsynaptic partners, which requires axons not only to faithfully transfer action potentials to distant synaptic regions but also to maintain their timing. This is particularly challenging when axons differ in their morphological and physiological properties, as timing is predicted to diverge between these axons when extrinsic conditions change. It is unknown if and how diverse axons maintain timing during temperature changes that animals and humans encounter. We studied whether ambient temperature changes cause different timing in the periphery of neurons that centrally produce temperature-robust activity. In an approach combining modeling, imaging, and electrophysiology, we explored mechanisms that support timing by exposing the axons of three different neuron types from the same crustacean (Cancer borealis) motor circuit and involved in the same functional task to a range of physiological temperatures. We show that despite substantial differences between axons, the effects of temperature on action potential propagation were moderate and supported temperature-robust timing over long-distances. Our modeling demonstrates that to maintain timing, the underlying channel properties of these axons do not need to be temperature-insensitive or highly restricted, but coordinating the temperature sensitivities of the Sodium activation gate time constant and the maximum Sodium conductance is required. Thus, even highly temperature-sensitive ion channel properties can support temperature-robust timing between distinct neuronal types and across long distances.


Assuntos
Potenciais de Ação , Axônios/fisiologia , Crustáceos/fisiologia , Neurônios/fisiologia , Canais de Sódio/fisiologia , Algoritmos , Animais , Biologia Computacional , Simulação por Computador , Masculino , Modelos Neurológicos , Condução Nervosa , Temperatura
20.
PLoS Comput Biol ; 16(7): e1008023, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32628719

RESUMO

In this study, we propose a new open-source simulation platform that comprises computer-aided design and computer-aided engineering tools for highly automated evaluation of electric field distribution and neural activation during Deep Brain Stimulation (DBS). It will be shown how a Volume Conductor Model (VCM) is constructed and examined using Python-controlled algorithms for generation, discretization and adaptive mesh refinement of the computational domain, as well as for incorporation of heterogeneous and anisotropic properties of the tissue and allocation of neuron models. The utilization of the platform is facilitated by a collection of predefined input setups and quick visualization routines. The accuracy of a VCM, created and optimized by the platform, was estimated by comparison with a commercial software. The results demonstrate no significant deviation between the models in the electric potential distribution. A qualitative estimation of different physics for the VCM shows an agreement with previous computational studies. The proposed computational platform is suitable for an accurate estimation of electric fields during DBS in scientific modeling studies. In future, we intend to acquire SDA and EMA approval. Successful incorporation of open-source software, controlled by in-house developed algorithms, provides a highly automated solution. The platform allows for optimization and uncertainty quantification (UQ) studies, while employment of the open-source software facilitates accessibility and reproducibility of simulations.


Assuntos
Encéfalo/fisiologia , Estimulação Encefálica Profunda , Reconhecimento Automatizado de Padrão , Software , Algoritmos , Anisotropia , Axônios/fisiologia , Mapeamento Encefálico , Simulação por Computador , Desenho Assistido por Computador , Análise de Fourier , Humanos , Processamento de Imagem Assistida por Computador , Modelos Neurológicos , Neurônios/fisiologia , Linguagens de Programação , Reprodutibilidade dos Testes
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