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.

Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC

Abstract

Fear can be acquired vicariously through social observation of others suffering from aversive stimuli. We found that mice (observers) developed freezing behavior by observing other mice (demonstrators) receive repetitive foot shocks. Observers had higher fear responses when demonstrators were socially related to themselves, such as siblings or mating partners. Inactivation of anterior cingulate cortex (ACC) and parafascicular or mediodorsal thalamic nuclei, which comprise the medial pain system representing pain affection, substantially impaired this observational fear learning, whereas inactivation of sensory thalamic nuclei had no effect. The ACC neuronal activities were increased and synchronized with those of the lateral amygdala at theta rhythm frequency during this learning. Furthermore, an ACC-limited deletion of Cav1.2 Ca2+ channels in mice impaired observational fear learning and reduced behavioral pain responses. These results demonstrate the functional involvement of the affective pain system and Cav1.2 channels of the ACC in observational social fear.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: Observational fear learning in the mouse.
Figure 2: Observational fear learning with female mating partners as demonstrators: effect of the duration of co-housing period (familiarity).
Figure 3: The ACC and MITN are involved in observational fear learning.
Figure 4: The ACC is involved in the acquisition of observational fear, but not in memory retrieval of observational fear and in classical fear conditioning.
Figure 5: Synchronized theta activity between the ACC and lateral amygdala during learning of fear by observation.
Figure 6: Cav1.2ACC/Cre mice showed impaired observational fear learning and reduced pain responses.

References

  1. Olsson, A. & Phelps, E.A. Social learning of fear. Nat. Neurosci. 10, 1095–1102 (2007).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  3. Phelps, E.A. & LeDoux, J.E. Contributions of the amygdala to emotion processing: from animal models to human behavior. Neuron 48, 175–187 (2005).

    Article  CAS  Google Scholar 

  4. Adolphs, R. Cognitive neuroscience of human social behavior. Nat. Rev. Neurosci. 4, 165–178 (2003).

    Article  CAS  Google Scholar 

  5. Frith, C.D. Social cognition. Phil. Trans. R. Soc. Lond. B 363, 2033–2039 (2008).

    Article  Google Scholar 

  6. Hooker, C.I., Germine, L.T., Knight, R.T. & D'Esposito, M. Amygdala response to facial expressions reflects emotional learning. J. Neurosci. 26, 8915–8922 (2006).

    Article  CAS  Google Scholar 

  7. Mineka, S. & Cook, M. Mechanisms involved in the observational conditioning of fear. J. Exp. Psychol. Gen. 122, 23–38 (1993).

    Article  CAS  Google Scholar 

  8. Olsson, A., Nearing, K.I. & Phelps, E.A. Learning fears by observing others: the neural systems of social fear transmission. Soc. Cogn. Affect. Neurosci. 2, 3–11 (2007).

    Article  Google Scholar 

  9. Olsson, A. & Phelps, E.A. Learned fear of “unseen” faces after Pavlovian, observational, and instructed fear. Psychol. Sci. 15, 822–828 (2004).

    Article  Google Scholar 

  10. Adolphs, R. et al. A mechanism for impaired fear recognition after amygdala damage. Nature 433, 68–72 (2005).

    Article  CAS  Google Scholar 

  11. Whalen, P.J. et al. Masked presentations of emotional facial expressions modulate amygdala activity without explicit knowledge. J. Neurosci. 18, 411–418 (1998).

    Article  CAS  Google Scholar 

  12. Miller, R.E., Murphy, J.V. & Mirsky, I.A. Non-verbal communication of affect. J. Clin. Psychol. 15, 155–158 (1959).

    Article  CAS  Google Scholar 

  13. Rice, G.E. & Gainer, P. “Altruism” in the albino rat. J. Comp. Physiol. Psychol. 55, 123–125 (1962).

    Article  CAS  Google Scholar 

  14. Church, R.M. Emotional reactions of rats to the pain of others. J. Comp. Physiol. Psychol. 52, 132–134 (1959).

    Article  CAS  Google Scholar 

  15. Chen, Q., Panksepp, J.B. & Lahvis, G.P. Empathy is moderated by genetic background in mice. PLoS One 4, e4387 (2009).

    Article  Google Scholar 

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

    Article  CAS  Google Scholar 

  17. Vogt, B.A. Pain and emotion interactions in subregions of the cingulate gyrus. Nat. Rev. Neurosci. 6, 533–544 (2005).

    Article  CAS  Google Scholar 

  18. Bush, G., Luu, P. & Posner, M.I. Cognitive and emotional influences in anterior cingulate cortex. Trends Cogn. Sci. 4, 215–222 (2000).

    Article  CAS  Google Scholar 

  19. Devinsky, O., Morrell, M.J. & Vogt, B.A. Contributions of anterior cingulate cortex to behavior. Brain 118, 279–306 (1995).

    Article  Google Scholar 

  20. Morrison, I. & Downing, P.E. Organization of felt and seen pain responses in anterior cingulate cortex. Neuroimage 37, 642–651 (2007).

    Article  Google Scholar 

  21. Gao, Y.J., Ren, W.H., Zhang, Y.Q. & Zhao, Z.Q. Contributions of the anterior cingulate cortex and amygdala to pain- and fear-conditioned place avoidance in rats. Pain 110, 343–353 (2004).

    Article  Google Scholar 

  22. 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 

  23. LaGraize, S.C. et al. Differential effect of anterior cingulate cortex lesion on mechanical hypersensitivity and escape/avoidance behavior in an animal model of neuropathic pain. Exp. Neurol. 188, 139–148 (2004).

    Article  Google Scholar 

  24. Jackson, P.L., Meltzoff, A.N. & Decety, J. How do we perceive the pain of others? A window into the neural processes involved in empathy. Neuroimage 24, 771–779 (2005).

    Article  Google Scholar 

  25. Singer, T. et al. Empathy for pain involves the affective but not sensory components of pain. Science 303, 1157–1162 (2004).

    Article  CAS  Google Scholar 

  26. Apkarian, A.V. Pain perception in relation to emotional learning. Curr. Opin. Neurobiol. 18, 464–468 (2008).

    Article  CAS  Google Scholar 

  27. Auvray, M., Myin, E. & Spence, C. The sensory-discriminative and affective-motivational aspects of pain. Neurosci. Biobehav. Rev. 34, 214–223 (2010).

    Article  Google Scholar 

  28. Day, M. et al. Stimulation of 5-HT(2) receptors in prefrontal pyramidal neurons inhibits Cav1.2 L-type Ca2+ currents via a PLCβ/IP3/calcineurin signaling cascade. J. Neurophysiol. 87, 2490–2504 (2002).

    Article  CAS  Google Scholar 

  29. Liauw, J., Wu, L.J. & Zhuo, M. Calcium-stimulated adenylyl cyclases required for long-term potentiation in the anterior cingulate cortex. J. Neurophysiol. 94, 878–882 (2005).

    Article  CAS  Google Scholar 

  30. Meredith, R.M. et al. Increased threshold for spike-timing-dependent plasticity is caused by unreliable calcium signaling in mice lacking fragile X gene FMR1. Neuron 54, 627–638 (2007).

    Article  CAS  Google Scholar 

  31. Moosmang, S. et al. Role of hippocampal Cav1.2 Ca2+ channels in NMDA receptor–independent synaptic plasticity and spatial memory. J. Neurosci. 25, 9883–9892 (2005).

    Article  CAS  Google Scholar 

  32. Wiltgen, B.J. & Silva, A.J. Memory for context becomes less specific with time. Learn. Mem. 14, 313–317 (2007).

    Article  Google Scholar 

  33. Lee, H.J., Choi, J.S., Brown, T.H. & Kim, J.J. Amygdalar NMDA receptors are critical for the expression of multiple conditioned fear responses. J. Neurosci. 21, 4116–4124 (2001).

    Article  CAS  Google Scholar 

  34. Bissière, S. et al. The rostral anterior cingulate cortex modulates the efficiency of amygdala-dependent fear learning. Biol. Psychiatry 63, 821–831 (2008).

    Article  Google Scholar 

  35. Seidenbecher, T., Laxmi, T.R., Stork, O. & Pape, H.C. Amygdalar and hippocampal theta rhythm synchronization during fear memory retrieval. Science 301, 846–850 (2003).

    Article  CAS  Google Scholar 

  36. Jo, D. et al. Epigenetic regulation of gene structure and function with a cell-permeable Cre recombinase. Nat. Biotechnol. 19, 929–933 (2001).

    Article  CAS  Google Scholar 

  37. Millan, M.J. The induction of pain: an integrative review. Prog. Neurobiol. 57, 1–164 (1999).

    Article  CAS  Google Scholar 

  38. Han, C.J. et al. Trace but not delay fear conditioning requires attention and the anterior cingulate cortex. Proc. Natl. Acad. Sci. USA 100, 13087–13092 (2003).

    Article  CAS  Google Scholar 

  39. Johansen, J.P. & Fields, H.L. Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat. Neurosci. 7, 398–403 (2004).

    Article  CAS  Google Scholar 

  40. Malin, E.L. & McGaugh, J.L. Differential involvement of the hippocampus, anterior cingulate cortex and basolateral amygdala in memory for context and footshock. Proc. Natl. Acad. Sci. USA 103, 1959–1963 (2006).

    Article  CAS  Google Scholar 

  41. Singer, W. Neuronal synchrony: a versatile code for the definition of relations? Neuron 24, 49–65, 111–125 (1999).

    Article  CAS  Google Scholar 

  42. Varela, F., Lachaux, J.P., Rodriguez, E. & Martinerie, J. The brainweb: phase synchronization and large-scale integration. Nat. Rev. Neurosci. 2, 229–239 (2001).

    Article  CAS  Google Scholar 

  43. Raghavachari, S. et al. Theta oscillations in human cortex during a working-memory task: evidence for local generators. J. Neurophysiol. 95, 1630–1638 (2006).

    Article  CAS  Google Scholar 

  44. Sarnthein, J. et al. Synchronization between prefrontal and posterior association cortex during human working memory. Proc. Natl. Acad. Sci. USA 95, 7092–7096 (1998).

    Article  CAS  Google Scholar 

  45. Mizuhara, H. & Yamaguchi, Y. Human cortical circuits for central executive function emerge by theta phase synchronization. Neuroimage 36, 232–244 (2007).

    Article  Google Scholar 

  46. Preston, S.D. & de Waal, F.B. Empathy: its ultimate and proximate bases. Behav. Brain Sci. 25, 1–20, discussion 20–71 (2002).

    Google Scholar 

  47. Hoffman, M.L. Empathy, its development and prosocial implications. Nebr. Symp. Motiv. 25, 169–217 (1977).

    CAS  PubMed  Google Scholar 

  48. Langford, D.J. et al. Social modulation of pain as evidence for empathy in mice. Science 312, 1967–1970 (2006).

    Article  CAS  Google Scholar 

  49. Phillips, M.L., Drevets, W.C., Rauch, S.L. & Lane, R. Neurobiology of emotion perception II. Implications for major psychiatric disorders. Biol. Psychiatry 54, 515–528 (2003).

    Article  Google Scholar 

  50. Seisenberger, C. et al. Functional embryonic cardiomyocytes after disruption of the L-type alpha1C (Cav1.2) calcium channel gene in the mouse. J. Biol. Chem. 275, 39193–39199 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank K. Lee for help with Matlab analysis. This work was supported by the National Honor Scientist program of Korea and the Center of Excellence program from the Korea Institute of Science and Technology.

Author information

Authors and Affiliations

Authors

Contributions

D. Jeon and H.-S.S. designed the experiments. D. Jeon purified Cre protein. D. Jo and H.E.R. made and provided the vector containing His6-NLS-Cre-MTS. D. Jeon, S.K. and M.C. performed surgeries, microinjections and immunostainings and analyzed the data. D. Jeon and S.K. performed in vivo electrophysiology. S.-Y.L., D.R. and J.-P. K. generated the Cav1.2 conditional mice. D. Jeon and H.-S.S. wrote the manuscript. All of the authors commented on the manuscript.

Corresponding author

Correspondence to Hee-Sup Shin.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–11 and Supplementary Discussion (PDF 618 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jeon, D., Kim, S., Chetana, M. et al. Observational fear learning involves affective pain system and Cav1.2 Ca2+ channels in ACC. Nat Neurosci 13, 482–488 (2010). https://doi.org/10.1038/nn.2504

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.2504

This article is cited by

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