Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal

Nature Neuroscience volume 7, pages 398–403 (2004)Cite this article

This article has been updated

Abstract

Noxious stimuli have motivational power and can support associative learning, but the neural circuitry mediating such avoidance learning is poorly understood. The anterior cingulate cortex (ACC) is implicated in the affective response to noxious stimuli and the motivational properties of conditioned stimuli that predict noxious stimulation. Using conditioned place aversion (CPA) in rats, we found that excitatory amino acid microinjection into the ACC during conditioning produces avoidance learning in the absence of a peripheral noxious stimulus. Furthermore, microinjection of an excitatory amino acid antagonist into the ACC during conditioning blocked learning elicited by a noxious stimulus. ACC lesions made after conditioning did not impair expression of CPA. Thus, ACC neuronal activity is necessary and sufficient for noxious stimuli to produce an aversive teaching signal. Our results support the idea that a shared ACC pathway mediates both pain-induced negative affect and a nociceptor-driven aversive teaching signal.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: ACC lesions after training do not affect expression of place aversion.
Figure 2: Intra-r-ACC microinjection of the ionotropic glutamate receptor antagonist kynurenic acid (KyA) blocks F-CPA.
Figure 3: CPA is produced by glutamatergic stimulation of the r-ACC.

Change history

  • 14 March 2004

    appended aop PDF with erratum PDF (will be corrected for print issue), updated Figure 2, and placed footnote in SGML at all occurrences of Figure 2

Notes

  1. *Note: In the version of this article initially published online, the y-axis label in Fig. 2a is incorrect. The correct label should be (pre-conditioning -- post-conditioning). This error has been corrected for the HTML and print versions of this article.

References

  1. Kandel, E., Schwartz, J. & Jessel, T. Principles of Neural Science (McGraw-Hill, New York, 2000).

    Google Scholar 

  2. LeDoux, J.E. Emotion circuits in the brain. Annu. Rev. Neurosci. 23, 155–184 (2000).

    Article  CAS  Google Scholar 

  3. Quirk, G.J., Repa, C. & LeDoux, J.E. Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995).

    Article  CAS  Google Scholar 

  4. Rosenkranz, J.A. & Grace, A.A. Dopamine-mediated modulation of odour-evoked amygdala potentials during pavlovian conditioning. Nature 417, 282–287 (2002).

    Article  CAS  Google Scholar 

  5. Fields, H.L. Pain: an unpleasant topic. Pain 6 (Suppl.), S61–S69 (1999).

    Article  Google Scholar 

  6. Vogt, B.A. & Sikes, R.W. The medial pain system, cingulate cortex, and parallel processing of nociceptive information. Prog. Brain Res. 122, 223–235 (2000).

    Article  CAS  Google Scholar 

  7. Price, D.D. Psychological and neural mechanisms of the affective dimension of pain. Science 288, 1769–1772 (2000).

    Article  CAS  Google Scholar 

  8. Treede, R.D., Kenshalo, D.R., Gracely, R.H. & Jones, A.K. The cortical representation of pain. Pain 79, 105–111 (1999).

    Article  CAS  Google Scholar 

  9. Casey, K.L. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc. Natl. Acad. Sci. USA 96, 7668–7674 (1999).

    Article  CAS  Google Scholar 

  10. Cliffer, K.D., Burstein, R. & Giesler, G.J. Jr. Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats. J. Neurosci. 11, 852–868 (1991).

    Article  CAS  Google Scholar 

  11. Peschanski, M. & Ralston, H.J. 3rd. Light and electron microscopic evidence of transneuronal labeling with WGA-HRP to trace somatosensory pathways to the thalamus. J. Comp. Neurol. 236, 29–41 (1985).

    Article  CAS  Google Scholar 

  12. Berendse, H.W. & Groenewegen, H.J. Restricted cortical termination fields of the midline and intralaminar thalamic nuclei in the rat. Neuroscience 42, 73–102 (1991).

    Article  CAS  Google Scholar 

  13. Sikes, R.W. & Vogt, B.A. Nociceptive neurons in area 24 of rabbit cingulate cortex. J. Neurophysiol. 68, 1720–1732 (1992).

    Article  CAS  Google Scholar 

  14. Hsu, M.M. & Shyu, B.C. Electrophysiological study of the connection between medial thalamus and anterior cingulate cortex in the rat. Neuroreport 8, 2701–2707 (1997).

    Article  CAS  Google Scholar 

  15. Craig, A.D. Pain mechanisms: labeled lines versus convergence in central processing. Annu. Rev. Neurosci. 26, 1–30 (2003).

    Article  CAS  Google Scholar 

  16. Rainville, P., Duncan, G.H., Price, D.D., Carrier, B. & Bushnell, M.C. Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science 277, 968–971 (1997).

    Article  CAS  Google Scholar 

  17. Hutchison, W.D., Davis, K.D., Lozano, A.M., Tasker, R.R. & Dostrovsky, J.O. Pain-related neurons in the human cingulate cortex. Nat. Neurosci. 2, 403–405 (1999).

    Article  CAS  Google Scholar 

  18. Koyama, T., Tanaka, Y.Z. & Mikami, A. Nociceptive neurons in the macaque anterior cingulate activate during anticipation of pain. Neuroreport 9, 2663–2667 (1998).

    Article  CAS  Google Scholar 

  19. Yamamura, H. et al. Morphological and electrophysiological properties of ACCx nociceptive neurons in rats. Brain Res. 735, 83–92 (1996).

    Article  CAS  Google Scholar 

  20. Foltz, E.L. & White, L.E. Pain relief by frontal cingulumotomy. J. Neurosurg. 19, 89–100 (1962).

    Article  CAS  Google Scholar 

  21. Hurt, R.W. & Ballantine, H.T. Jr. Stereotactic anterior cingulate lesions for persistent pain: a report on 68 cases. Clin. Neurosurg. 21, 334–351 (1974).

    Article  CAS  Google Scholar 

  22. Allen, G.V. & Hopkins, D.A. Mamillary body in the rat: topography and synaptology of projections from the subicular complex, prefrontal cortex, and midbrain tegmentum. J. Comp. Neurol. 286, 311–336 (1989).

    Article  CAS  Google Scholar 

  23. Cassell, M.D. & Wright, D.J. Topography of projections from the medial prefrontal cortex to the amygdala in the rat. Brain Res. Bull. 17, 321–333 (1986).

    Article  CAS  Google Scholar 

  24. Christie, M.J., Summers, R.J., Stephenson, J.A., Cook, C.J. & Beart, P.M. Excitatory amino acid projections to the nucleus accumbens septi in the rat: a retrograde transport study utilizing D[3H]aspartate and [3H]GABA. Neuroscience 22, 425–439 (1987).

    Article  CAS  Google Scholar 

  25. Reep, R.L. & Corwin, J.V. Topographic organization of the striatal and thalamic connections of rat medical agranular cortex. Brain Res. 841, 43–52 (1999).

    Article  CAS  Google Scholar 

  26. Gabriel, M., Kubota, Y., Sparenborg, S., Straube, K. & Vogt, B.A. Effects of cingulate cortical lesions on avoidance learning and training-induced unit activity in rabbits. Exp. Brain Res. 86, 585–600 (1991).

    Article  CAS  Google Scholar 

  27. Salamone, J.D., Cousins, M.S. & Snyder, B.J. Behavioral functions of nucleus accumbens dopamine: empirical and conceptual problems with the anhedonia hypothesis. Neurosci. Biobehav. Rev. 21, 341–359 (1997).

    Article  CAS  Google Scholar 

  28. Johansen, J.P., Fields, H.L. & Manning, B.H. The affective component of pain in rodents: direct evidence for a contribution of the anterior cingulate cortex. Proc. Natl. Acad. Sci. USA 98, 8077–8082 (2001).

    Article  CAS  Google Scholar 

  29. Peretz, E. The effects of lesions of the anterior cingulate cortex on the behavior of the rat. J. Comp. Physiol. Psychol. 53, 540–548 (1960).

    Article  CAS  Google Scholar 

  30. Ploghaus, A. et al. Dissociating pain from its anticipation in the human brain. Science 284, 1979–1981 (1999).

    Article  CAS  Google Scholar 

  31. Takenouchi, K. et al. Emotional and behavioral correlates of the anterior cingulate cortex during associative learning in rats. Neuroscience 93, 1271–1287 (1999).

    Article  CAS  Google Scholar 

  32. Nishijo, H. et al. Single neuron responses in the monkey anterior cingulate cortex during visual discrimination. Neurosci. Lett. 227, 79–82 (1997).

    Article  CAS  Google Scholar 

  33. Gigg, J., Tan, A.M. & Finch, D.M. Glutamatergic excitatory responses of anterior cingulate neurons to stimulation of the mediodorsal thalamus and their regulation by GABA: an in vivo iontophoretic study. Cereb. Cortex 2, 477–484 (1992).

    Article  CAS  Google Scholar 

  34. Puig, S. & Sorkin, L.S. Formalin-evoked activity in identified primary afferent fibers: systemic lidocaine suppresses phase-2 activity. Pain 64, 345–355 (1996).

    Article  CAS  Google Scholar 

  35. Dubuisson, D. & Dennis, S.G. The formalin test: a quantitative study of the analgesic effects of morphine, meperidine, and brain stem stimulation in rats and cats. Pain 4, 161–174 (1977).

    Article  CAS  Google Scholar 

  36. Pastoriza, L.N., Morrow, T.J. & Casey, K.L. Medial frontal cortex lesions selectively attenuate the hot plate response: possible nocifensive apraxia in the rat. Pain 64, 11–17 (1996).

    Article  CAS  Google Scholar 

  37. Vaccarino, A.L. & Melzack, R. Analgesia produced by injection of lidocaine into the anterior cingulum bundle of the rat. Pain 39, 213–219 (1989).

    Article  CAS  Google Scholar 

  38. Donahue, R.R., LaGraize, S.C. & Fuchs, P.N. Electrolytic lesion of the anterior cingulate cortex decreases inflammatory, but not neuropathic nociceptive behavior in rats. Brain Res. 897, 131–138 (2001).

    Article  CAS  Google Scholar 

  39. Morgan, M.A. & LeDoux, J.E. Differential contribution of dorsal and ventral medial prefrontal cortex to the acquisition and extinction of conditioned fear in rats. Behav. Neurosci. 109, 681–688 (1995).

    Article  CAS  Google Scholar 

  40. Barros, D.M. et al. Molecular signaling pathways in the cerebral cortex are required for retrieval of one-trial avoidance learning in rats. Behav. Brain Res. 114, 183–192 (2000).

    Article  CAS  Google Scholar 

  41. Kung, J.C., Su, N.M., Fan, R.J., Chai, S.C. & Shyu, B.C. Contribution of the anterior cingulate cortex to laser-pain conditioning in rats. Brain Res. 970, 58–72 (2003).

    Article  CAS  Google Scholar 

  42. Hardy, S.G. Analgesia elicited by prefrontal stimulation. Brain Res. 339, 281–284 (1985).

    Article  CAS  Google Scholar 

  43. Hardy, S.G. & Haigler, H.J. Prefrontal influences upon the midbrain: a possible route for pain modulation. Brain Res. 339, 285–293 (1985).

    Article  CAS  Google Scholar 

  44. Lee, D.E., Kim, S.J. & Zhuo, M. Comparison of behavioral responses to noxious cold and heat in mice. Brain Res. 845, 117–121 (1999).

    Article  CAS  Google Scholar 

  45. Calejesan, A.A., Kim, S.J. & Zhuo, M. Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. Eur. J. Pain 4, 83–96 (2000).

    Article  CAS  Google Scholar 

  46. Buchanan, S.L. & Powell, D.A. Cingulate cortex: its role in Pavlovian conditioning. J. Comp. Physiol. Psychol. 96, 755–774 (1982).

    Article  CAS  Google Scholar 

  47. Mao, J., Mayer, D.J. & Price, D.D. Patterns of increased brain activity indicative of pain in a rat model of peripheral mononeuropathy. J. Neurosci. 13, 2689–2702 (1993).

    Article  CAS  Google Scholar 

  48. Wei, F., Li, P. & Zhuo, M. Loss of synaptic depression in mammalian anterior cingulate cortex after amputation. J. Neurosci. 19, 9346–9354 (1999).

    Article  CAS  Google Scholar 

  49. Wei, F. & Zhuo, M. Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J. Physiol. 532, 823–833 (2001).

    Article  CAS  Google Scholar 

  50. Manning, B.H. A lateralized deficit in morphine antinociception after unilateral inactivation of the central amygdala. J. Neurosci. 18, 9453–9470 (1998).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank I. Meng for valuable discussions throughout the course of this work. We also thank G. Hjelmstad, J. Levine, J. Mitchell and S. Nicola for reading this manuscript, and C. Evans and C. Bryant for assistance in the completion of this study. Supported by a United States Public Health Service grant NS 21445.

Author information

Author notes

  1. Joshua P Johansen

    Present address: Interdepartmental Ph.D. Program for Neuroscience, UCLA, Los Angeles, California, 90095, USA

Authors and Affiliations

  1. Departments of Neurology and Physiology, University of California, San Francisco, 513 Parnassus Avenue, S-784, San Francisco, 94143-0453, California, USA

    Joshua P Johansen & Howard L Fields

  2. The W.M. Keck Foundation Center for Integrative Neuroscience, University of California, San Francisco, 513 Parnassus Avenue, S-784, San Francisco, 94143-0453, California, USA

    Joshua P Johansen & Howard L Fields

Authors
  1. Joshua P Johansen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Howard L Fields
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Howard L Fields.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Johansen, J., Fields, H. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat Neurosci 7, 398–403 (2004). https://doi.org/10.1038/nn1207

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn1207

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing