Abstract

The identity of cortical circuits mediating nociception and pain is largely unclear. The cingulate cortex is consistently activated during pain, but the functional specificity of cingulate divisions, the roles at distinct temporal phases of central plasticity and the underlying circuitry are unknown. Here we show in mice that the midcingulate division of the cingulate cortex (MCC) does not mediate acute pain sensation and pain affect, but gates sensory hypersensitivity by acting in a wide cortical and subcortical network. Within this complex network, we identified an afferent MCC–posterior insula pathway that can induce and maintain nociceptive hypersensitivity in the absence of conditioned peripheral noxious drive. This facilitation of nociception is brought about by recruitment of descending serotonergic facilitatory projections to the spinal cord. These results have implications for our understanding of neuronal mechanisms facilitating the transition from acute to long-lasting pain.

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Acknowledgements

We thank R. LeFaucheur for secretarial help, as well as N. Gehrig, V. Buchert, L. Brenner, H.-J. Wrede, D. Baumgartl-Ahlert and K. Meyer for technical assistance. We are grateful to the Interdisciplinary Neurobehavioral Core Facility in Heidelberg for support with behavioral experiments. We gratefully acknowledge funding in form of SFB1158 grants from the Deutsche Forschungsgemeinschaft (DFG) to R.K. (project B01), T.K. (project B08), R.S. (project A05) and H.F. (project B07), European Research Council (ERC) Advanced Investigator grants to R.K. (Pain Plasticity 294293) and H.F. (Phantommind 230249) and DFG funding via the Excellence Cluster CellNetworks (Ectop funding to R.K. and H.F.). We acknowledge support from the European Molecular Biology Organization (EMBO) to L.L.T. in the form of an EMBO long-term postdoctoral fellowship.

Author information

Author notes

    • Patric Pelzer
    •  & Wannan Tang

    Present addresses: Letten Centre and GliaLab, Department of Physiology, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway (W.T.) and Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany (P.P.).

Affiliations

  1. Institute of Pharmacology, Heidelberg University, Heidelberg, Germany.

    • Linette Liqi Tan
    • , Céline Heinl
    • , Vijayan Gangadharan
    •  & Rohini Kuner
  2. Department of Functional Neuroanatomy, Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.

    • Patric Pelzer
    •  & Thomas Kuner
  3. Max Planck Institute for Medical Research, Department of Molecular Neurobiology, Heidelberg, Germany.

    • Wannan Tang
    •  & Rolf Sprengel
  4. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.

    • Herta Flor
  5. CellNetworks Cluster of Excellence, Heidelberg University, Heidelberg, Germany.

    • Herta Flor
    • , Thomas Kuner
    •  & Rohini Kuner
  6. Max Planck Research Group at the Institute for Anatomy and Cell Biology, Heidelberg University, Heidelberg, Germany.

    • Rolf Sprengel

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Contributions

L.L.T., R.S., H.F., T.K. and R.K. were involved in manuscript preparation. L.L.T. conducted the experiments and analyzed data. R.K. designed the study and wrote the manuscript. W.T. generated the viruses; V.G. helped with behavioral experiments; C.H. and P.P. performed electrophysiology experiments.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rohini Kuner.

Integrated supplementary information

Supplementary figures

  1. 1.

    Atlas representations of the midcingulate (MCC) region targeted in this study compared against the anterior cingulate (ACC) region commonly reported.

  2. 2.

    Cellular properties of opsin- and control GFP-expressing neurons obtained from patch clamp whole-cell recordings performed in slices from the MCC.

  3. 3.

    Lack of phototoxicity in morphological analyses on opsin-expressing cortical sections.

  4. 4.

    Fos expression in the MCC after capsaicin injection in the hindpaw.

  5. 5.

    Optogenetic modulation of activity in the MCC and/or the hind limb region of the primary somatosensory cortex (S1HL) on capsaicin-evoked nocifensive behaviors and basal mechanical sensitivities of the hindpaws.

  6. 6.

    Effects of cortical illumination on paw mechanical sensitivity of control animals.

  7. 7.

    Effects of silencing the MCC or hind limb area of the primary somatosensory (S1HL) activity on capsaicin-evoked secondary mechanical hypersensitivity in the paw.

  8. 8.

    Effects of optogenetic inhibition and activation in the MCC on paw mechanical withdrawal responses.

  9. 9.

    Functional characterization of rAVV-CaMKII-ChR2 expression in the cortex.

  10. 10.

    Effects of MCC stimulation on mechanical withdrawal responses in hindpaws.

  11. 11.

    Quantification of Fos-positive cells in various cortical regions.

  12. 12.

    Example of Fos downregulation in the PI upon inhibition of the MCC in the capsaicin model.

  13. 13.

    Quantification and examples of Fos expression in the thalamus upon manipulation of activity in the MCC.

  14. 14.

    Mechanical behavioral responses of hindpaws upon silencing activity of the MCC–PI pathway or MCC–NAc pathway, or in the PI directly.

  15. 15.

    Viral tracing examples showing projections of excitatory neurons from the PI within the raphe nucleus (RMg) regions.

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DOI

https://doi.org/10.1038/nn.4645

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