scholarly journals Functional connectivity networks of common synaptic inputs to motor neurons reveal neural spinal synergies during a multi-joint task

2021 ◽  
Author(s):  
Francois Hug ◽  
Simon Avrillon ◽  
Aurelie Sarcher ◽  
Alessandro Del Vecchio ◽  
Dario Farina
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Neural Control ◽  
Essential Feature ◽  
Human Study ◽  
Movement Control ◽  
Common Input ◽  
Synaptic Inputs ◽  
Spinal Motor ◽  
Joint Task

Movements are reportedly controlled through the combination of synergies that generate specific motor outputs by imposing an activation pattern on a group of muscles. To date, the smallest unit of analysis has been the muscle through the measurement of its activation. However, the muscle is not the lowest neural level of movement control. In this human study, we identified the common synaptic inputs received by motor neurons during an isometric multi-joint task. We decoded the spiking activities of dozens of spinal motor neurons innervating six lower limb muscles in 10 participants. Furthermore, we analyzed these activities by identifying their common low-frequency components, from which networks of common synaptic inputs to the motor neurons were derived. The vast majority of the identified motor neurons shared common inputs with other motor neuron(s). In addition, groups of motor neurons were partly decoupled from their innervated muscle, such that motor neurons innervating the same muscle did not necessarily receive common inputs. Conversely, some motor neurons from different muscles, including distant muscles, received common inputs. Our results provide evidence of a synergistic control of a multi-joint motor task at the spinal motor neuron level. Moreover, we showed that common input to motor neurons is an essential feature of the neural control of movement. We conclude that the central nervous system controls flexible groups of motor neurons by distributing common inputs to substantially reduce the dimensionality of movement control.

Daily acute intermittent hypoxia enhances phrenic motor output and stimulus-evoked phrenic responses in rats

2021 ◽  
Author(s):  
Raphael Rodrigues Perim ◽  
Michael D. Sunshine ◽  
Joseph F. Welch ◽  
Juliet Santiago ◽  
Ashley Holland ◽  
...  
Keyword(s):  
Motor Neurons ◽  
Phrenic Nerve ◽  
Intermittent Hypoxia ◽  
Neural Control ◽  
Respiratory Cycle ◽  
Evoked Responses ◽  
Nerve Activity ◽  
Synaptic Inputs ◽  
Phrenic Nerve Activity ◽  
The Impact

Plasticity is a hallmark of the respiratory neural control system. Phrenic long-term facilitation (pLTF) is one form of respiratory plasticity characterized by persistent increases in phrenic nerve activity following acute intermittent hypoxia (AIH). Although there is evidence that key steps in the cellular pathway giving rise to pLTF are localized within phrenic motor neurons (PMNs), the impact of AIH on the strength of breathing-related synaptic inputs to PMNs remains unclear. Further, the functional impact of AIH is enhanced by repeated/daily exposure to AIH (dAIH). Here, we explored the effects of AIH vs. 2 weeks of dAIH preconditioning on spontaneous and evoked responses recorded in anesthetized, paralyzed (with pancuronium bromide) and mechanically ventilated rats. Evoked phrenic potentials were elicited by respiratory cycle-triggered lateral funiculus stimulation at C2 delivered prior to- and 60 min post-AIH (or an equivalent time in controls). Charge-balanced biphasic pulses (100 µs/phase) of progressively increasing intensity (100 to 700 µA) were delivered during the inspiratory and expiratory phases of the respiratory cycle. Although robust pLTF (~60% from baseline) was observed after a single exposure to moderate AIH (3 x 5 min; 5 min intervals), there was no effect on evoked phrenic responses, contrary to our initial hypothesis. However, in rats preconditioned with dAIH, baseline phrenic nerve activity and evoked responses were increased, suggesting that repeated exposure to AIH enhances functional synaptic strength when assessed using this technique. The impact of daily AIH preconditioning on synaptic inputs to PMNs raises interesting questions that require further exploration.

scholarly journals Contemporary Circulating Enterovirus D68 Strains Infect and Undergo Retrograde Axonal Transport in Spinal Motor Neurons Independent of Sialic Acid

2019 ◽  
Vol 93 (16) ◽  
Author(s):  
Alison M. Hixon ◽  
Penny Clarke ◽  
Kenneth L. Tyler
Keyword(s):  
Sialic Acid ◽  
Motor Neuron ◽  
Axonal Transport ◽  
Motor Neurons ◽  
The United States ◽  
Retrograde Axonal Transport ◽  
Spinal Motor Neurons ◽  
Acute Flaccid Myelitis ◽  
Spinal Motor ◽  
Enterovirus D68

ABSTRACTEnterovirus D68 (EV-D68) is an emerging virus that has been identified as a cause of recent outbreaks of acute flaccid myelitis (AFM), a poliomyelitis-like spinal cord syndrome that can result in permanent paralysis and disability. In experimental mouse models, EV-D68 spreads to, infects, and kills spinal motor neurons following infection by various routes of inoculation. The topography of virus-induced motor neuron loss correlates with the pattern of paralysis. The mechanism(s) by which EV-D68 spreads to target motor neurons remains unclear. We sought to determine the capacity of EV-D68 to spread by the neuronal route and to determine the role of known EV-D68 receptors, sialic acid and intracellular adhesion molecule 5 (ICAM-5), in neuronal infection. To do this, we utilized a microfluidic chamber culture system in which human induced pluripotent stem cell (iPSC) motor neuron cell bodies and axons can be compartmentalized for independent experimental manipulation. We found that EV-D68 can infect motor neurons via their distal axons and spread by retrograde axonal transport to the neuronal cell bodies. Virus was not released from the axons via anterograde axonal transport after infection of the cell bodies. Prototypic strains of EV-D68 depended on sialic acid for axonal infection and transport, while contemporary circulating strains isolated during the 2014 EV-D68 outbreak did not. The pattern of infection did not correspond with the ICAM-5 distribution and expression in either human tissue, the mouse model, or the iPSC motor neurons.IMPORTANCEEnterovirus D68 (EV-D68) infections are on the rise worldwide. Since 2014, the United States has experienced biennial spikes in EV-D68-associated acute flaccid myelitis (AFM) that have left hundreds of children paralyzed. Much remains to be learned about the pathogenesis of EV-D68 in the central nervous system (CNS). Herein we investigated the mechanisms of EV-D68 CNS invasion through neuronal pathways. A better understanding of EV-D68 infection in experimental models may allow for better prevention and treatment strategies of EV-D68 CNS disease.

Restricted expression of mutant SOD1 in spinal motor neurons and interneurons induces motor neuron pathology

2008 ◽  
Vol 29 (3) ◽  
pp. 400-408 ◽  
Author(s):  
Lijun Wang ◽  
Kamal Sharma ◽  
Han-Xiang Deng ◽  
Teepu Siddique ◽  
Gabriella Grisotti ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Motor Neurons ◽  
Mutant Sod1 ◽  
Spinal Motor Neurons ◽  
Spinal Motor

scholarly journals Using a Model to Assess the Role of the Spatiotemporal Pattern of Inhibitory Input and Intrasegmental Electrical Coupling in the Intersegmental and Side-to-Side Coordination of Motor Neurons by the Leech Heartbeat Central Pattern Generator

2008 ◽  
Vol 100 (3) ◽  
pp. 1354-1371 ◽  
Author(s):  
Paul S. García ◽  
Terrence M. Wright ◽  
Ian R. Cunningham ◽  
Ronald L. Calabrese
Keyword(s):  
Motor Neuron ◽  
Central Pattern Generator ◽  
Motor Neurons ◽  
Electrical Coupling ◽  
Pattern Generator ◽  
Living System ◽  
Phase Relations ◽  
Spatiotemporal Pattern ◽  
Intrinsic Properties ◽  
Synaptic Inputs

Previously we presented a quantitative description of the spatiotemporal pattern of inhibitory synaptic input from the heartbeat central pattern generator (CPG) to segmental motor neurons that drive heartbeat in the medicinal leech and the resultant coordination of CPG interneurons and motor neurons. To begin elucidating the mechanisms of coordination, we explore intersegmental and side-to-side coordination in an ensemble model of all heart motor neurons and their known synaptic inputs and electrical coupling. Model motor neuron intrinsic properties were kept simple, enabling us to determine the extent to which input and electrical coupling acting together can account for observed coordination in the living system in the absence of a substantive contribution from the motor neurons themselves. The living system produces an asymmetric motor pattern: motor neurons on one side fire nearly in synchrony (synchronous), whereas on the other they fire in a rear-to-front progression (peristaltic). The model reproduces the general trends of intersegmental and side-to-side phase relations among motor neurons, but the match with the living system is not quantitatively accurate. Thus realistic (experimentally determined) inputs do not produce similarly realistic output in our model, suggesting that motor neuron intrinsic properties may contribute to their coordination. By varying parameters that determine electrical coupling, conduction delays, intraburst synaptic plasticity, and motor neuron excitability, we show that the most important determinant of intersegmental and side-to-side phase relations in the model was the spatiotemporal pattern of synaptic inputs, although phasing was influenced significantly by electrical coupling.

scholarly journals Single-cell transcriptomic analysis of the adult mouse spinal cord

2020 ◽  
Author(s):  
Jacob A. Blum ◽  
Sandy Klemm ◽  
Lisa Nakayama ◽  
Arwa Kathiria ◽  
Kevin A. Guttenplan ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Single Cell ◽  
Motor Neurons ◽  
The Body ◽  
Molecular Heterogeneity ◽  
Spinal Motor Neuron ◽  
Spinal Motor ◽  
Full Complement ◽  
Adult Spinal Cord

AbstractThe spinal cord is a fascinating structure responsible for coordinating all movement in vertebrates. Spinal motor neurons control the activity of virtually every organ and muscle throughout the body by transmitting signals that originate in the spinal cord. These neurons are remarkably heterogeneous in their activity and innervation targets. However, because motor neurons represent only a small fraction of cells within the spinal cord and are difficult to isolate, the full complement of motor neuron subtypes remains unknown. Here we comprehensively describe the molecular heterogeneity of motor neurons within the adult spinal cord. We profiled 43,890 single-nucleus transcriptomes using fluorescence-activated nuclei sorting to enrich for spinal motor neuron nuclei. These data reveal a transcriptional map of the adult mammalian spinal cord and the first unbiased characterization of all transcriptionally distinct autonomic and somatic spinal motor neuron subpopulations. We identify 16 sympathetic motor neuron subtypes that segregate spatially along the spinal cord. Many of these subtypes selectively express specific hormones and receptors, suggesting neuromodulatory signaling within the autonomic nervous system. We describe skeletal motor neuron heterogeneity in the adult spinal cord, revealing numerous novel markers that distinguish alpha and gamma motor neurons—cell populations that are specifically affected in neurodegenerative disease. We also provide evidence for a novel transcriptional subpopulation of skeletal motor neurons. Collectively, these data provide a single-cell transcriptional atlas for investigating motor neuron diversity as well as the cellular and molecular basis of motor neuron function in health and disease.

Developmental regulation of the orphan receptor COUP-TF II gene in spinal motor neurons

Development ◽  
1994 ◽  
Vol 120 (1) ◽  
pp. 25-36 ◽  
Author(s):  
B. Lutz ◽  
S. Kuratani ◽  
A.J. Cooney ◽  
S. Wawersik ◽  
S.Y. Tsai ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Thyroid Hormone ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Orphan Receptor ◽  
Northern Analysis ◽  
Spinal Motor Neurons ◽  
Spinal Motor

Members of the steroid/thyroid hormone receptor superfamily are involved in the control of cell identity and of pattern formation during embryonic development. Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) can act as regulators of various steroid/thyroid hormone receptor pathways. To begin to study the role of COUP-TFs during embryogenesis, we cloned a chicken COUP-TF (cCOUP-TF II) which is highly homologous to human COUP-TF II. Northern analysis revealed high levels of cCOUP-TF II transcripts during organogenesis. Nuclear extracts from whole embryos and from embryonic spinal cords were used in electrophoretic mobility shift assays. These assays showed that COUP-TF protein is present in these tissues and is capable of binding to a COUP element (a direct repeat of AGGTCA with one base pair spacing). Analysis of cCOUP-TF expression by in situ hybridization revealed high levels of cCOUP-TF II mRNA in the developing spinal motor neurons. Since the ventral properties of the spinal cord, including the development of motor neurons, is in part established by inductive signals from the notochord, we transplanted an additional notochord next to the dorsal region of the neural tube in order to induce ectopic motor neurons. We observed that an ectopic notochord induced cCOUP-TF II gene expression in the dorsal spinal cord in a region coextensive with ectopic domains of SC1 and Islet-1, two previously identified motor neuron markers. Collectively, our studies raise the possibility that cCOUP-TF II is involved in motor neuron development.

The zebrafish detour gene is essential for cranial but not spinal motor neuron induction

Development ◽  
1999 ◽  
Vol 126 (12) ◽  
pp. 2727-2737 ◽  
Author(s):  
A. Chandrasekhar ◽  
H.E. Schauerte ◽  
P. Haffter ◽  
J.Y. Kuwada
Keyword(s):  
Spinal Cord ◽  
Cell Death ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Spinal Motor Neuron ◽  
Neuronal Phenotype ◽  
Spinal Motor Neurons ◽  
Spinal Motor ◽  
Hh Signaling ◽  
Function Cell

The zebrafish detour (dtr) mutation generates a novel neuronal phenotype. In dtr mutants, most cranial motor neurons, especially the branchiomotor, are missing. However, spinal motor neurons are generated normally. The loss of cranial motor neurons is not due to aberrant hindbrain patterning, failure of neurogenesis, increased cell death or absence of hh expression. Furthermore, activation of the Hh pathway, which normally induces branchiomotor neurons, fails to induce motor neurons in the dtr hindbrain. Despite this, not all Hh-mediated regulation of hindbrain development is abolished since the regulation of a neural gene by Hh is intact in the dtr hindbrain. Finally, dtr can function cell autonomously to induce branchiomotor neurons. These results suggest that detour encodes a component of the Hh signaling pathway that is essential for the induction of motor neurons in the hindbrain but not in the spinal cord and that dtr function is required for the induction of only a subset of Hh-mediated events in the hindbrain.

scholarly journals The pathogenic role of c-Kit+ mast cells in the spinal motor neuron-vascular niche in ALS

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Mariángeles Kovacs ◽  
Catalina Alamón ◽  
Cecilia Maciel ◽  
Valentina Varela ◽  
Sofía Ibarburu ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Mast Cells ◽  
Motor Neuron ◽  
Motor Neurons ◽  
Immune Cells ◽  
Spinal Cord Tissue ◽  
Cell Reactivity ◽  
Spinal Motor Neuron ◽  
Spinal Motor ◽  
Vascular Niche

AbstractDegeneration of motor neurons, glial cell reactivity, and vascular alterations in the CNS are important neuropathological features of amyotrophic lateral sclerosis (ALS). Immune cells trafficking from the blood also infiltrate the affected CNS parenchyma and contribute to neuroinflammation. Mast cells (MCs) are hematopoietic-derived immune cells whose precursors differentiate upon migration into tissues. Upon activation, MCs undergo degranulation with the ability to increase vascular permeability, orchestrate neuroinflammation and modulate the neuroimmune response. However, the prevalence, pathological significance, and pharmacology of MCs in the CNS of ALS patients remain largely unknown. In autopsy ALS spinal cords, we identified for the first time that MCs express c-Kit together with chymase, tryptase, and Cox-2 and display granular or degranulating morphology, as compared with scarce MCs in control cords. In ALS, MCs were mainly found in the niche between spinal motor neuron somas and nearby microvascular elements, and they displayed remarkable pathological abnormalities. Similarly, MCs accumulated in the motor neuron-vascular niche of ALS murine models, in the vicinity of astrocytes and motor neurons expressing the c-Kit ligand stem cell factor (SCF), suggesting an SCF/c-Kit-dependent mechanism of MC differentiation from precursors. Mechanistically, we provide evidence that fully differentiated MCs in cell cultures can be generated from the murine ALS spinal cord tissue, further supporting the presence of c-Kit+ MC precursors. Moreover, intravenous administration of bone marrow-derived c-Kit+ MC precursors infiltrated the spinal cord in ALS mice but not in controls, consistent with aberrant trafficking through a defective microvasculature. Pharmacological inhibition of c-Kit with masitinib in ALS mice reduced the MC number and the influx of MC precursors from the periphery. Our results suggest a previously unknown pathogenic mechanism triggered by MCs in the ALS motor neuron-vascular niche that might be targeted pharmacologically.

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