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.

  • Review Article
  • Published:

Parallels between cerebellum- and amygdala-dependent conditioning

Nature Reviews Neuroscience volume 3, pages 122–131 (2002)Cite this article

Key Points

  • Some of the clearest evidence on the localization of memory within the mammalian brain has come from studies of associative learning, especially through the use of classical or Pavlovian conditioning, in which animals learn to express a conditioned response to a predictive or conditioned stimulus (CS) paired with an unconditioned stimulus (US). This review focuses on two of the most widely used forms of Pavlovian learning: eyelid and fear conditioning.

  • In eyelid conditioning, the deep cerebellar nuclei and overlying cerebellar cortex seem to mediate the acquisition and storage of discrete motor memories. By contrast, evidence from fear conditioning points to the lateral nucleus of the amygdala (LA) as a key component of the brain system that is responsible for the formation of aversive emotional memories.

  • Despite being mediated by different brain systems, these forms of learning might use a similar sequence of events to form new memories. Recent data point to a 'trigger-and-storage' model, in which the initial encoding and subsequent long-term storage of memory are mediated by separate groups of neurons.

  • Two sets of cerebellar neurons, the Purkinje cells and neurons in the anterior interpositus nucleus, change their activity during eyelid conditioning and so represent potential sites of plasticity. Recent evidence indicates that the cerebellar cortex might participate in the initiation of learning, whereas the deep cerebellar nuclei are more involved in the long-term storage of memory.

  • The dorsal region of the LA (LAd) is a site of CS–US convergence. Two distinct sets of neurons in the LAd could contribute differentially to the initiation and storage of fear-conditioning memories. Cells in the dorsal tip of the LAd develop conditioning-induced enhancement of their auditory responses very early in training, but cells in more ventral regions take longer to reach maximal response levels.

  • Several important questions remain unanswered, including whether there is complete transfer of memory from the 'soft' trigger cells to the 'hard' storage cells. It is also not known whether plasticity in the trigger cells is required for the induction of plasticity in the storage cells, or if the induction of soft and hard plasticity can proceed independently, but at different rates.

Abstract

Recent evidence from cerebellum-dependent motor learning and amygdala-dependent fear conditioning indicates that, despite being mediated by different brain systems, these forms of learning might use a similar sequence of events to form new memories. In each case, learning seems to induce changes in two different groups of neurons. Changes in the first class of cells are induced very rapidly during the initial stages of learning, whereas changes in the second class of cells develop more slowly and are resistant to extinction. So, anatomically distinct cell populations might contribute differentially to the initial encoding and the long-term storage of memory in these two systems.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Neural circuits engaged during eyelid conditioning.
Figure 2: Neural circuits engaged during fear conditioning.
Figure 3: The trigger-and-storage model.

Similar content being viewed by others

References

  1. Pavlov, I. P. Conditioned Reflexes. An Investigation of the Physiological Activity of the Cerebral Cortex (Oxford Univ. Press, London, 1927).

    Google Scholar 

  2. Gormezano, I., Prokasy, W. F. & Thompson, R. F. Classical Conditioning (Lawrence Erlbaum Associates, Hillsdale, New Jersey, 1987).

    Google Scholar 

  3. Gormezano, I., Kehoe, E. J. & Marshall, B. S. Twenty years of classical conditioning research with the rabbit. Prog. Psychobiol. Physiol. Psychol. 10, 197–275 (1983).

    Google Scholar 

  4. Schneiderman, N., Fuentes, I. & Gormezano, I. Acquisition and extinction of the classically conditioned eyelid response in the albino rabbit. Science 136, 650–652 (1962).

    Article  CAS  PubMed  Google Scholar 

  5. Mauk, M. D. & Ruiz, B. P. Learning-dependent timing of Pavlovian eyelid responses: differential conditioning using multiple interstimulus intervals. Behav. Neurosci. 106, 666–681 (1992).

    Article  CAS  PubMed  Google Scholar 

  6. Millenson, J. R., Kehoe, E. J. & Gormezano, I. Classical conditioning of the rabbit's nictitating membrane response under fixed and mixed CS–US intervals. Learn. Motiv. 8, 351–366 (1977).

    Article  Google Scholar 

  7. Schreurs, B. G. Long-term memory and extinction of the classically conditioned rabbit nictitating membrane response. Learn. Motiv. 24, 293–302 (1993).

    Article  Google Scholar 

  8. Medina, J. F., Garcia, K. S. & Mauk, M. D. A mechanism for savings in the cerebellum. J. Neurosci. 21, 4081–4089 (2001).Showed that plasticity located outside the cerebellar cortex persists after behavioural extinction. The amount of plasticity that remained after extinction was a reliable predictor of the rate of reacquisition.

    Article  CAS  PubMed  Google Scholar 

  9. Napier, R. M., Macrae, M. & Kehoe, E. J. Rapid reacquisition in conditioning of the rabbit's nictitating membrane response. J. Exp. Psychol. Anim. Behav. Process. 18, 182–192 (1992).

    Article  CAS  PubMed  Google Scholar 

  10. Lennartz, R. C. & Weinberger, N. M. Analysis of response systems in Pavlovian conditioning reveals rapidly versus slowly acquired conditioned responses: support for two factors, implications for behavior and neurobiology. Psychobiology 20, 93–119 (1992).

    Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  12. Brown, J. S., Kalish, H. I. & Farber, I. E. Conditioned fear as revealed by magnitude of startle response to an auditory stimulus. J. Exp. Psychol. 41, 317–328 (1951).

    Article  CAS  PubMed  Google Scholar 

  13. Bolles, R. C. & Fanselow, M. S. A perceptual–defensive–recuperative model of fear and pain. Behav. Brain Sci. 3, 291–323 (1980).

    Article  Google Scholar 

  14. Bouton, M. E. Conditioning, remembering, and forgetting. J. Exp. Psychol. Anim. Behav. Process. 20, 219–231 (1994).

    Article  Google Scholar 

  15. Kim, J. J. & Thompson, R. F. Cerebellar circuits and synaptic mechanisms involved in classical eyeblink conditioning. Trends Neurosci. 20, 177–181 (1997).

    Article  CAS  PubMed  Google Scholar 

  16. Raymond, J. L., Lisberger, S. G. & Mauk, M. D. The cerebellum: a neuronal learning machine? Science 272, 1126–1131 (1996).

    Article  CAS  PubMed  Google Scholar 

  17. Fanselow, M. S. & LeDoux, J. E. Why we think plasticity underlying Pavlovian fear conditioning occurs in the basolateral amygdala. Neuron 23, 229–232 (1999).

    Article  CAS  PubMed  Google Scholar 

  18. Blair, H. T., Schafe, G. E., Bauer, E. P., Rodrigues, S. M. & LeDoux, J. E. Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. Learn. Mem. 8, 229–242 (2001).

    Article  CAS  PubMed  Google Scholar 

  19. Maren, S. Neurobiology of Pavlovian fear conditioning. Annu. Rev. Neurosci. 24, 897–931 (2001).

    Article  CAS  PubMed  Google Scholar 

  20. Aitkin, L. M. & Boyd, J. Acoustic input to the lateral pontine nuclei. Hear. Res. 1, 67–77 (1978).

    Article  CAS  PubMed  Google Scholar 

  21. Eccles, J. C., Ito, M. & Szentágothai, J. The Cerebellum as a Neuronal Machine (Springer, New York, 1967).

    Book  Google Scholar 

  22. Llinas, R. in Handbook of Physiology II. The Nervous System (ed. Brokks, V. B.) 831–976 (Am. Physiol. Soc., Bethesda, Maryland, 1981).

    Google Scholar 

  23. Voogd, J. & Glickstein, M. The anatomy of the cerebellum. Trends Neurosci. 21, 370–375 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Solomon, P. R., Lewis, J. L., LoTurco, J. J., Steinmetz, J. E. & Thompson, R. F. The role of the middle cerebellar peduncle in acquisition and retention of the rabbit's classically conditioned nictitating membrane response. Bull. Psychon. Soc. 24, 74–78 (1986).

    Article  Google Scholar 

  25. Lewis, J. L., LoTurco, J. J. & Solomon, P. R. Lesions of the middle cerebellar peduncle disrupt acquisition and retention of the rabbit's classically conditioned nictitating membrane response. Behav. Neurosci. 101, 151–157 (1987).

    Article  CAS  PubMed  Google Scholar 

  26. Steinmetz, J. E. et al. Classical conditioning of the rabbit eyelid response with a mossy-fiber stimulation CS. I. Pontine nuclei and middle cerebellar peduncle stimulation. Behav. Neurosci. 100, 878–887 (1986).

    Article  CAS  PubMed  Google Scholar 

  27. Hesslow, G., Svensson, P. & Ivarsson, M. Learned movements elicited by direct stimulation of cerebellar mossy fiber afferents. Neuron 24, 179–185 (1999).

    Article  CAS  PubMed  Google Scholar 

  28. Sears, L. L. & Steinmetz, J. E. Dorsal accessory inferior olive activity diminishes during acquisition of the rabbit classically conditioned eyelid response. Brain Res. 545, 114–122 (1991).

    Article  CAS  PubMed  Google Scholar 

  29. Linden, D. J. & Connor, J. A. Cellular mechanisms of long-term depression in the cerebellum. Curr. Opin. Neurobiol. 3, 401–406 (1993).

    Article  CAS  PubMed  Google Scholar 

  30. Ito, M. Cerebellar long-term depression: characterization, signal transduction, and functional roles. Physiol. Rev. 81, 1143–1195 (2001).

    Article  CAS  PubMed  Google Scholar 

  31. McCormick, D. A., Steinmetz, J. E. & Thompson, R. F. Lesions of the inferior olivary complex cause extinction of the classically conditioned eyeblink response. Brain Res. 359, 120–130 (1985).

    Article  CAS  PubMed  Google Scholar 

  32. Yeo, C. H., Hardiman, M. J. & Glickstein, M. Classical conditioning of the nictitating membrane response of the rabbit. IV. Lesions of the inferior olive. Exp. Brain Res. 63, 81–92 (1986).

    Article  CAS  PubMed  Google Scholar 

  33. Welsh, J. P. & Harvey, J. A. Acute inactivation of the inferior olive blocks associative learning. Eur. J. Neurosci. 10, 3321–3332 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Mauk, M. D., Steinmetz, J. E. & Thompson, R. F. Classical conditioning using stimulation of the inferior olive as the unconditioned stimulus. Proc. Natl Acad. Sci. USA 83, 5349–5353 (1986).

    Article  CAS  PubMed  Google Scholar 

  35. Hesslow, G. & Ivarsson, M. Suppression of cerebellar Purkinje cells during conditioned responses in ferrets. Neuroreport 5, 649–652 (1994).

    Article  CAS  PubMed  Google Scholar 

  36. McCormick, D. A. & Thompson, R. F. Neuronal responses of the rabbit cerebellum during acquisition and performance of a classically conditioned nictitating membrane-eyelid response. J. Neurosci. 4, 2811–2822 (1984).The first clear evidence that the cerebellum is involved in eyelid conditioning. Lesions of the cerebellum prevented learning; recording data showed cells within the interpositus nucleus that developed activity resembling the conditioning response; stimulation of those interpositus sites caused eyelid closure.

    Article  CAS  PubMed  Google Scholar 

  37. Berthier, N. E. & Moore, J. W. Activity of deep cerebellar nuclear cells during classical conditioning of nictitating membrane extension in rabbits. Exp. Brain Res. 83, 44–54 (1990).

    Article  CAS  PubMed  Google Scholar 

  38. Berthier, N. E. & Moore, J. W. Cerebellar Purkinje cell activity related to the classically conditioned nictitating membrane response. Exp. Brain Res. 63, 341–350 (1986).

    Article  CAS  PubMed  Google Scholar 

  39. Gould, T. J., Sears, L. L. & Steinmetz, J. E. Possible CS and US pathways for rabbit classical eyelid conditioning: electrophysiological evidence for projections from the pontine nuclei and inferior olive to cerebellar cortex and nuclei. Behav. Neural Biol. 60, 172–185 (1993).

    Article  CAS  PubMed  Google Scholar 

  40. Steinmetz, J. E., Lavond, D. G. & Thompson, R. F. Classical conditioning in rabbits using pontine nucleus stimulation as a conditioned stimulus and inferior olive stimulation as an unconditioned stimulus. Synapse 3, 225–233 (1989).

    Article  CAS  PubMed  Google Scholar 

  41. Middleton, F. A. & Strick, P. L. Cerebellar output channels. Int. Rev. Neurobiol. 41, 61–82 (1997).

    Article  CAS  PubMed  Google Scholar 

  42. Ito, M. The Cerebellum and Neural Control (Raven, New York, 1984).

    Google Scholar 

  43. McCormick, D. A. & Thompson, R. F. Cerebellum: essential involvement in the classically conditioned eyelid response. Science 223, 296–299 (1984).

    Article  CAS  PubMed  Google Scholar 

  44. Shi, C. & Davis, M. Visual pathways involved in fear conditioning measured with fear-potentiated startle: behavioral and anatomic studies. J. Neurosci. 21, 9844–9855 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Linke, R., De Lima, A. D., Schwegler, H. & Pape, H. C. Direct synaptic connections of axons from superior colliculus with identified thalamo-amygdaloid projection neurons in the rat: possible substrates of a subcortical visual pathway to the amygdala. J. Comp. Neurol. 403, 158–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  46. Fanselow, M. S. Contextual fear, Gestalt memories, and the hippocampus. Behav. Brain Res. 110, 73–81 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Anagnostaras, S. G., Gale, G. D. & Fanselow, M. S. Hippocampus and contextual fear conditioning: recent controversies and advances. Hippocampus 11, 8–17 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Mascagni, F., McDonald, A. J. & Coleman, J. R. Corticoamygdaloid and corticocortical projections of the rat temporal cortex: a Phaseolus vulgaris leucoagglutinin study. Neuroscience 57, 697–715 (1993).

    Article  CAS  PubMed  Google Scholar 

  49. Romanski, L. M. & LeDoux, J. E. Information cascade from primary auditory cortex to the amygdala: corticocortical and corticoamygdaloid projections of temporal cortex in the rat. Cereb. Cortex 3, 515–532 (1993).

    Article  CAS  PubMed  Google Scholar 

  50. LeDoux, J. E., Farb, C. & Ruggiero, D. A. Topographic organization of neurons in the acoustic thalamus that project to the amygdala. J. Neurosci. 10, 1043–1054 (1990).

    Article  CAS  PubMed  Google Scholar 

  51. Amaral, D. G., Price, J. L., Pitkänen, A. & Carmichael, S. T. in The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (ed. Aggleton, J. P.) 1–66 (Wiley–Liss, New York, 1992).

    Google Scholar 

  52. McDonald, A. J. Cortical pathways to the mammalian amygdala. Prog. Neurobiol. 55, 257–332 (1998).

    Article  CAS  PubMed  Google Scholar 

  53. LeDoux, J. E., Cicchetti, P., Xagoraris, A. & Romanski, L. M. The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J. Neurosci. 10, 1062–1069 (1990).The first demonstration of the role of the LA in fear conditioning. It shifted the emphasis from the central to the lateral nucleus in the search for sites of plasticity.

    Article  CAS  PubMed  Google Scholar 

  54. Goosens, K. A. & Maren, S. Contextual and auditory fear conditioning are mediated by the lateral, basal, and central amygdaloid nuclei in rats. Learn. Mem. 8, 148–155 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Doron, N. N. & LeDoux, J. E. Cells in the posterior thalamus project to both amygdala and temporal cortex: a quantitative retrograde double-labeling study in the rat. J. Comp. Neurol. 425, 257–274 (2000).

    Article  CAS  PubMed  Google Scholar 

  56. Romanski, L. M. & LeDoux, J. E. Equipotentiality of thalamo-amygdala and thalamo-cortico-amygdala projections as auditory conditioned stimulus pathways. J. Neurosci. 12, 4501–4509 (1992).

    Article  CAS  PubMed  Google Scholar 

  57. Jarrell, T. W., Gentile, C. G., Romanski, L. M., McCabe, P. M. & Schneiderman, N. Involvement of cortical and thalamic auditory regions in retention of differential bradycardia conditioning to acoustic conditioned stimuli in rabbits. Brain Res. 412, 285–294 (1987).

    Article  CAS  PubMed  Google Scholar 

  58. Armony, J. L., Servan-Schreiber, D., Romanski, L. M., Cohen, J. D. & LeDoux, J. E. Stimulus generalization of fear responses: effects of auditory cortex lesions in a computational model and in rats. Cereb. Cortex 7, 157–165 (1997).

    Article  CAS  PubMed  Google Scholar 

  59. Campeau, S. & Davis, M. Involvement of the central nucleus and basolateral complex of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J. Neurosci. 15, 2301–2311 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Shi, C. & Davis, M. Pain pathways involved in fear conditioning measured with fear-potentiated startle: lesion studies. J. Neurosci. 19, 420–430 (1999).The first attempt to map the US pathways to the amygdala. Indicates that as in the case of the auditory CS pathways, the US reaches the amygdala by way of thalamic and cortical somatosensory routes.

    Article  CAS  PubMed  Google Scholar 

  61. Quirk, G. J., Repa, J. 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).The first demonstration of cellular plasticity in the LA. Latencies indicated a role for direct thalamic inputs to the LA from the auditory thalamus.

    Article  CAS  PubMed  Google Scholar 

  62. Quirk, G. J., Armony, J. L. & LeDoux, J. E. Fear conditioning enhances different temporal components of toned-evoked spike trains in auditory cortex and lateral amygdala. Neuron 19, 613–624 (1997).

    Article  CAS  PubMed  Google Scholar 

  63. Morris, J. S., Ohman, A. & Dolan, R. J. A subcortical pathway to the right amygdala mediating 'unseen' fear. Proc. Natl Acad. Sci. USA 96, 1680–1685 (1999).Presented evidence for the existence of a subcortical CS transmission route to the amygdala in the human brain, mirroring the findings in rats.

    Article  CAS  PubMed  Google Scholar 

  64. LeDoux, J. E., Ruggiero, D. A., Forest, R., Stornetta, R. & Reis, D. J. Topographic organization of convergent projections to the thalamus from the inferior colliculus and spinal cord in the rat. J. Comp. Neurol. 264, 123–146 (1987).

    Article  CAS  PubMed  Google Scholar 

  65. Romanski, L. M., LeDoux, J. E., Clugnet, M. C. & Bordi, F. Somatosensory and auditory convergence in the lateral nucleus of the amygdala. Behav. Neurosci. 107, 444–450 (1993).

    Article  CAS  PubMed  Google Scholar 

  66. Turner, B. H. & Zimmer, J. The architecture and some interconnections of the rat amygdala and lateral periallocortex. J. Comp. Neurol. 227, 540–557 (1984).

    Article  CAS  PubMed  Google Scholar 

  67. Bernard, J. F. & Besson, J. M. The spino(trigemino)pontoamygdaloid pathway: electrophysiological evidence for an involvement in pain processes. J. Neurophysiol. 63, 473–489 (1990).

    Article  CAS  PubMed  Google Scholar 

  68. Burstein, R. & Potrebic, S. Retrograde labeling of neurons in the spinal cord that project directly to the amygdala or the orbital cortex in the rat. J. Comp. Neurol. 335, 469–485 (1993).

    Article  CAS  PubMed  Google Scholar 

  69. Pitkanen, A., Savander, V. & LeDoux, J. E. Organization of intra-amygdaloid circuitries in the rat: an emerging framework for understanding functions of the amygdala. Trends Neurosci. 20, 517–523 (1997).

    Article  CAS  PubMed  Google Scholar 

  70. Kapp, B. S., Whalen, P. J., Supple, W. F. & Pascoe, J. P. in The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (ed. Aggleton, J. P.) 229–254 (Wiley–Liss, New York, 1992).

    Google Scholar 

  71. LeDoux, J. E., Iwata, J., Cicchetti, P. & Reis, D. J. Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear. J. Neurosci. 8, 2517–2529 (1988).

    Article  CAS  PubMed  Google Scholar 

  72. Gentile, C. G., Jarrell, T. W., Teich, A., McCabe, P. M. & Schneiderman, N. The role of amygdaloid central nucleus in the retention of differential Pavlovian conditioning of bradycardia in rabbits. Behav. Brain Res. 20, 263–273 (1986).

    Article  CAS  PubMed  Google Scholar 

  73. Davis, M. The role of the amygdala in fear-potentiated startle: implications for animal models of anxiety. Trends Pharmacol. Sci. 13, 35–41 (1992).

    Article  CAS  PubMed  Google Scholar 

  74. Hitchcock, J. & Davis, M. Lesions of the amygdala but not of the cerebellum or red nucleus block conditioned fear as measured with the potentiated startle paradigm. Behav. Neurosci. 100, 11–22 (1986).

    Article  CAS  PubMed  Google Scholar 

  75. Iwata, J., LeDoux, J. E., Meeley, M. P., Arneric, S. & Reis, D. J. Intrinsic neurons in the amygdaloid field projected to by the medial geniculate body mediate emotional responses conditioned to acoustic stimuli. Brain Res. 383, 195–214 (1986).

    Article  CAS  PubMed  Google Scholar 

  76. Kapp, B. S., Frysinger, R. C., Gallagher, M. & Haselton, J. Amygdala central nucleus lesions: effect on heart rate conditioning in the rabbit. Physiol. Behav. 23, 1109–1117 (1979).The first clear demonstration of the role of the amygdala in auditory fear conditioning, and the first clear indication that an amygdala region was involved in such learning by virtue of its anatomical connectivity with areas that control CRs — autonomic responses in this case.

    Article  CAS  PubMed  Google Scholar 

  77. Van de Kar, L. D., Piechowski, R. A., Rittenhouse, P. A. & Gray, T. S. Amygdaloid lesions: differential effect on conditioned stress and immobilization-induced increases in corticosterone and renin secretion. Neuroendocrinology 54, 89–95 (1991).

    Article  CAS  PubMed  Google Scholar 

  78. Pare, D. & Smith, Y. Intrinsic circuitry of the amygdaloid complex: common principles of organization in rats and cats. Trends Neurosci. 21, 240–241 (1998).

    Article  CAS  PubMed  Google Scholar 

  79. Collins, D. R. & Pare, D. Reciprocal changes in the firing probability of lateral and central medial amygdala neurons. J. Neurosci. 19, 836–844 (1999).

    Article  CAS  PubMed  Google Scholar 

  80. Royer, S., Martina, M. & Pare, D. An inhibitory interface gates impulse traffic between the input and output stations of the amygdala. J. Neurosci. 19, 10575–10583 (1999).

    Article  CAS  PubMed  Google Scholar 

  81. Nader, K., Majidishad, P., Amorapanth, P. & LeDoux, J. E. Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning. Learn. Mem. 8, 156–163 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Amorapanth, P., LeDoux, J. E. & Nader, K. Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus. Nature Neurosci. 3, 74–79 (2000).

    Article  CAS  PubMed  Google Scholar 

  83. Majidishad, P., Pelli, D. G. & LeDoux, J. E. Disruption of fear conditioning to contextual stimuli but not to a tone by lesions of the accessory basal nucleus of the amygdala. Soc. Neurosci. Abstr. 22, 1116 (1996).

    Google Scholar 

  84. Killcross, S., Robbins, T. W. & Everitt, B. J. Different types of fear-conditioned behavior mediated by separate nuclei within amygdala. Nature 388, 377–380 (1997).Showed that different routes of information flow in the amygdala might be involved in the control of different types of fear-related response, especially reflexive responses.

    Article  CAS  PubMed  Google Scholar 

  85. Nader, K. & LeDoux, J. E. Is it time in invoke multiple fear learning systems? Trends Cogn. Sci. 1, 241–244 (1997).

    Article  CAS  PubMed  Google Scholar 

  86. Marquis, D. G. & Hilgard, E. R. Conditioned lid responses to light in dogs after removal of the visual cortex. J. Comp. Psychol. 22, 157–178 (1936).

    Article  Google Scholar 

  87. Mauk, M. D. & Thompson, R. F. Retention of classically conditioned eyelid responses following acute decerebration. Brain Res. 403, 89–95 (1987).

    Article  CAS  PubMed  Google Scholar 

  88. Norman, R. J., Buchwald, J. S. & Villablanca, J. R. Classical conditioning with auditory discrimination of the eye blink in decerebrate cats. Science 196, 551–553 (1977).

    Article  CAS  PubMed  Google Scholar 

  89. McCormick, D. A., Clark, G. A., Lavond, D. G. & Thompson, R. F. Initial localization of the memory trace for a basic form of learning. Proc. Natl Acad. Sci. USA 79, 2731–2735 (1982).

    Article  CAS  PubMed  Google Scholar 

  90. Welsh, J. P. & Harvey, J. A. Cerebellar lesions and the nictitating membrane reflex: performance deficits of the conditioned and unconditioned response. J. Neurosci. 9, 299–311 (1989).

    Article  CAS  PubMed  Google Scholar 

  91. Bloedel, J. R. & Bracha, V. On the cerebellum, cutaneomuscular reflexes, movement control and the elusive engrams of memory. Behav. Brain Res. 68, 1–44 (1995).

    Article  CAS  PubMed  Google Scholar 

  92. Steinmetz, J. E. et al. Disruption of classical eyelid conditioning after cerebellar lesions: damage to a memory trace system or a simple performance deficit? J. Neurosci. 12, 4403–4426 (1992).

    Article  CAS  PubMed  Google Scholar 

  93. Krupa, D. J., Thompson, J. K. & Thompson, R. F. Localization of a memory trace in the mammalian brain. Science 260, 989–991 (1993).

    Article  CAS  PubMed  Google Scholar 

  94. Nordholm, A. F., Thompson, J. K., Dersarkissian, C. & Thompson, R. F. Lidocaine infusion in a critical region of cerebellum completely prevents learning of the conditioned eyeblink response. Behav. Neurosci. 107, 882–886 (1993).

    Article  CAS  PubMed  Google Scholar 

  95. Attwell, P. J., Rahman, S. & Yeo, C. H. Acquisition of eyeblink conditioning is critically dependent on normal function in cerebellar cortical lobule HVI. J. Neurosci. 21, 5715–5722 (2001).Pharmacological inactivation of the cerebellar cortex prevented both the acquisition of new responses and the expression of previously acquired responses. By using a reversible lesion technique, the authors were able to rule out a simple performance deficit as the cause of the observed impairment in learning.

    Article  CAS  PubMed  Google Scholar 

  96. Krupa, D. J., Weng, J. & Thompson, R. F. Inactivation of brainstem motor nuclei blocks expression but not acquisition of the rabbit's classically conditioned eyeblink response. Behav. Neurosci. 110, 219–227 (1996).

    Article  CAS  PubMed  Google Scholar 

  97. Krupa, D. J. & Thompson, R. F. Inactivation of the superior cerebellar peduncle blocks expression but not acquisition of the rabbit's classically conditioned eye-blink response. Proc. Natl Acad. Sci. USA 92, 5097–5101 (1995).

    Article  CAS  PubMed  Google Scholar 

  98. Yeo, C. H., Hardiman, M. J. & Glickstein, M. Classical conditioning of the nictitating membrane response of the rabbit. II. Lesions of the cerebellar cortex. Exp. Brain Res. 60, 99–113 (1985).

    Article  CAS  PubMed  Google Scholar 

  99. Yeo, C. H., Hardiman, M. J. & Glickstein, M. Discrete lesions of the cerebellar cortex abolish the classically conditioned nictitating membrane response of the rabbit. Behav. Brain Res. 13, 261–266 (1984).

    Article  CAS  PubMed  Google Scholar 

  100. Perrett, S. P., Ruiz, B. P. & Mauk, M. D. Cerebellar cortex lesions disrupt learning-dependent timing of conditioned eyelid responses. J. Neurosci. 13, 1708–1718 (1993).

    Article  CAS  PubMed  Google Scholar 

  101. Garcia, K. S., Steele, P. M. & Mauk, M. D. Cerebellar cortex lesions prevent acquisition of conditioned eyelid responses. J. Neurosci. 19, 10940–10947 (1999).When cerebellar cortex lesions caused a disruption of response to a previously trained CS1, the same lesions prevented acquisition of responses to a different CS2.

    Article  CAS  PubMed  Google Scholar 

  102. Blanchard, C. D. & Blanchard, R. J. Innate and conditioned reactions to threat in rats with amygdaloid lesions. J. Comp. Physiol. Psychol. 81, 281–290 (1972).

    Article  CAS  PubMed  Google Scholar 

  103. LeDoux, J. E. in The Amygdala: Neurobiological Aspects of Emotion, Memory, and Mental Dysfunction (ed. Aggleton, J. P.) 339–351 (Wiley–Liss, New York, 1992).

    Google Scholar 

  104. LeDoux, J. E., Farb, C. & Romanski, L. Overlapping projections to the amygdala and striatum from auditory processing areas of the thalamus and cortex. Neurosci. Lett. 134, 139–144 (1991).

    Article  CAS  PubMed  Google Scholar 

  105. Bordi, F. & LeDoux, J. Sensory tuning beyond the sensory system: an initial analysis of auditory properties of neurons in the lateral amygdaloid nucleus and overlying areas of the striatum. J. Neurosci. 12, 2493–2503 (1992).

    Article  CAS  PubMed  Google Scholar 

  106. Clugnet, M. C., LeDoux, J. E. & Morrison, S. F. Unit responses evoked in the amygdala and striatum by electrical stimulation of the medial geniculate body. J. Neurosci. 10, 1055–1061 (1990).

    Article  CAS  PubMed  Google Scholar 

  107. Helmstetter, F. J. & Bellgowan, P. S. Effects of muscimol applied to the basolateral amygdala on acquisition and expression of contextual fear conditioning in rats. Behav. Neurosci. 108, 1005–1009 (1994).

    Article  CAS  PubMed  Google Scholar 

  108. Muller, J., Corodimas, K. P., Fridel, Z. & LeDoux, J. E. Functional inactivation of the lateral and basal nuclei of the amygdala by muscimol infusion prevents fear conditioning to an explicit conditioned stimulus and to contextual stimuli. Behav. Neurosci. 111, 683–691 (1997).

    Article  CAS  PubMed  Google Scholar 

  109. McGaugh, J. L. Memory — a century of consolidation. Science 287, 248–251 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Cahill, L., Weinberger, N. M., Roozendaal, B. & McGaugh, J. L. Is the amygdala a locus of 'conditioned fear'? Some questions and caveats. Neuron 23, 227–228 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Wilensky, A. E., Schafe, G. E. & LeDoux, J. E. Functional inactivation of the amygdala before but not after auditory fear conditioning prevents memory formation. J. Neurosci. 19, RC48 (1999).

    Article  CAS  PubMed  Google Scholar 

  112. Wilensky, A. E., Schafe, G. E. & LeDoux, J. E. The amygdala modulates memory consolidation of fear-motivated inhibitory avoidance learning but not classical fear conditioning. J. Neurosci. 20, 7059–7066 (2000).

    Article  CAS  PubMed  Google Scholar 

  113. Wallace, K. J. & Rosen, J. B. Neurotoxic lesions of the lateral nucleus of the amygdala decrease conditioned fear but not unconditioned fear of a predator odor: comparison with electrolytic lesions. J. Neurosci. 21, 3619–3627 (2001).

    Article  CAS  PubMed  Google Scholar 

  114. Gould, T. J. & Steinmetz, J. E. Changes in rabbit cerebellar cortical and interpositus nucleus activity during acquisition, extinction, and backward classical eyelid conditioning. Neurobiol. Learn. Mem. 65, 17–34 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. Logan, C. G. & Grafton, S. T. Functional anatomy of human eyeblink conditioning determined with regional cerebral glucose metabolism and positron-emission tomography. Proc. Natl Acad. Sci. USA 92, 7500–7504 (1995).

    Article  CAS  PubMed  Google Scholar 

  116. Ramnani, N., Toni, I., Josephs, O., Ashburner, J. & Passingham, R. E. Learning- and expectation-related changes in the human brain during motor learning. J. Neurophysiol. 84, 3026–3035 (2000).

    Article  CAS  PubMed  Google Scholar 

  117. Schreurs, B. G. et al. Lateralization and behavioral correlation of changes in regional cerebral blood flow with classical conditioning of the human eyeblink response. J. Neurophysiol. 77, 2153–2163 (1997).

    Article  CAS  PubMed  Google Scholar 

  118. Hansel, C., Linden, D. J. & D'Angelo, E. Beyond parallel fiber LTD: the diversity of synaptic and non-synaptic plasticity in the cerebellum. Nature Neurosci. 4, 467–475 (2001).

    Article  CAS  PubMed  Google Scholar 

  119. Aizenman, C. D. & Linden, D. J. Rapid, synaptically driven increases in the intrinsic excitability of cerebellar deep nuclear neurons. Nature Neurosci. 3, 109–111 (2000).

    Article  CAS  PubMed  Google Scholar 

  120. Racine, R. J., Wilson, D. A., Gingell, R. & Sunderland, D. Long-term potentiation in the interpositus and vestibular nuclei in the rat. Exp. Brain Res. 63, 158–162 (1986).

    Article  CAS  PubMed  Google Scholar 

  121. Repa, J. C. et al. Two different lateral amygdala cell populations contribute to the initiation and storage of memory. Nature Neurosci. 4, 724–731 (2001).Discovered different populations of cells that are involved in triggering and storing physiological changes in LA subregions during fear conditioning.

    Article  CAS  PubMed  Google Scholar 

  122. Rogan, M., Staubli, U. & LeDoux, J. Fear conditioning induces associative long-term potentiation in the amygdala. Nature 390, 604–607 (1997).

    Article  CAS  PubMed  Google Scholar 

  123. Pare, D. & Collins, D. R. Neuronal correlates of fear in the lateral amygdala: multiple extracellular recordings in conscious cats. J. Neurosci. 20, 2701–2710 (2000).

    Article  CAS  PubMed  Google Scholar 

  124. Maren, S. Auditory fear conditioning increases CS-elicited spike firing in lateral amygdala neurons even after extensive overtraining. Eur. J. Neurosci. 12, 4047–4054 (2000).

    Article  CAS  PubMed  Google Scholar 

  125. McKernan, M. G. & Shinnick-Gallagher, P. Fear conditioning induces a lasting potentiation of synaptic currents in vitro. Nature 390, 607–611 (1997).

    Article  CAS  PubMed  Google Scholar 

  126. Rogan, M. T., Weisskopf, M. G., Huang, Y.-Y., Kandel, E. R. & LeDoux, J. E. in Neuronal Mechanisms of Memory Formation (ed. Hölscher, C.) 58–76 (Cambridge Univ. Press, Cambridge, 2001).

    Google Scholar 

  127. Schafe, G. E., Nader, K., Blair, H. T. & LeDoux, J. E. Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective. Trends Neurosci. 24, 540–546 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. LaBar, K. S., Gatenby, J. C., Gore, J. C., LeDoux, J. E. & Phelps, E. A. Human amygdala activation during conditioned fear acquisition and extinction: a mixed-trial fMRI study. Neuron 20, 937–945 (1998).

    Article  CAS  PubMed  Google Scholar 

  129. Buchel, C., Morris, J., Dolan, R. J. & Friston, K. J. Brain systems mediating aversive conditioning: an event-related fMRI study. Neuron 20, 947–957 (1998).

    Article  CAS  PubMed  Google Scholar 

  130. Morris, J. S., Buchel, C. & Dolan, R. J. Parallel neural responses in amygdala subregions and sensory cortex during implicit fear conditioning. Neuroimage 13, 1044–1052 (2001).

    Article  CAS  PubMed  Google Scholar 

  131. Phelps, E. A. et al. Activation of the left amygdala to a cognitive representation of fear. Nature Neurosci. 4, 437–441 (2001).

    Article  CAS  PubMed  Google Scholar 

  132. Ohyama, T. & Mauk, M. Latent acquisition of timed responses in cerebellar cortex. J. Neurosci. 21, 682–690 (2001).Presented evidence indicating that during eyelid conditioning, plasticity in the cerebellar cortex is induced before any behavioral responses are evident.

    Article  CAS  PubMed  Google Scholar 

  133. Schafe, G. E. et al. Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of Pavlovian fear conditioning. J. Neurosci. 20, 8177–8187 (2000).

    Article  CAS  PubMed  Google Scholar 

  134. Weinberger, N. M. Physiological memory in primary auditory cortex: characteristics and mechanisms. Neurobiol. Learn. Mem. 70, 226–251 (1998).

    Article  CAS  PubMed  Google Scholar 

  135. Armony, J. L., Quirk, G. J. & LeDoux, J. E. Differential effects of amygdala lesions on early and late plastic components of auditory cortex spiketrains during fear conditioning. J. Neurosci. 18, 2592–2601 (1998).

    Article  CAS  PubMed  Google Scholar 

  136. Poremba, A. & Gabriel, M. Amygdalar efferents initiate auditory thalamic discriminative training-induced neuronal activity. J. Neurosci. 21, 270–278 (2001).

    Article  CAS  PubMed  Google Scholar 

  137. Maren, S., Yap, S. A. & Goosens, K. A. The amygdala is essential for the development of neuronal plasticity in the medial geniculate nucleus during auditory fear conditioning in rats. J. Neurosci. 21, RC135 (2001).

    Article  CAS  PubMed  Google Scholar 

  138. Garcia, K. S. & Mauk, M. D. Pharmacological analysis of cerebellar contributions to the timing and expression of conditioned eyelid responses. Neuropharmacology 37, 471–480 (1998).

    Article  CAS  PubMed  Google Scholar 

  139. Chen, L., Bao, S. & Thompson, R. F. Bilateral lesions of the interpositus nucleus completely prevent eyeblink conditioning in Purkinje cell-degeneration mutant mice. Behav. Neurosci. 113, 204–210 (1999).

    Article  CAS  PubMed  Google Scholar 

  140. Chen, L., Bao, S., Lockard, J. M., Kim, J. K. & Thompson, R. F. Impaired classical eyeblink conditioning in cerebellar-lesioned and Purkinje cell degeneration (pcd) mutant mice. J. Neurosci. 16, 2829–2838 (1996).This study provides some of the strongest evidence in support of the idea that learning of the conditioned eyelid response does not require the cerebellar cortex.

    Article  CAS  PubMed  Google Scholar 

  141. Miyata, M. et al. Deficient long-term synaptic depression in the rostral cerebellum correlated with impaired motor learning in phospholipase C β4 mutant mice. Eur. J. Neurosci. 13, 1945–1954 (2001).In contrast to the pcd mice (Reference 140 ), mice with deficient cerebellar LTD could not learn the conditioned eyelid response, even though other properties of the granule-to-Purkinje synapse seemed to be normal.

    Article  CAS  PubMed  Google Scholar 

  142. Perrett, S. P. & Mauk, M. D. Extinction of conditioned eyelid responses requires the anterior lobe of cerebellar cortex. J. Neurosci. 15, 2074–2080 (1995).

    Article  CAS  PubMed  Google Scholar 

  143. Medina, J. F., Nores, W. L., Ohyama, T. & Mauk, M. D. Mechanisms of cerebellar learning suggested by eyelid conditioning. Curr. Opin. Neurobiol. 10, 717–724 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Physiology, Howard Hughes Medical Institute, W. M. Keck Foundation Center for Integrative Neuroscience, University of California, 513 Parnassus Avenue, Room HSE-808, San Francisco, 94143-0444, California, USA

    Javier F. Medina

  2. W. M. Keck Foundation Laboratory of Neurobiology, Center for Neural Science, New York University, 4 Washington Place, Room 809, New York, 10003, New York, USA

    J. Christopher Repa & Joseph E. LeDoux

  3. Department of Neurobiology and Anatomy, W. M. Keck Center for the Neurobiology of Learning and Memory, University of Texas Medical School, 6431 Fannin Street, Houston, 77030, Texas, USA

    Michael D. Mauk

Authors
  1. Javier F. Medina
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Christopher Repa
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Michael D. Mauk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Joseph E. LeDoux
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Javier F. Medina.

Related links

Related links

FURTHER INFORMATION

learning and memory

 MIT Encyclopedia of Cognitive Sciences

conditioning

conditioning and the brain

learning

magnetic resonance imaging

memory

single-neuron recording

Glossary

EXTINCTION

The reduction and cessation of a predictive relationship and behaviour after the omission of a reinforcer (negative prediction error).

GOLGI CELLS

Cerebellar interneurons located in the granule cell layer. Their axonal terminals form part of the cerebellar glomeruli.

PURKINJE CELLS

Inhibitory interneurons in the cerebellum that use GABA as their neurotransmitter. Their cell bodies are situated beneath the molecular layer, and their dendrites branch extensively in this layer. Their axons project into the underlying white matter, and they provide the only output from the cerebellar cortex.

INFERIOR OLIVARY NUCLEUS

A nucleus situated in a bulge on the ventral medullary surface of the brainstem. Its neurons form very strong excitatory synapses with those of the cerebellum.

PARABRACHIAL AREA

A nucleus situated in the pons that transmits information from the viscera to the hypothalamus and amygdala.

STRIA TERMINALIS

One of the main efferent projections of the amygdala. It innervates regions that include the nucleus accumbens and the hypothalamus.

MITOGEN-ACTIVATED PROTEIN KINASE

Any member of a family of protein kinases that are important for relaying signals from the cell membrane to the nucleus.

PROTEIN KINASE A

Also known as cyclic-AMP-dependent protein kinase. One of a class of enzymes that use ATP as a phosphoryl-group donor to phosphorylate hydroxyl or phenolic groups on their target proteins.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Medina, J., Christopher Repa, J., Mauk, M. et al. Parallels between cerebellum- and amygdala-dependent conditioning. Nat Rev Neurosci 3, 122–131 (2002). https://doi.org/10.1038/nrn728

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrn728

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