Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 17.866
Filtrar
1.
Nat Commun ; 12(1): 6010, 2021 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-34650077

RESUMO

Lizards regenerate amputated tails but fail to recapitulate the dorsoventral patterning achieved during embryonic development. Regenerated lizard tails form ependymal tubes (ETs) that, like embryonic tail neural tubes (NTs), induce cartilage differentiation in surrounding cells via sonic hedgehog (Shh) signaling. However, adult ETs lack characteristically roof plate-associated structures and express Shh throughout their circumferences, resulting in the formation of unpatterned cartilage tubes. Both NTs and ETs contain neural stem cells (NSCs), but only embryonic NSC populations differentiate into roof plate identities when protected from endogenous Hedgehog signaling. NSCs were isolated from parthenogenetic lizard embryos, rendered unresponsive to Hedgehog signaling via CRISPR/Cas9 gene knockout of smoothened (Smo), and implanted back into clonally-identical adults to regulate tail regeneration. Here we report that Smo knockout embryonic NSCs oppose cartilage formation when engrafted to adult ETs, representing an important milestone in the creation of regenerated lizard tails with dorsoventrally patterned skeletal tissues.


Assuntos
Células-Tronco Embrionárias/fisiologia , Edição de Genes , Lagartos/genética , Lagartos/fisiologia , Células-Tronco Neurais/fisiologia , Regeneração/fisiologia , Cauda/fisiologia , Animais , Padronização Corporal/genética , Padronização Corporal/fisiologia , Sistemas CRISPR-Cas , Cartilagem , Epêndima , Lagartos/embriologia , Transdução de Sinais/genética , Receptor Smoothened/genética , Medula Espinal/fisiologia
2.
Elife ; 102021 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-34473059

RESUMO

Many spinal circuits dedicated to locomotor control have been identified in the developing zebrafish. How these circuits operate together to generate the various swimming movements during development remains to be clarified. In this study, we iteratively built models of developing zebrafish spinal circuits coupled to simplified musculoskeletal models that reproduce coiling and swimming movements. The neurons of the models were based upon morphologically or genetically identified populations in the developing zebrafish spinal cord. We simulated intact spinal circuits as well as circuits with silenced neurons or altered synaptic transmission to better understand the role of specific spinal neurons. Analysis of firing patterns and phase relationships helped to identify possible mechanisms underlying the locomotor movements of developing zebrafish. Notably, our simulations demonstrated how the site and the operation of rhythm generation could transition between coiling and swimming. The simulations also underlined the importance of contralateral excitation to multiple tail beats. They allowed us to estimate the sensitivity of spinal locomotor networks to motor command amplitude, synaptic weights, length of ascending and descending axons, and firing behavior. These models will serve as valuable tools to test and further understand the operation of spinal circuits for locomotion.


Assuntos
Locomoção/fisiologia , Modelos Biológicos , Rede Nervosa/fisiologia , Medula Espinal/fisiologia , Peixe-Zebra/crescimento & desenvolvimento , Peixe-Zebra/fisiologia , Animais , Atividade Motora/fisiologia , Neurônios Motores/fisiologia , Neurônios/fisiologia , Natação/fisiologia
3.
Int J Mol Sci ; 22(18)2021 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-34575886

RESUMO

Chronic discogenic back pain is associated with increased inflammatory cytokine levels that can influence the proximal peripheral nervous system, namely the dorsal root ganglion (DRG). However, transition to chronic pain is widely thought to involve glial activation in the spinal cord. In this study, an in vitro model was used to evaluate the communication between DRG and spinal cord glia. Primary neonatal rat DRG cells were treated with/without inflammatory cytokines (TNF-α, IL-1ß, and IL-6). The conditioned media were collected at two time points (12 and 24 h) and applied to spinal cord mixed glial culture (MGC) for 24 h. Adult bovine DRG and spinal cord cell cultures were also tested, as an alternative large animal model, and results were compared with the neonatal rat findings. Compared with untreated DRG-conditioned medium, the second cytokine-treated DRG-conditioned medium (following medium change, thus containing solely DRG-derived molecules) elevated CD11b expression and calcium signal in neonatal rat microglia and enhanced Iba1 expression in adult bovine microglia. Cytokine treatment induced a DRG-mediated microgliosis. The described in vitro model allows the use of cells from large species and may represent an alternative to animal pain models (3R principles).


Assuntos
Comunicação Celular , Gânglios Espinais/fisiologia , Neuroglia/fisiologia , Medula Espinal/fisiologia , Transmissão Sináptica , Animais , Animais Recém-Nascidos , Biomarcadores , Cálcio/metabolismo , Células Cultivadas , Citocinas/metabolismo , Suscetibilidade a Doenças , Imunofluorescência , Mediadores da Inflamação/metabolismo , Microglia/metabolismo , Modelos Biológicos , Neurônios/metabolismo , Ratos
4.
Elife ; 102021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34497004

RESUMO

It is generally assumed that the main function of the corticospinal tract (CST) is to convey motor commands to bulbar or spinal motoneurons. Yet the CST has also been shown to modulate sensory signals at their entry point in the spinal cord through primary afferent depolarization (PAD). By sequentially investigating different routes of corticofugal pathways through electrophysiological recordings and an intersectional viral strategy, we here demonstrate that motor and sensory modulation commands in mice belong to segregated paths within the CST. Sensory modulation is executed exclusively by the CST via a population of lumbar interneurons located in the deep dorsal horn. In contrast, the cortex conveys the motor command via a relay in the upper spinal cord or supraspinal motor centers. At lumbar level, the main role of the CST is thus the modulation of sensory inputs, which is an essential component of the selective tuning of sensory feedback used to ensure well-coordinated and skilled movement.


Assuntos
Tratos Piramidais/fisiologia , Medula Espinal/fisiologia , Vias Aferentes , Animais , Axônios , Encéfalo , Córtex Cerebral , Interneurônios/metabolismo , Camundongos , Neurônios Motores , Neurônios/metabolismo , Medula Espinal/patologia , Corno Dorsal da Medula Espinal
5.
Int J Mol Sci ; 22(15)2021 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-34360697

RESUMO

BACKGROUND: Spinal cord injury (SCI) causes a primary injury at the lesion site and triggers a secondary injury and prolonged inflammation. There has been no definitive treatment till now. Promoting angiogenesis is one of the most important strategies for functional recovery after SCI. The omentum, abundant in blood and lymph vessels, possesses the potent ability of tissue regeneration. METHODS: The present work examines the efficacy of autologous omentum, either as a flap (with vascular connection intact) or graft (severed vascular connection), on spinal nerve regeneration. After contusive SCI in rats, a thin sheath of omentum was grafted to the injured spinal cord. RESULTS: Omental graft improved behavior scores significantly from the 3rd to 6th week after injury (6th week, 5.5 ± 0.5 vs. 8.6 ± 1.3, p < 0.05). Furthermore, the reduction in cavity and the preservation of class III ß-tubulin-positive nerve fibers in the injury area was noted. Next, the free omental flap was transposed to a completely transected SCI in rats through a pre-implanted tunnel. The flap remained vascularized and survived well several weeks after the operation. At 16 weeks post-treatment, SCI rats with omentum flap treatment displayed the preservation of significantly more nerve fibers (p < 0.05) and a reduced injured cavity, though locomotor scores were similar. CONCLUSIONS: Taken together, the findings of this study indicate that treatment with an omental graft or transposition of an omental flap on an injured spinal cord has a positive effect on nerve protection and tissue preservation in SCI rats. The current data highlight the importance of omentum in clinical applications.


Assuntos
Omento/transplante , Recuperação de Função Fisiológica , Traumatismos da Medula Espinal/cirurgia , Regeneração da Medula Espinal , Medula Espinal/cirurgia , Retalhos Cirúrgicos/transplante , Animais , Neuroproteção , Ratos , Medula Espinal/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Retalhos Cirúrgicos/irrigação sanguínea , Transplante Autólogo , Resultado do Tratamento
6.
Development ; 148(15)2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34351410

RESUMO

The spinal cord receives input from peripheral sensory neurons and controls motor output by regulating muscle innervating motor neurons. These functions are carried out by neural circuits comprising molecularly distinct neuronal subtypes generated in a characteristic spatiotemporal arrangement from progenitors in the embryonic neural tube. To gain insight into the diversity and complexity of cells in the developing human neural tube, we used single-cell mRNA sequencing to profile cervical and thoracic regions in four human embryos of Carnegie stages (CS) CS12, CS14, CS17 and CS19 from gestational weeks 4-7. Analysis of progenitor and neuronal populations from the neural tube and dorsal root ganglia identified dozens of distinct cell types and facilitated the reconstruction of the differentiation pathways of specific neuronal subtypes. Comparison with mouse revealed overall similarity of mammalian neural tube development while highlighting some human-specific features. These data provide a catalogue of gene expression and cell type identity in the human neural tube that will support future studies of sensory and motor control systems. The data can be explored at https://shiny.crick.ac.uk/scviewer/neuraltube/.


Assuntos
Medula Espinal/fisiologia , Transcriptoma/genética , Transcriptoma/fisiologia , Animais , Diferenciação Celular/fisiologia , Embrião de Mamíferos/fisiologia , Gânglios Espinais/fisiologia , Expressão Gênica/genética , Perfilação da Expressão Gênica/métodos , Humanos , Camundongos , Neurônios Motores/fisiologia , Tubo Neural/fisiologia , Células Receptoras Sensoriais/fisiologia , Tórax/fisiologia
7.
J Neurosci ; 41(41): 8545-8561, 2021 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-34446573

RESUMO

In the spinal cord, classes of interneurons have been studied in vitro to determine their role in producing or regulating locomotion. It is unclear whether all locomotor behaviors are produced by the same circuitry or engage different subsets of neurons. Here, in neonatal mice of either sex, we test this idea by comparing the actions of a class of spinal, inhibitory interneuron (V1) expressing channelrhodopsin driven by the engrailed-1 transcription factor on the rhythms elicited by different methods. We find that, although the overall locomotor activities in vitro are similar, V1 interneuron depolarization produces opposite effects depending of the mode of activation of the locomotor circuitry. The differential behavior of V1 neurons suggests that their function depends on how the locomotor rhythm is activated and is consistent with the idea that the functional organization of the corresponding locomotor networks also differs.SIGNIFICANCE STATEMENT The neural networks dictating the execution of fictive locomotion are located in the spinal cord. It is generally assumed that the mode of activation of these spinal networks should not change the recruitment or function of neurons. Here, we manipulated the activity of a class of interneuron (V1), which targets these networks and found that their activation induces opposite effects depending on the mode of activation. This suggests that the mode of activation of the spinal networks differentially recruits either V1 interneurons or other interneurons, or both.


Assuntos
Interneurônios/fisiologia , Locomoção/fisiologia , Rede Nervosa/fisiologia , Optogenética/métodos , Medula Espinal/fisiologia , Animais , Animais Recém-Nascidos , Feminino , Interneurônios/química , Masculino , Camundongos , Camundongos Transgênicos , Rede Nervosa/química , Técnicas de Cultura de Órgãos , Medula Espinal/química
8.
Nat Commun ; 12(1): 4857, 2021 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-34381039

RESUMO

Physical exercise stimulates adult neurogenesis, yet the underlying mechanisms remain poorly understood. A fundamental component of the innate neuroregenerative capacity of zebrafish is the proliferative and neurogenic ability of the neural stem/progenitor cells. Here, we show that in the intact spinal cord, this plasticity response can be activated by physical exercise by demonstrating that the cholinergic neurotransmission from spinal locomotor neurons activates spinal neural stem/progenitor cells, leading to neurogenesis in the adult zebrafish. We also show that GABA acts in a non-synaptic fashion to maintain neural stem/progenitor cell quiescence in the spinal cord and that training-induced activation of neurogenesis requires a reduction of GABAA receptors. Furthermore, both pharmacological stimulation of cholinergic receptors, as well as interference with GABAergic signaling, promote functional recovery after spinal cord injury. Our findings provide a model for locomotor networks' activity-dependent neurogenesis during homeostasis and regeneration in the adult zebrafish spinal cord.


Assuntos
Locomoção , Neuroglia/metabolismo , Neurônios/metabolismo , Medula Espinal/crescimento & desenvolvimento , Animais , Interneurônios/metabolismo , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Neurogênese , Condicionamento Físico Animal , Receptores Colinérgicos/metabolismo , Receptores de GABA-A/metabolismo , Recuperação de Função Fisiológica , Medula Espinal/citologia , Medula Espinal/fisiologia , Transmissão Sináptica , Peixe-Zebra , Ácido gama-Aminobutírico/metabolismo
9.
Int J Mol Sci ; 22(13)2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202085

RESUMO

Neuronal circuits in the spinal cord are essential for the control of locomotion. They integrate supraspinal commands and afferent feedback signals to produce coordinated rhythmic muscle activations necessary for stable locomotion. For several decades, computational modeling has complemented experimental studies by providing a mechanistic rationale for experimental observations and by deriving experimentally testable predictions. This symbiotic relationship between experimental and computational approaches has resulted in numerous fundamental insights. With recent advances in molecular and genetic methods, it has become possible to manipulate specific constituent elements of the spinal circuitry and relate them to locomotor behavior. This has led to computational modeling studies investigating mechanisms at the level of genetically defined neuronal populations and their interactions. We review literature on the spinal locomotor circuitry from a computational perspective. By reviewing examples leading up to and in the age of molecular genetics, we demonstrate the importance of computational modeling and its interactions with experiments. Moving forward, neuromechanical models with neuronal circuitry modeled at the level of genetically defined neuronal populations will be required to further unravel the mechanisms by which neuronal interactions lead to locomotor behavior.


Assuntos
Estudos de Associação Genética , Locomoção , Modelos Neurológicos , Neurônios Motores/fisiologia , Medula Espinal/fisiologia , Animais , Retroalimentação Sensorial , Humanos , Interneurônios/fisiologia
10.
Biomed Tech (Berl) ; 66(3): 293-304, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34062633

RESUMO

The damage in the spinal cord due to vertebral fractures may result in loss of sensation and muscle function either permanently or temporarily. The neurological condition of the patient can be improved only with the early detection and the treatment of the injury in the spinal cord. This paper proposes a spinal cord segmentation and injury detection system based on the proposed Crow search-Rider Optimization-based DCNN (CS-ROA DCNN) method, which can detect the injury in the spinal cord in an effective manner. Initially, the segmentation of the CT image of the spinal cord is performed using the adaptive thresholding method, followed by which the localization of the disc is performed using the Sparse FCM clustering algorithm (Sparse-FCM). The localized discs are subjected to a feature extraction process, where the features necessary for the classification process are extracted. The classification process is done using DCNN trained using the proposed CS-ROA, which is the integration of the Crow Search Algorithm (CSA) and Rider Optimization Algorithm (ROA). The experimentation is performed using the evaluation metrics, such as accuracy, sensitivity, and specificity. The proposed method achieved the high accuracy, sensitivity, and specificity of 0.874, 0.8961, and 0.8828, respectively that shows the effectiveness of the proposed CS-ROA DCNN method in spinal cord injury detection.


Assuntos
Traumatismos da Medula Espinal/fisiopatologia , Medula Espinal/fisiologia , Algoritmos , Animais , Corvos , Humanos , Processamento de Imagem Assistida por Computador/métodos , Redes Neurais de Computação
11.
Int J Mol Sci ; 22(11)2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-34070932

RESUMO

The neuronal networks that generate locomotion are well understood in swimming animals such as the lamprey, zebrafish and tadpole. The networks controlling locomotion in tetrapods remain, however, still enigmatic with an intricate motor pattern required for the control of the entire limb during the support, lift off, and flexion phase, and most demandingly when the limb makes contact with ground again. It is clear that the inhibition that occurs between bursts in each step cycle is produced by V2b and V1 interneurons, and that a deletion of these interneurons leads to synchronous flexor-extensor bursting. The ability to generate rhythmic bursting is distributed over all segments comprising part of the central pattern generator network (CPG). It is unclear how the rhythmic bursting is generated; however, Shox2, V2a and HB9 interneurons do contribute. To deduce a possible organization of the locomotor CPG, simulations have been elaborated. The motor pattern has been simulated in considerable detail with a network composed of unit burst generators; one for each group of close synergistic muscle groups at each joint. This unit burst generator model can reproduce the complex burst pattern with a constant flexion phase and a shortened extensor phase as the speed increases. Moreover, the unit burst generator model is versatile and can generate both forward and backward locomotion.


Assuntos
Geradores de Padrão Central/fisiologia , Interneurônios/fisiologia , Locomoção/fisiologia , Atividade Motora/fisiologia , Redes Neurais de Computação , Medula Espinal/fisiologia , Animais , Gatos , Geradores de Padrão Central/citologia , Simulação por Computador , Extremidades/inervação , Extremidades/fisiologia , Humanos , Interneurônios/citologia , Lampreias/fisiologia , Larva/fisiologia , Neurônios Motores/citologia , Neurônios Motores/fisiologia , Músculo Esquelético/inervação , Músculo Esquelético/fisiologia , Roedores/fisiologia , Medula Espinal/citologia , Peixe-Zebra/fisiologia
12.
Science ; 373(6553)2021 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-34083447

RESUMO

The meninges are a membranous structure enveloping the central nervous system (CNS) that host a rich repertoire of immune cells mediating CNS immune surveillance. Here, we report that the mouse meninges contain a pool of monocytes and neutrophils supplied not from the blood but by adjacent skull and vertebral bone marrow. Under pathological conditions, including spinal cord injury and neuroinflammation, CNS-infiltrating myeloid cells can originate from brain borders and display transcriptional signatures distinct from their blood-derived counterparts. Thus, CNS borders are populated by myeloid cells from adjacent bone marrow niches, strategically placed to supply innate immune cells under homeostatic and pathological conditions. These findings call for a reinterpretation of immune-cell infiltration into the CNS during injury and autoimmunity and may inform future therapeutic approaches that harness meningeal immune cells.


Assuntos
Células da Medula Óssea/fisiologia , Doenças do Sistema Nervoso Central/imunologia , Sistema Nervoso Central/imunologia , Meninges/imunologia , Células Mieloides/fisiologia , Crânio/anatomia & histologia , Coluna Vertebral/anatomia & histologia , Animais , Medula Óssea/fisiologia , Encéfalo/citologia , Encéfalo/imunologia , Encéfalo/fisiologia , Movimento Celular , Sistema Nervoso Central/citologia , Doenças do Sistema Nervoso Central/patologia , Dura-Máter/citologia , Dura-Máter/imunologia , Dura-Máter/fisiologia , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Homeostase , Meninges/citologia , Meninges/fisiologia , Camundongos , Monócitos/fisiologia , Neutrófilos/fisiologia , Medula Espinal/citologia , Medula Espinal/imunologia , Medula Espinal/fisiologia , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/patologia
13.
Sci Rep ; 11(1): 12544, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131162

RESUMO

Knowledge on the organization of motor function in the reticulospinal tract (RST) is limited by the lack of methods for measuring RST function in humans. Behavioral studies suggest the involvement of the RST in long latency responses (LLRs). LLRs, elicited by precisely controlled perturbations, can therefore act as a viable paradigm to measure motor-related RST activity using functional Magnetic Resonance Imaging (fMRI). Here we present StretchfMRI, a novel technique developed to study RST function associated with LLRs. StretchfMRI combines robotic perturbations with electromyography and fMRI to simultaneously quantify muscular and neural activity during stretch-evoked LLRs without loss of reliability. Using StretchfMRI, we established the muscle-specific organization of LLR activity in the brainstem. The observed organization is partially consistent with animal models, with activity primarily in the ipsilateral medulla for flexors and in the contralateral pons for extensors, but also includes other areas, such as the midbrain and bilateral pontomedullary contributions.


Assuntos
Tronco Encefálico/fisiologia , Cerebelo/fisiologia , Bulbo/fisiologia , Córtex Motor/fisiologia , Adulto , Animais , Tronco Encefálico/diagnóstico por imagem , Cerebelo/diagnóstico por imagem , Eletromiografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Bulbo/diagnóstico por imagem , Córtex Motor/diagnóstico por imagem , Músculo Esquelético/diagnóstico por imagem , Músculo Esquelético/fisiologia , Neurônios/fisiologia , Tempo de Reação/fisiologia , Medula Espinal/diagnóstico por imagem , Medula Espinal/fisiologia , Adulto Jovem
14.
Sci Rep ; 11(1): 11544, 2021 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-34078987

RESUMO

Environmental cues associated with an action can prime the motor system, decreasing response times and activating motor regions of the brain. However, when task goals change, the same responses to former go-associated cues are no longer required and motor priming needs to be inhibited to avoid unwanted behavioural errors. The present study tested whether the inhibition of motor system activity to presentations of former go cues is reliant on top-down, goal-directed cognitive control processes using a working memory (WM) load manipulation. Applying transcranial magnetic stimulation over the primary motor cortex to measure motor system activity during a Go/No-go task, we found that under low WM, corticospinal excitability was suppressed to former go and trained no-go cues relative to control cues. Under high WM, the cortical suppression to former go cues was reduced, suggesting that the underlying mechanism required executive control. Unexpectedly, we found a similar result for trained no-go cues and showed in a second experiment that the corticospinal suppression and WM effects were unrelated to local inhibitory function as indexed by short-interval intracortical inhibition. Our findings reveal that the interaction between former response cues and WM is complex and we discuss possible explanations of our findings in relation to models of response inhibition.


Assuntos
Sinais (Psicologia) , Memória de Curto Prazo , Córtex Motor/fisiologia , Medula Espinal/fisiologia , Eletroencefalografia , Potencial Evocado Motor/fisiologia , Feminino , Humanos , Masculino , Estimulação Luminosa , Análise e Desempenho de Tarefas , Adulto Jovem
15.
Nat Protoc ; 16(6): 3072-3088, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34031611

RESUMO

The use of optogenetics to regulate neuronal activity has revolutionized the study of the neural circuitry underlying a number of complex behaviors in rodents. Advances have been particularly evident in the study of brain circuitry and related behaviors, while advances in the study of spinal circuitry have been less striking because of technical hurdles. We have developed and characterized a wireless and fully implantable optoelectronic device that enables optical manipulation of spinal cord circuitry in mice via a microscale light-emitting diode (µLED) placed in the epidural space (NeuroLux spinal optogenetic device). This protocol describes how to surgically implant the device into the epidural space and then analyze light-induced behavior upon µLED activation. We detail optimized optical parameters for in vivo stimulation and demonstrate typical behavioral effects of optogenetic activation of nociceptive spinal afferents using this device. This fully wireless spinal µLED system provides considerable versatility for behavioral assays compared with optogenetic approaches that require tethering of animals, and superior temporal and spatial resolution when compared with other methods used for circuit manipulation such as chemogenetics. The detailed surgical approach and improved functionality of these spinal optoelectronic devices substantially expand the utility of this approach for the study of spinal circuitry and behaviors related to mechanical and thermal sensation, pruriception and nociception. The surgical implantation procedure takes ~1 h. The time required for the study of behaviors that are modulated by the light-activated circuit is variable and will depend upon the nature of the study.


Assuntos
Implantes Experimentais , Optogenética , Procedimentos Ortopédicos , Animais , Espaço Epidural/cirurgia , Feminino , Masculino , Camundongos , Técnicas de Patch-Clamp , Medula Espinal/fisiologia
16.
Elife ; 102021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-34042587

RESUMO

Non-random functional connectivity during unconsciousness is a defining feature of supraspinal networks. However, its generalizability to intrinsic spinal networks remains incompletely understood. Previously, Barry et al., 2014 used fMRI to reveal bilateral resting state functional connectivity within sensory-dominant and, separately, motor-dominant regions of the spinal cord. Here, we record spike trains from large populations of spinal interneurons in vivo in rats and demonstrate that spontaneous functional connectivity also links sensory- and motor-dominant regions during unconsciousness. The spatiotemporal patterns of connectivity could not be explained by latent afferent activity or by populations of interconnected neurons spiking randomly. We also document connection latencies compatible with mono- and disynaptic interactions and putative excitatory and inhibitory connections. The observed activity is consistent with the hypothesis that salient, experience-dependent patterns of neural transmission introduced during behavior or by injury/disease are reactivated during unconsciousness. Such a spinal replay mechanism could shape circuit-level connectivity and ultimately behavior.


Assuntos
Interneurônios , Neurônios Motores , Plasticidade Neuronal , Medula Espinal/fisiologia , Nervos Espinhais/fisiopatologia , Transmissão Sináptica , Inconsciência/fisiopatologia , Potenciais de Ação , Animais , Modelos Animais de Doenças , Masculino , Rede Nervosa/fisiopatologia , Inibição Neural , Ratos Sprague-Dawley , Tempo de Reação , Fatores de Tempo
17.
Nat Commun ; 12(1): 2471, 2021 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-33931636

RESUMO

In vertebrates, motor control relies on cholinergic neurons in the spinal cord that have been extensively studied over the past hundred years, yet the full heterogeneity of these neurons and their different functional roles in the adult remain to be defined. Here, we develop a targeted single nuclear RNA sequencing approach and use it to identify an array of cholinergic interneurons, visceral and skeletal motor neurons. Our data expose markers for distinguishing these classes of cholinergic neurons and their rich diversity. Specifically, visceral motor neurons, which provide autonomic control, can be divided into more than a dozen transcriptomic classes with anatomically restricted localization along the spinal cord. The complexity of the skeletal motor neurons is also reflected in our analysis with alpha, gamma, and a third subtype, possibly corresponding to the elusive beta motor neurons, clearly distinguished. In combination, our data provide a comprehensive transcriptomic description of this important population of neurons that control many aspects of physiology and movement and encompass the cellular substrates for debilitating degenerative disorders.


Assuntos
Neurônios Colinérgicos/citologia , Interneurônios/citologia , Neurônios Motores/citologia , Análise de Célula Única/métodos , Núcleo Solitário/metabolismo , Medula Espinal/metabolismo , Transcriptoma/genética , Animais , Núcleo Celular/genética , Núcleo Celular/metabolismo , Neurônios Colinérgicos/metabolismo , Neurônios Colinérgicos/fisiologia , Feminino , Hibridização In Situ , Interneurônios/metabolismo , Interneurônios/fisiologia , Masculino , Camundongos , Camundongos Transgênicos , Neurônios Motores/metabolismo , Neurônios Motores/fisiologia , RNA-Seq , Medula Espinal/citologia , Medula Espinal/fisiologia
18.
Exp Neurol ; 341: 113715, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33819448

RESUMO

Motor recovery after spinal cord injury is limited due to sparse descending pathway axons caudal to the injury. Rehabilitation is the primary treatment for paralysis in humans with SCI, but only produces modest functional recovery. Here, we determined if dual epidural motor cortex (M1) intermittent theta burst stimulation (iTBS) and cathodal transcutaneous spinal direct stimulation (tsDCS) enhances the efficacy of rehabilitation in improving motor function after cervical SCI. iTBS produces CST axon sprouting and tsDCS enhances M1-evoked spinal activity and muscle contractions after SCI. Rats were trained to perform the horizontal ladder task. Animals received a moderate midline C4 contusion, producing bilateral forelimb impairments. After 2 weeks, animals either received 10 days of iTBS+tsDCS or no stimulation; subsequently, all animals received 6 weeks of daily rehabilitation on the horizontal ladder task. Lesion size was not different in the two animal groups. Rehabilitation alone improved performance by a 22% reduction in skilled locomotion error rate, whereas stimulation+rehabilitation was markedly more effective (52%), and restored error rate to pre-injury levels. Stimulation+rehabilitation significantly increased CST axon length caudal to the injury and the amount of ventral horn label was positively correlated with functional improvement. The stimulation+rehabilitation group had significantly less proprioceptive afferent terminal labelling in the intermediate zone and fewer synapses on motoneurons . Afferent fiber terminal labeling was negatively correlated with motor recovery. Thus, the dual neuromodulation protocol promotes adaptive plasticity in corticospinal and proprioceptive afferents networks after contusion SCI, leading to enhanced rehabilitation efficacy and recovery of skilled locomotion.


Assuntos
Locomoção/fisiologia , Córtex Motor/fisiologia , Reabilitação Neurológica/métodos , Traumatismos da Medula Espinal/reabilitação , Estimulação da Medula Espinal/métodos , Estimulação Transcraniana por Corrente Contínua/métodos , Animais , Medula Cervical/lesões , Contusões/fisiopatologia , Contusões/reabilitação , Eletrodos Implantados , Feminino , Plasticidade Neuronal/fisiologia , Ratos , Ratos Sprague-Dawley , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/fisiologia , Traumatismos da Medula Espinal/fisiopatologia , Resultado do Tratamento
19.
Exp Neurol ; 341: 113720, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33848513

RESUMO

Vascular and mitochondrial dysfunction are well-established consequences of spinal cord injury (SCI). Evidence suggests mitigating these dysfunctions may be an effective approach in treating SCI. The goal of this study was to elucidate if mitochondrial biogenesis (MB) induction with a new, selective and FDA-approved 5-hydroxytryptamine receptor 1F (5-HT1F) receptor agonist, lasmiditan, can stimulate locomotor recovery and restoration of the blood-spinal cord barrier (BSCB) after SCI. Female C57BL/6 J mice were subjected to moderate SCI using a force-controlled impactor-induced contusion model followed by daily administration of lasmiditan (0.1 mg/kg, i.p.) beginning 1 h after injury. In the naïve spinal cord, electron microscopy revealed increased mitochondrial density and mitochondrial area, as well as enhanced mitochondrial DNA content. FCCP-uncoupled oxygen consumption rate (OCR), a functional marker of MB, was also increased in the naïve spinal cord following lasmiditan treatment. We observed disrupted mitochondrial DNA content, PGC-1α levels and FCCP-OCR in the injury site 3d after SCI. Lasmiditan treatment attenuated, and in some cases restored these deficits. Lasmiditan treatment also resulted in increased locomotor capability as early as 7d post-SCI, with treated mice reaching a Basso-Mouse Scale score of 3.3 by 21d, while vehicle-treated mice exhibited a score of 2.0. Integrity of the BSCB was assessed using Evans Blue dye extravasation. While SCI increased dye extravasation at 3d and 7d, dye accumulation in the spinal cord of lasmiditan-treated mice was attenuated 7d post-SCI, suggesting accelerated BSCB recovery. Finally, lasmiditan treatment resulted in decreased lesion volume and spared myelinated tissue 7d post-SCI. Collectively, these data reveal that 5-HT1F receptor agonist-induced MB using the FDA-approved drug lasmiditan may be an effective therapeutic strategy for the treatment of SCI.


Assuntos
Benzamidas/uso terapêutico , Barreira Hematoencefálica/efeitos dos fármacos , Locomoção/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Biogênese de Organelas , Piperidinas/uso terapêutico , Piridinas/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Animais , Benzamidas/farmacologia , Barreira Hematoencefálica/patologia , Barreira Hematoencefálica/fisiopatologia , Feminino , Locomoção/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/fisiologia , Piperidinas/farmacologia , Piridinas/farmacologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Agonistas do Receptor de Serotonina/uso terapêutico , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologia , Medula Espinal/fisiologia , Traumatismos da Medula Espinal/patologia , Traumatismos da Medula Espinal/fisiopatologia
20.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800863

RESUMO

The ability to sense and move within an environment are complex functions necessary for the survival of nearly all species. The spinal cord is both the initial entry site for peripheral information and the final output site for motor response, placing spinal circuits as paramount in mediating sensory responses and coordinating movement. This is partly accomplished through the activation of complex spinal microcircuits that gate afferent signals to filter extraneous stimuli from various sensory modalities and determine which signals are transmitted to higher order structures in the CNS and to spinal motor pathways. A mechanistic understanding of how inhibitory interneurons are organized and employed within the spinal cord will provide potential access points for therapeutics targeting inhibitory deficits underlying various pathologies including sensory and movement disorders. Recent studies using transgenic manipulations, neurochemical profiling, and single-cell transcriptomics have identified distinct populations of inhibitory interneurons which express an array of genetic and/or neurochemical markers that constitute functional microcircuits. In this review, we provide an overview of identified neural components that make up inhibitory microcircuits within the dorsal and ventral spinal cord and highlight the importance of inhibitory control of sensorimotor pathways at the spinal level.


Assuntos
Vias Aferentes/fisiologia , Interneurônios/fisiologia , Movimento/fisiologia , Inibição Neural/fisiologia , Sensação/fisiologia , Filtro Sensorial/fisiologia , Medula Espinal/citologia , Animais , Células do Corno Anterior/química , Células do Corno Anterior/classificação , Células do Corno Anterior/fisiologia , Humanos , Interneurônios/química , Interneurônios/classificação , Modelos Neurológicos , Neurônios Motores/fisiologia , Transtornos dos Movimentos/fisiopatologia , Fibras Nervosas/fisiologia , Proteínas do Tecido Nervoso/análise , Neuropeptídeos/análise , Células do Corno Posterior/química , Células do Corno Posterior/classificação , Transtornos das Sensações/fisiopatologia , Células Receptoras Sensoriais/fisiologia , Medula Espinal/fisiologia , Sinapses/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...