What are the implications of the vagus nerve being able to mediate the time-dependent plasticity of an array of sensorimotor networks

Alvarez-Dieppa

De Ridder

Edelman

Ganzer

Hays

Hulsey

English

Edgerton, V Reggie

Gad, Parag

eScholarship - University of California

UCLAUCLA Previously Published WorksTitleIs the vagus nerve our neural connectome?Permalinkhttps://escholarship.org/uc/item/9754q423AuthorsEdgerton, V ReggieGad, ParagPublication Date2018DOI10.7554/elife.35592 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaSPINAL CORD INJURYIs the vagus nerve our neuralconnectome?What are the implications of the vagus nerve being able to mediate thetime-dependent plasticity of an array of sensorimotor networks?V REGGIE EDGERTON AND PARAG GADThe vagus nerve reports on the state ofmany of the organs in our body, includ-ing the heart, the lungs and the gut, andit relays this information to various neural controlnetworks that unconsciously regulate internalorgans. It has also been shown that artificialelectric stimulation of the vagus nerve helps withrecovery in animal models of stroke, tinnitus andspinal cord injury (De Ridder et al., 2014;Hays, 2016). In particular, stimulation of thevagus nerve promotes the recuperation of motorskills and, maybe, autonomic functions (such asbreathing), even when the injuries took placeyears before the intervention. However, we donot fully understand how stimulating this singlenerve can lead to such results.Now, in eLife, Patrick Ganzer, Robert Ren-naker at the University of Texas at Dallas and theTexas Biomedical Device Center, and col-leagues, report that stimulating the vagus nerveof a rat with spinal injuries helps it to recovermobility of an affected limb – in this case, itsfront paw (Ganzer et al., 2018). The stimulationhas to be applied during a short time windowafter the rat manages to perform a specificmovement with this paw, such as grasping alever with a specific level of strength.In this scenario, grasping the lever activates anetwork of neurons. The connections betweenthese neurons will then be reinforced if thevagus nerve is stimulated within seconds of thistask being completed (Figure 1). Classical long-term potentiation experiments show that simul-taneous activation leaves ‘tags’ in neurons,which help to strengthen any connectionsbetween these neurons (He et al., 2015). Yet,during vagus nerve stimulation, there is no directsynaptic link between the circuits that performthe motor task and the synapses that are excitedby the vagus nerve (Alvarez-Dieppa et al.,2016; Hulsey et al., 2017).Instead, the effects of vagus nerve stimulationcould be mediated by a wide range of neuromo-dulatory mechanisms, which are non-specific toa given synapse. Because the vagus nerve is con-nected to so many different organs, both in sen-sorimotor and autonomic ways, it provides theentry point to various neuroendocrine and neu-rotransmitter systems. Essentially, it seems thatthe vagus nerve can form a ’connectome’ formany functions, which means that interventionsvia the vagus nerve have the potential to helpwith the recovery of multiple functions.Remarkably, similar effects can be obtainedby stimulating the spinal cord before the actionis performed (Figure 1; Gad et al., 2013). Inboth cases, there are activity-dependent mecha-nisms that identify the synapses that have beenactivated, and the stimulation triggers a series ofCopyright Edgerton and Gad. Thisarticle is distributed under the termsof the Creative Commons AttributionLicense, which permits unrestricteduse and redistribution provided thatthe original author and source arecredited.Related research article Ganzer PD, Dar-row MJ, Meyers EC, Solorzano BR, RuizAD, Robertson NM, Adcock KS, James JT,Jeong HS, Becker AM, Goldberg MP, PruittDT, Hays SA, Kilgard MP, Rennaker RL.2018. Closed-loop neuromodulationrestores network connectivity and motorcontrol after spinal cord injury. eLife 7:e32058. DOI: 10.7554/eLife.32058Edgerton and Gad. eLife 2018;7:e35592. DOI: https://doi.org/10.7554/eLife.35592 1 of 4INSIGHTFigure 1. The effects of vagus nerve and spinal cord stimulations on neural networks. The schematic shows theeffect of two types of artificial stimulations on a network of neurons (circles), which is activated when a rat withspinal cord injury pulls a lever with its affected limb. Column A shows the effect of vagus nerve stimulation onneural networks that are activated when the rat pulls that lever. In A1, when the rat performs the task, it activatesneurons. Some of these are specific to this task (encircled by solid black lines), some of which are not(dashed black line). In A2, the vagus nerve (not represented) is stimulated (pink cloud and lightning bolts). Theneurons previously activated are also modulated by this stimulation, and certain new neurons are activated(dashed red line). This combination of activation and modulation strengthens the connections between theneurons that previously fired together, which leads to a transformation of the network. Ultimately, this more robustnetwork supports better physical performance by the rats. Column B shows the effect of spinal cord stimulation onthe same neural networks. In B1, spinal cord stimulation is applied (blue cloud and lighting bolt) before the tasktakes place. When the task is performed (B2), the synapses between the groups of neurons that are involved arefurther reinforced, a result that is comparable to what is obtained with vagus nerve stimulation. Similar results mayFigure 1 continued on next pageEdgerton and Gad. eLife 2018;7:e35592. DOI: https://doi.org/10.7554/eLife.35592 2 of 4Insight Spinal Cord Injury Is the vagus nerve our neural connectome?time-dependent events that reinforce the con-nections between the relevant neurons.More broadly, there are at least four funda-mental biological concepts relevant to the find-ings by Ganzer et al. First, the vagus nervemediates physiological systems (including senso-rimotor and autonomic systems) which areextensively and comprehensively integratedtogether. Second, these systems are dynamicand can reorganize and interact in ways that candramatically change our behavior. Third, time-dependence has a central role in defining activ-ity-dependent plasticity. Fourth, the networksunder the influence of the vagus nerve may beconstantly reshaped by neural and biochemicalsignals via activity-dependent mechanisms.These four points are consistent with the the-ory of neural group selection put forward byGerald Edelman, the American biologist whoshared the Nobel Prize in Physiology or Medi-cine in 1972 (Edelman, 1987). According to thistheory, during early and neonatal developmentneurons form somewhat malleable connectionsbased on genetic (i.e., internal) signals.Thereafter, throughout life, these networksdynamically and continuously create differentcombinations of functional neuronal connections– called neural networks, orsomatically formed groups – by functionallypruning or reinforcing the strength of their con-nections. This remodeling is determined by thelevel of activity of the neural connections as theyare constantly responding to internal and exter-nal stimuli. Finally, which neural groups firetogether determines the overall shape of thesenetworks. In terms of behavior, the basic func-tional unit of the brain is therefore not a neuron,but instead a group of connections among neu-rons that tend to fire together. Thus, fully under-standing the mechanisms at play during vagusnerve stimulation requires thinking at the level ofsystems, as well as of subcellular components.V Reggie Edgerton is in the Department of IntegrativeBiology and Physiology at the University of California,Los Angeles, United Statesvre@ucla.eduhttps://orcid.org/0000-0001-6534-1875Parag Gad is in the Department of Integrative Biologyand Physiology at the University of California, LosAngeles, United Statesparaggad@gmail.comhttps://orcid.org/0000-0001-8352-7614Competing interests: V Reggie Edgerton: V ReggieEdgerton holds shareholder interest in NeuroRecoveryTechnologies and holds certain inventorship rights onintellectual property licensed by The Regents of theUniversity of California to NeuroRecovery Technolo-gies and its subsidiaries. The other author declaresthat no competing interests exist.Published 16 March 2018ReferencesAlvarez-Dieppa AC, Griffin K, Cavalier S, McIntyre CK.2016. Vagus nerve stimulation enhances extinction ofconditioned fear in rats and modulates arc protein,CaMKII, and GluN2B-Containing NMDA receptors inthe basolateral amygdala. Neural Plasticity 2016:4273280. DOI: https://doi.org/10.1155/2016/4273280,PMID: 27957346De Ridder D, Vanneste S, Engineer ND, Kilgard MP.2014. Safety and efficacy of vagus nerve stimulationpaired with tones for the treatment of tinnitus: a caseseries. Neuromodulation: Technology at the NeuralInterface 17:170–179. DOI: https://doi.org/10.1111/ner.12127Edelman GM. 1987. Neural Darwinism: The Theory ofNeuronal Group Selection. New York: Basic Books.Gad P, Choe J, Shah P, Garcia-Alias G, Rath M,Gerasimenko Y, Zhong H, Roy RR, Edgerton VR. 2013.Sub-threshold spinal cord stimulation facilitatesspontaneous motor activity in spinal rats. Journal ofNeuroEngineering and Rehabilitation 10:108.DOI: https://doi.org/10.1186/1743-0003-10-108,PMID: 24156340Ganzer PD, Darrow MJ, Meyers EC, Solorzano BR,Ruiz AD, Robertson NM, Adcock KS, James JT, JeongHS, Becker AM, Goldberg MP, Pruitt DT, Hays SA,Kilgard MP, Rennaker RL. 2018. Closed-loopneuromodulation restores network connectivity andmotor control after spinal cord injury. eLife 7:e32058.DOI: https://doi.org/10.7554/eLife.32058, PMID: 29533186Hays SA. 2016. Enhancing rehabilitative therapies withvagus nerve stimulation. Neurotherapeutics 13:382–394. DOI: https://doi.org/10.1007/s13311-015-0417-z,PMID: 26671658He K, Huertas M, Hong SZ, Tie X, Hell JW, Shouval H,Kirkwood A. 2015. Distinct eligibility traces for LTP andLTD in cortical synapses. Neuron 88:528–538.DOI: https://doi.org/10.1016/j.neuron.2015.09.037,PMID: 26593091Hulsey DR, Riley JR, Loerwald KW, Rennaker RL,Kilgard MP, Hays SA. 2017. ParametricFigure 1 continuedalso be obtained by performing the stimulation during the task itself. Both vagus nerve and spinal cordstimulations depend on the subject performing a certain task that activates the networks which need reinforcing.However, how these two types of stimulations differ, and how they modulate neural connections, remains unclear.IMAGE CREDITS: Figure courtesy of V Reggie Edgerton.Edgerton and Gad. eLife 2018;7:e35592. DOI: https://doi.org/10.7554/eLife.35592 3 of 4Insight Spinal Cord Injury Is the vagus nerve our neural connectome?characterization of neural activity in the locus coeruleusin response to vagus nerve stimulation. ExperimentalNeurology 289:21–30. DOI: https://doi.org/10.1016/j.expneurol.2016.12.005, PMID: 27988257Edgerton and Gad. eLife 2018;7:e35592. DOI: https://doi.org/10.7554/eLife.35592 4 of 4Insight Spinal Cord Injury Is the vagus nerve our neural connectome?

Is the vagus nerve our neural connectome?

What are the implications of the vagus nerve being able to mediate the time-dependent plasticity of an array of sensorimotor networks?</jats:p

Is the vagus nerve our neural connectome?

Abstract

Similar works

Full text

Available Versions

eScholarship - University of California

Crossref