1. Neuroscience
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Identification of a novel spinal nociceptive-motor gate control for Aδ pain stimuli in rats

  1. Dvir Blivis  Is a corresponding author
  2. Gal Haspel
  3. Philip Z Mannes
  4. Michael James O'Donovan
  5. Michael J Iadarola
  1. National Institutes of Health, United States
Research Article
  • Cited 13
  • Views 1,319
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Cite this article as: eLife 2017;6:e23584 doi: 10.7554/eLife.23584

Abstract

Physiological responses to nociceptive stimuli are initiated within tens of milliseconds, but the corresponding sub-second behavioral responses have not been adequately explored in awake, unrestrained animals. A detailed understanding of these responses is crucial for progress in pain neurobiology. Here, high-speed videography during nociceptive Aδ fiber stimulation demonstrated engagement of a multi-segmental motor program coincident with, or even preceding, withdrawal of the stimulated paw. The motor program included early head orientation and adjustments of the torso and un-stimulated paws. Moreover, we observed a remarkably potent gating mechanism when the animal was standing on its hindlimbs and which was partially dependent on the endogenous opioid system. These data reveal a profound, immediate and precise integration of nociceptive inputs with ongoing motor activities leading to the initiation of complex, yet behaviorally appropriate, response patterns and the mobilization of a new type of analgesic mechanism within this early temporal nociceptive window.

Article and author information

Author details

  1. Dvir Blivis

    Developmental Neurobiology Section, Laboratory of Neural Control, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
    For correspondence
    blivisd@ninds.nih.gov
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6203-7325
  2. Gal Haspel

    Developmental Neurobiology Section, Laboratory of Neural Control, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Newark, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Philip Z Mannes

    Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Michael James O'Donovan

    Developmental Neurobiology Section, Laboratory of Neural Control, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2487-7547
  5. Michael J Iadarola

    Department of Perioperative Medicine, National Institutes of Health, Bethesda, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7188-9810

Funding

National Institute of Neurological Disorders and Stroke (Intramural Research Program)

  • Dvir Blivis
  • Gal Haspel
  • Michael James O'Donovan

National Institutes of Health (Clinical Center Intramural Research Program)

  • Michael J Iadarola

National Institute of Dental and Craniofacial Research (Intramural Research Program)

  • Philip Z Mannes
  • Michael J Iadarola

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled and procedures conducted according to approved animal care and use committee (ACUC) protocol (#10-555).

Reviewing Editor

  1. Peggy Mason, University of Chicago, United States

Publication history

  1. Received: November 23, 2016
  2. Accepted: May 22, 2017
  3. Accepted Manuscript published: May 24, 2017 (version 1)
  4. Accepted Manuscript updated: May 26, 2017 (version 2)
  5. Accepted Manuscript updated: June 6, 2017 (version 3)
  6. Version of Record published: June 14, 2017 (version 4)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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    Motoneurons (MNs) control muscle contractions, and their recruitment by premotor circuits is tuned to produce accurate motor behaviours. To understand how these circuits coordinate movement across and between joints, it is necessary to understand whether spinal neurons pre-synaptic to motor pools have divergent projections to more than one MN population. Here, we used modified rabies virus tracing in mice to investigate premotor interneurons projecting to synergist flexor or extensor MNs, as well as those projecting to antagonist pairs of muscles controlling the ankle joint. We show that similar proportions of premotor neurons diverge to synergist and antagonist motor pools. Divergent premotor neurons were seen throughout the spinal cord, with decreasing numbers but increasing proportion with distance from the hindlimb enlargement. In the cervical cord, divergent long descending propriospinal neurons were found in contralateral lamina VIII, had large somata, were neither glycinergic, nor cholinergic, and projected to both lumbar and cervical MNs. We conclude that distributed spinal premotor neurons coordinate activity across multiple motor pools and that there are spinal neurons mediating co-contraction of antagonist muscles.

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    Takamitsu Watanabe
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    The prefrontal cortex (PFC) is thought to orchestrate cognitive dynamics. However, in tests of bistable visual perception, no direct evidence supporting such presumable causal roles of the PFC has been reported except for a recent work. Here, using a novel brain-state-dependent neural stimulation system, we identified causal effects on percept dynamics in three PFC activities—right frontal eye fields, dorsolateral PFC (DLPFC), and inferior frontal cortex (IFC). The causality is behaviourally detectable only when we track brain state dynamics and modulate the PFC activity in brain-state-/state-history-dependent manners. The behavioural effects are underpinned by transient neural changes in the brain state dynamics, and such neural effects are quantitatively explainable by structural transformations of the hypothetical energy landscapes. Moreover, these findings indicate distinct functions of the three PFC areas: in particular, the DLPFC enhances the integration of two PFC-active brain states, whereas IFC promotes the functional segregation between them. This work resolves the controversy over the PFC roles in spontaneous perceptual switching and underlines brain state dynamics in fine investigations of brain-behaviour causality.