Martin, J

Mentis, G

Tosolini, A

English

UCL Discovery

EDITORIALpublished: 22 March 2021doi: 10.3389/fnmol.2021.669824Frontiers in Molecular Neuroscience | www.frontiersin.org 1 March 2021 | Volume 14 | Article 669824Edited by:Peter Claus,Hannover Medical School, GermanyReviewed by:Lars Klimaschewski,Innsbruck Medical University, Austria*Correspondence:Andrew Paul Tosolinia.tosolini@ucl.ac.ukGeorge Z. Mentisgzmentis@columbia.eduJohn H. Martinjmartin@med.cuny.edu†These authors have contributedequally to this workReceived: 19 February 2021Accepted: 26 February 2021Published: 22 March 2021Citation:Tosolini AP, Mentis GZ and Martin JH(2021) Editorial: Dysfunction andRepair of Neural Circuits for MotorControl.Front. Mol. Neurosci. 14:669824.doi: 10.3389/fnmol.2021.669824Editorial: Dysfunction and Repair ofNeural Circuits for Motor ControlAndrew Paul Tosolini 1*, George Z. Mentis 2*† and John H. Martin 3*†1Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, University College London, London,United Kingdom, 2Department of Pathology & Cell Biology and Neurology, Center for Motor Neuron Biology and Disease,Columbia University, New York, NY, United States, 3Department of Molecular, Cellular and Biomedical Sciences, Center forDiscovery and Innovation, City University of New York School of Medicine, New York, NY, United StatesKeywords: motor neurons, sensory neurons, regeneration, spinal cord injury, ALS, SMA, inflammation, gliaEditorial on the Research TopicDysfunction and Repair of Neural Circuits for Motor ControlThe dissolution of normal behavior in pathological conditions, after trauma, or inneurodegenerative diseases is often attributed to the selective dysfunction and degenerationof particular classes of vulnerable neurons. However, vulnerable neurons are embedded inneuronal circuits that often play major roles in the progression of the pathophysiological state, bycell-autonomous and non-cell autonomous mechanisms. For example, voluntary motor behavioralimpairments occur after brain or spinal cord injury because descending projection neurons arevulnerable to axonal damage and are unable to regenerate anew. This limitation reflects both a lossof intrinsic axon regenerative capacity in mature neurons and extrinsic regulation by non-neuronalcells. Similarly, motor neurons deprived of supraspinal inputs or in neurodegeneration (e.g., ALS,SMA) undergo an array of well-described molecular events (Schwab and Bartholdi, 1996; Brownand Al-Chalabi, 2017; Groen et al., 2018) that also include morphological remodeling (Boseet al., 2005; Dukkipati et al., 2018). If therefore, repair or restoration of normal function issought after, a clear understanding is required for the molecular, cellular, and neuronal circuitmechanisms involved. Over the last decade, several significant advances in our understandingof the development and operational principles of neural circuits demonstrate the complexityof the central nervous system under normal conditions and the diverse mechanisms that leadto dysfunction.Everyday actions in essential complex behaviors such as walking, feeding, and breathing, requirethe specific integration of neural circuits that flawlessly operate with precision, co-ordination, andsynchrony (Arber, 2012). As summarized in Figure 1, for voluntary movement to occur, the motorcortical areas must initiate communication with the spinal cord circuitry, which in turn conveythese commands via spinal motor neurons to the skeletal muscles. Equally important, sensoryinformation from the periphery is essential for the proper activation and function of neural circuitsinvolved in motor control. Intrinsic to these processes are the influences of spinal excitatory andinhibitory interneurons.However, after injury or in disease states, these neural circuits may be affected in subtle ways butover time may result in a multitude of effects causing dysfunction; not only in vulnerable neuronsbut also by disrupting the signaling and connectivity of integrated neural circuits. As neural circuitsare disrupted through trauma [spinal cord injury (SCI), peripheral nerve injury, stroke] or inneurodegenerative diseases [amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA)],determining the timing and primacy of the earliest pathological events are critical questions tobe addressed if normal function is to be restored. Uncovering therefore the initiating pathogenicevents are critical steps in proposing potential therapeutic avenues.Tosolini et al. Editorial: Neural Circuits for Motor ControlFIGURE 1 | Execution of all movements in health and after trauma require a complex series of co-ordination of cellular and molecular actions involved within the (A)descending motor system, (B) intrinsic spinal cord circuitry, (C) neuromuscular junction, and (D) afferent feedback through the ascending sensory system. Createdwith BioRender.com.However, a paramount challenge for the field is to harmonizeand integrate effectively the increasing number of studiesthat separately focus on molecular events in single cells (e.g.,transcriptomics, proteomics) or on cellular phenotypes inneurons and glia (e.g., neuronal dysfunction, neurodegeneration,synaptic plasticity, astrocytic, or microglia proliferation) (Stuartand Satija, 2019). To this end, an exciting challenge is todecipher adaptive from maladaptive molecular and cellularchanges within individual neurons and their supporting cells andthe influence they exert on motor circuits after neural trauma(Ilieva et al., 2009; Eroglu and Barres, 2010; Huntley, 2012).We launched this Research Topic to provide a platform toencourage discussion on recent advances in knowledge and/ortherapeutic tools to investigate motor circuitry following certainpathological conditions.The topic on Dysfunction and Repair of Neural Circuits forMotor Control is devoted to neuronal circuits involving cortical,spinal, and peripheral neurons in healthy and pathologicalconditions. The articles in this collection—comprising fiveoriginal studies, three extensive-reviews and two mini-reviews—explore how certain circuits regulate and integrate their actions,how they are altered in disease or after trauma, and effortsto repair circuits to restore normal function. Discussions spanhuman and animal models of impairedmotor circuits and a focusthat includes much of the neuraxis: the motor cortex, hindbrain,spinal cord, somatic sensory neurons, and peripheral nerves.The five original studies traverse the neuroanatomicalspectrum, spanning hindbrain neurons, upper motor neurons,and sensory neurons to glial-peripheral nerve interactions,with particular focus on regeneration, inflammation, andexcitability in ALS animal models (Table 1). Huang et al.study the modulation of miR-133b to promote axonregeneration of Mauthner-cells in zebrafish hindbrain.Ballou et al. characterize the inflammatory and glialresponse to cortical transplants after injury. Chen et al.reveal the involvement of Schwann cells in peripheralnerve regeneration. Zeng et al. describe inflammationcascades in DRG sensory neurons. Jara et al. describecircuitry changes in the motor cortex of pre-symptomaticALS mice.The five reviews discuss signaling cascades involvingmotor neurons, sensory neurons, spinal motor circuits,and electrical stimulation relevant for ALS, SMA, SCI, andregeneration (Table 2). Sobrido-Cameán and Barreiro-Iglesiasconsider apoptotic signaling cascades after SCI. Shorrock etal. discuss sensory-motor molecular mechanisms in SMA.Eisdorfer et al. contemplate how epidural electrical stimulationcan enhance motility after SCI. Alvarez et al. examine theinfluence of spinal cord circuitry in regeneration of peripheralnerves. Falgairolle and O’Donovan deliberate on the influenceof motor circuits on motor neuron vulnerability in ALSand SMA.Frontiers in Molecular Neuroscience | www.frontiersin.org 2 March 2021 | Volume 14 | Article 669824Tosolini et al. Editorial: Neural Circuits for Motor ControlTABLE 1 | Highlights from the original research published within this Research Topic.Paper Purpose Highlights Model and neuronlocationHuang et al. To examine the role ofmiR-133b in Mauthner-cellregeneration in zebrafish• Overexpression of miR-133b inhibited axonregeneration, whereas down-regulation ofmiR-133b, promoted axon outgrowth• miR-133b regulates axon regeneration by directlytargeting tppp3, a novel regeneration-associatedgene which belongs to Tubulinpolymerization-promoting protein family• miR-133b overexpression attenuatedmitochondrial motility in M-cells in vivo, correlatingwith enhanced axon regenerative propertiesWild-type, Zebrafish,HindbrainBallout et al. • To determine the extentto which post-traumaticinflammation followingcortical lesion couldinfluence the survival ofgrafted neurons,• To understand thedevelopment of theirprojections to target brainregions whilstunderstanding howtransplanted cells canmodulatehost inflammation• Embryonic motor cortical tissue grafted 1 weekafter adult motor cortex lesion resulted in anincreasing numbers of astrocytes, microglia,oligodendrocytes and hematopoietic cells,compared to implanted grafts at the time of lesion• One week after cortical lesion resulted in morerecruitment and activation of inflammatory brainresident mediators and peripheral infiltrating cellscompared to day 0• Graft implantation one week after cortical lesionresulted in (i) increased recruitment of A2astrocytes in the host transplant and adjacentcortex, (ii) increased oligodendrocytes only withinthe transplant, and (iii) decreased M1 microgliaonly within the transplantWild-type Mouse,Motor cortexChen et al. • To understand thebehavior of Schwann cellsmigrating into a nerve gapfollowing a transectioninjury• To reveal their interactionswith regenerating axonswithin the nerve bridge• After peripheral transection, axonal outgrowth firstbegins from the proximal stump, followed bySchwann cells migration from proximal and distalnerve stumps• Schwann cells overtake the axonal outgrowth,forming Schwann cell cords within the nervebridge and most regenerating axons attach to themigrating Schwann cells and follow theirtrajectory across the nerve gap• Schwann cells play a crucial role in controlling thedirectionality and speed of axon regenerationacross the nerve gapWild-type Mouse,Peripheral NerveZeng et al. Uncover the effects ofSIRT1 on IL-33/ST2signaling and initiation of theinflammatory cascade byTNF-α and IL-1β modulation• After spared nerve injury, IL-33 and its receptorST2 were upregulated in sensory neurons indorsal root ganglia• Intrathecal injections of IL-33 or ST2 antibodiesalleviated mechanical allodynia whilstdownregulating the expression of TNF-α andIL-1β induced by injury• Reductions of SIRT1 activates IL-33/ST2signaling and subsequently triggers the TNF-αand IL1β inflammatory cascades that contributeto the mechanical allodynia induced by sparednerve injuryWild-type Rats, DorsalRoot Ganglia SensoryNeuronsJara et al. Determine the mechanismsthat contribute to uppermotor neuron vulnerability inhSOD1G93A mice• Pre-symptomatic hSOD1G93A mice display alteredinhibitory, but not excitatory, circuitry specific tothe L2/3 pyramidal neurons in the motor cortex• Exon microarray analysis provides somemolecular evidence of altered inhibitorytransmission in hSOD1G93A upper motor neurons• GABA and potassium receptor subunits aredifferentially expressed in diseased corticospinalmotor neurons in hSOD1G93A micehSOD1G93A Mouse,Motor cortexFrontiers in Molecular Neuroscience | www.frontiersin.org 3 March 2021 | Volume 14 | Article 669824Tosolini et al. Editorial: Neural Circuits for Motor ControlTABLE 2 | Highlights from the mini- and full- reviews published within this Research Topic.Paper Highlights Paper type Disease/DysfunctionmodelSobrido-CameánandBarreiro-Iglesias• Reviews the literature on caspase-8 mediated cell death after spinal cordinjury in a variety of animal models• Discusses caspase-8 activated signaling pathways following spinal cordinjury• Proposes novel areas to advance the knowledge on the role of caspase-8and Fas in cell death after spinal cord injuryMini-Review Spinal Cord Injury (SCI)Shorrock et al. • Highlights that defects in sensory components of the sensory-motorsystem contribute to motor neuron dysfunction early in SMA• Emphasizes that cell types other than motor neurons play an importantrole in SMA pathogenesis• Reiterates that therapeutic interventions must rescue the wide array ofdefects that are observed in SMAMini-Review Spinal MuscularAtrophy (SMA)Eisdorfer et al. • Describes the utility of epidural electrical stimulation (EES) in enhancingmotility in SCI patients• Identifies several sensorimotor plasticity mechanisms that are consideredto be evoked by EES through the activation of peripheral afferents• Evaluates emerging genetic modification tools that modulate afferentfibers to uncovering molecular and circuit mechanisms of EES-inducedrecovery from SCIReview Spinal Cord Injury (SCI)Alvarez et al. • Provides a comprehensive conceptual framework to understand howdifferent types of nerve injuries that result in motor neuron axotomyinduce distinct regenerative programs that drastically differ in motoneuronpreservation, and speed and efficiency of regeneration• Proposes that synaptic plasticity of axotomized motor neurons should bedivided into two distinct processes: (1) a reversible, rapid,cell-autonomous, microglia-independent shedding of synapses; and (2) aslower, microglial dependent mechanism that permanently alters spinalcord circuitry• Considers the significance of differential removal of excitatory andinhibitory synapses on synaptic plasticity of axotomized motor neuronsReview Peripheral Nerve InjuryFalgairolle andO’Donovan• Discusses abnormalities in the spinal cord circuitry in both ALS and SMA• Describes the sensitivity of the different motor neuron subtypes in bothmotor neuron diseases• Deliberates on if the selective vulnerability or resistance of different motorneuron types in ALS/SMA can be attributed to theirintraspinal connectivityReview Amyotrophic lateralsclerosis (ALS) andspinal muscularatrophy (SMA)Overall, this Research Topic describes anatomical,electrophysiological, cellular, and molecular interactionsbetween neural networks and how advancing technologiesenable clearer characterizations of dysfunctionalneural circuitry.AUTHOR CONTRIBUTIONSAll authors listed have made a substantial, direct andintellectual contribution to the work, and approved itfor publication.FUNDINGAT holds a postdoctoral position supported by a WellcomeTrust Senior Investigator Award [107116/Z/15/Z] to GiampietroSchiavo (Institute of Neurology, University College London).GZM has been supported by the NINDS, NIH (R01-NS078375),The NIH Blueprint for Neuroscience Research, NIAAAand NINDS (R01-AA027079), the Department of Defense(GR.10235006), The SMA Foundation and Project-ALS.JHM was supported by NIH (R01NS064004), NYS Dept ofHealth Spinal Cord Injury Research Board (C31291GG),Paralyzed Veterans Association (3160), and The Craig H NeilsenFoundation (547040).REFERENCESArber, S. (2012). Motor circuits in action: specification, connectivity,and function. Neuron. 74, 975–989. doi: 10.1016/j.neuron.2012.05.011Bose, P., Parmer, R., Reier, P. J., and Thompson, F. J. (2005). Morphologicalchanges of the soleus motoneuron pool in chronic midthoracic contused rats.Exp. Neurol. 191, 13–23. doi: 10.1016/j.expneurol.2004.08.028Brown, R. H., and Al-Chalabi, A. (2017). Amyotrophic lateral sclerosis. N. Engl. J.Med. 377, 162–172. doi: 10.1056/NEJMra1603471Frontiers in Molecular Neuroscience | www.frontiersin.org 4 March 2021 | Volume 14 | Article 669824Tosolini et al. Editorial: Neural Circuits for Motor ControlDukkipati, S. S., Garrett, T. L., and Elbasiouny, S. M. (2018). The vulnerability ofspinal motoneurons and soma size plasticity in a mouse model of amyotrophiclateral sclerosis. J. Physiol. 596, 1723–1745. doi: 10.1113/JP275498Eroglu, C., and Barres, B. A. (2010). Regulation of synaptic connectivity by glia.Nature 468, 223–231. doi: 10.1038/nature09612Groen, E. J. N., Talbot, K., and Gillingwater, T. H. (2018). Advances in therapyfor spinal muscular atrophy: promises and challenges. Nat. Rev. Neurol. 14,214–224. doi: 10.1038/nrneurol.2018.4Huntley, G. W. (2012). Synaptic circuit remodelling by matrix metalloproteinasesin health and disease. Nat. Rev. Neurosci. 13, 743–757. doi: 10.1038/nrn3320Ilieva, H., Polymenidou, M., and Cleveland, D. W. (2009). Non-cell autonomoustoxicity in neurodegenerative disorders: ALS and beyond. J. Cell Biol. 187,761–772. doi: 10.1083/jcb.200908164Schwab, M. E., and Bartholdi, D. (1996). Degeneration and regenerationof axons in the lesioned spinal cord. Physiol. Rev. 76, 319–370.doi: 10.1152/physrev.1996.76.2.319Stuart, T., and Satija, R. (2019). Integrative single-cell analysis.Nat. Rev. Genetics 20, 257–272. doi: 10.1038/s41576-019-0093-7Conflict of Interest: The authors declare that the researchwas conducted in the absence of any commercial or financialrelationships that could be construed as a potential conflictof interest.Copyright © 2021 Tosolini, Mentis and Martin. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY).The use, distribution or reproduction in other forums is permitted, provided theoriginal author(s) and the copyright owner(s) are credited and that the originalpublication in this journal is cited, in accordance with accepted academic practice.No use, distribution or reproduction is permitted which does not comply with theseterms.Frontiers in Molecular Neuroscience | www.frontiersin.org 5 March 2021 | Volume 14 | Article 669824

Editorial: Dysfunction and Repair of Neural Circuits for Motor Control

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Editorial: Dysfunction and Repair of Neural Circuits for Motor Control

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