Article | Published:

Neural substrates for expectation-modulated fear learning in the amygdala and periaqueductal gray

Nature Neuroscience volume 13, pages 979986 (2010) | Download Citation

Abstract

A form of aversively motivated learning called fear conditioning occurs when a neutral conditioned stimulus is paired with an aversive unconditioned stimulus (UCS). UCS-evoked depolarization of amygdala neurons may instruct Hebbian plasticity that stores memories of the conditioned stimulus–unconditioned stimulus association, but the origin of UCS inputs to the amygdala is unknown. Theory and evidence suggest that instructive UCS inputs to the amygdala will be inhibited when the UCS is expected, but this has not been found during fear conditioning. We investigated neural pathways that relay information about the UCS to the amygdala by recording neurons in the amygdala and periaqueductal gray (PAG) of rats during fear conditioning. UCS-evoked responses in both amygdala and PAG were inhibited by expectation. Pharmacological inactivation of the PAG attenuated UCS-evoked responses in the amygdala and impaired acquisition of fear conditioning, indicating that PAG may be an important part of the pathway that relays instructive signals to the amygdala.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    & Neuronal signaling of fear memory. Nat. Rev. Neurosci. 5, 844–852 (2004).

  2. 2.

    , , , & Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. Learn. Mem. 8, 229–242 (2001).

  3. 3.

    & Emotion, motivation, and the brain: reflex foundations in animal and human research. Prog. Brain Res. 156, 3–29 (2006).

  4. 4.

    & The neuroscience of mammalian associative learning. Annu. Rev. Psychol. 56, 207–234 (2005).

  5. 5.

    , & Fear conditioning and long-term potentiation in the amygdala: what really is the connection? Ann. NY Acad. Sci. 1129, 88–95 (2008).

  6. 6.

    & Dopamine-mediated modulation of odour-evoked amygdala potentials during Pavlovian conditioning. Nature 417, 282–287 (2002).

  7. 7.

    & Differential fear conditioning induces reciprocal changes in the sensory responses of lateral amygdala neurons to the CS(+) and CS(−). Learn. Mem. 7, 97–103 (2000).

  8. 8.

    , & Auditory-evoked spike firing in the lateral amygdala and Pavlovian fear conditioning: mnemonic code or fear bias? Neuron 40, 1013–1022 (2003).

  9. 9.

    et al. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nat. Neurosci. 4, 724–731 (2001).

  10. 10.

    , & Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: parallel recordings in the freely behaving rat. Neuron 15, 1029–1039 (1995).

  11. 11.

    , , & Somatosensory and auditory convergence in the lateral nucleus of the amygdala. Behav. Neurosci. 107, 444–450 (1993).

  12. 12.

    & Fear conditioning to tone, but not to context, is attenuated by lesions of the insular cortex and posterior extension of the intralaminar complex in rats. Behav. Neurosci. 115, 365–375 (2001).

  13. 13.

    & Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies. J. Neurosci. 19, 420–430 (1999).

  14. 14.

    , & Unconditioned stimulus pathways to the amygdala: effects of posterior thalamic and cortical lesions on fear conditioning. Neuroscience 125, 305–315 (2004).

  15. 15.

    Contribution of the ventromedial hypothalamus to generation of the affective dimension of pain. Pain 123, 155–168 (2006).

  16. 16.

    et al. Pavlovian fear memory induced by activation in the anterior cingulate cortex. Mol. Pain 1, 6 (2005).

  17. 17.

    & A theory of pavlovian conditioning: variations in the effectiveness of reinforcement and nonreinforcement. in Classical Conditioning II: Current Research and Theory (eds. Black, A.H. & Prokasy, W.F.) (Appleton-Century-Crofts, New York, 1972).

  18. 18.

    Pavlovian conditioning, negative feedback and blocking: mechanisms that regulate association formation. Neuron 20, 625–627 (1998).

  19. 19.

    & A perceptual-defensive-recuperative model of fear and pain. Behav. Brain Sci. 3, 291–323 (1980).

  20. 20.

    & Predicting danger: the nature, consequences and neural mechanisms of predictive fear learning. Learn. Mem. 13, 245–253 (2006).

  21. 21.

    & Opioid receptors in the midbrain periaqueductal gray regulate prediction errors during Pavlovian fear conditioning. Behav. Neurosci. 120, 313–323 (2006).

  22. 22.

    Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1–27 (1998).

  23. 23.

    , , , & The nature of reinforcement in cerebellar learning. Neurobiol. Learn. Mem. 70, 150–176 (1998).

  24. 24.

    Instructed learning in the auditory localization pathway of the barn owl. Nature 417, 322–328 (2002).

  25. 25.

    et al. Processing of temporal unpredictability in human and animal amygdala. J. Neurosci. 27, 5958–5966 (2007).

  26. 26.

    et al. Dissociable systems for gain- and loss-related value predictions and errors of prediction in the human brain. J. Neurosci. 26, 9530–9537 (2006).

  27. 27.

    , , & Expectation modulates neural responses to pleasant and aversive stimuli in primate amygdala. Neuron 55, 970–984 (2007).

  28. 28.

    et al. Unilateral storage of fear memories by the amygdala. J. Neurosci. 25, 4198–4205 (2005).

  29. 29.

    , , & Postsynaptic receptor trafficking underlying a form of associative learning. Science 308, 83–88 (2005).

  30. 30.

    et al. Neuronal competition and selection during memory formation. Science 316, 457–460 (2007).

  31. 31.

    & Lesions of the periaqueductal gray and rostral ventromedial medulla disrupt antinociceptive but not cardiovascular aversive conditional responses. J. Neurosci. 14, 7099–7108 (1994).

  32. 32.

    , , & Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529 (1988).

  33. 33.

    , & Effects of amygdala, hippocampus, and periaqueductal gray lesions on short- and long-term contextual fear. Behav. Neurosci. 107, 1093–1098 (1993).

  34. 34.

    & Fear-potentiated startle in rats is mediated by neurons in the deep layers of the superior colliculus/deep mesencephalic nucleus of the rostral midbrain through the glutamate non-NMDA receptors. J. Neurosci. 24, 10326–10334 (2004).

  35. 35.

    Attention-like processes in classical conditioning. in Miami Symp. Predictability, Behavior and Aversive Stimulation (ed. Jones, M.R.) 9–32 (University of Miami Press, Miami, 1968).

  36. 36.

    & Associative regulation of Pavlovian fear conditioning: unconditional stimulus intensity, incentive shifts and latent inhibition. J. Exp. Psychol. Anim. Behav. Process. 18, 400–413 (1992).

  37. 37.

    & Reinforcement Learning (MIT Press, Cambridge, Massachusetts, 1998).

  38. 38.

    , , & Neuronal responsiveness to various sensory stimuli, and associative learning in the rat amygdala. Neuroscience 68, 339–361 (1995).

  39. 39.

    The midbrain periaqueductal gray as a coordinator of action in response to fear and anxiety. in The Midbrain Periaqueductal Gray Matter (eds. Depaulis, A. & Bandler, R.) (Plenum, New York, 1991).

  40. 40.

    , & Macromolecular synthesis, distributed synaptic plasticity and fear conditioning. Neurobiol. Learn. Mem. 89, 324–337 (2008).

  41. 41.

    , , , & Spinal afferents to functionally distinct periaqueductal gray columns in the rat: an anterograde and retrograde tracing study. J. Comp. Neurol. 385, 207–229 (1997).

  42. 42.

    & A comparative reappraisal of projections from the superficial laminae of the dorsal horn in the rat: the forebrain. J. Comp. Neurol. 468, 24–56 (2004).

  43. 43.

    , , & Evidence of Pavlovian conditioned fear following electrical stimulation of the periaqueductal grey in the rat. Physiol. Behav. 40, 55–63 (1987).

  44. 44.

    Afferent connections to the amygdaloid complex of the rat with some observations in the cat. III. Afferents from the lower brain stem. J. Comp. Neurol. 202, 335–356 (1981).

  45. 45.

    , & Cortically projecting cells in the periaqueductal gray matter of the rat. A retrograde fluorescent tracer study. Brain Res. 543, 201–212 (1991).

  46. 46.

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

  47. 47.

    et al. Afferent regulation of locus coeruleus neurons: anatomy, physiology and pharmacology. Prog. Brain Res. 88, 47–75 (1991).

  48. 48.

    , , , & Projections from the periaqueductal gray to the rostromedial pericoerulear region and nucleus locus coeruleus: anatomic and physiologic studies. J. Comp. Neurol. 306, 480–494 (1991).

  49. 49.

    The projections of the ventral tegmental area and adjacent regions: a combined fluorescent retrograde tracer and immunofluorescence study in the rat. Brain Res. Bull. 9, 321–353 (1982).

  50. 50.

    & Glutamatergic activation of anterior cingulate cortex produces an aversive teaching signal. Nat. Neurosci. 7, 398–403 (2004).

Download references

Acknowledgements

We are grateful to S. Nicola and A. Welday for comments on an earlier version of the manuscript and M. Fanselow, D. Buonomano, R. Thompson, D. Schiller and Y. Niv for valuable discussions. This work was supported by a National Science Foundation Graduate Research Fellowship to J.P.J. and a National Alliance for Research on Schizophrenia and Depression Young Investigator Award and US National Institutes of Health grant (R01 MH073700-01) to H.T.B.

Author information

Author notes

    • Joshua P Johansen

    Present address: Center for Neural Science, New York University, New York, New York, USA.

    • Joshua P Johansen
    •  & Jason W Tarpley

    These authors contributed equally to this work.

Affiliations

  1. Psychology Department, University of California Los Angeles, Los Angeles, California, USA.

    • Joshua P Johansen
    • , Jason W Tarpley
    •  & Hugh T Blair
  2. Interdepartmental Program in Neuroscience, University of California Los Angeles, Los Angeles, California, USA.

    • Joshua P Johansen
    •  & Jason W Tarpley
  3. Center for Neural Science, New York University, New York, New York, USA.

    • Joseph E LeDoux
  4. The Emotional Brain Institute at the Nathan S. Kline Institute for Psychiatric Research, Orangeburg, New York, USA.

    • Joseph E LeDoux

Authors

  1. Search for Joshua P Johansen in:

  2. Search for Jason W Tarpley in:

  3. Search for Joseph E LeDoux in:

  4. Search for Hugh T Blair in:

Contributions

All authors contributed to the planning and design of the study. Data collection was performed by J.P.J. and J.W.T. Data analysis and writing of the manuscript were performed by J.P.J., J.W.T. and H.T.B. The neurophysiology and fear conditioning experiments were conducted in the laboratory of H.T.B. and the blocking experiments were conducted in the laboratory of J.E.L.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Jason W Tarpley or Hugh T Blair.

Supplementary information

PDF files

  1. 1.

    Supplementary Text and Figures

    Supplementary Figures 1–12 and Supplementary Discussion

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/nn.2594

Further reading