Abstract
A leading model for studying how the brain forms memories about unpleasant experiences is fear conditioning. A cumulative body of work has identified major components of the neural system mediating this form of learning. The pathways involve transmission of sensory information from processing areas in the thalamus and cortex to the amygdala. The amygdala's lateral nucleus receives and integrates the sensory inputs from the thalamic and cortical areas, and the central nucleus provides the interface with motor systems controlling specific fear responses in various modalities (behavioural, autonomic, endocrine). Internal connections within the amygdala allow the lateral and central nuclei to communicate. Recent studies have begun to identify some sites of plasticity in the circuitry and the cellular mechanisms involved in fear conditioning. Through studies of fear conditioning, our understanding of emotional memory is being taken to the level of cells and synapses in the brain. Advances in understanding emotional memory hold out the possibility that emotional disorders may be better defined and treatment improved.
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Selected References
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- 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. 1997 Mar;7(2):157–165. doi: 10.1093/cercor/7.2.157. [DOI] [PubMed] [Google Scholar]
- BRADY J. V., HUNT H. F. A further demonstration of the effects of electro-convulsive shock on a conditioned emotional response. J Comp Physiol Psychol. 1951 Apr;44(2):204–209. doi: 10.1037/h0060588. [DOI] [PubMed] [Google Scholar]
- Bechara A., Tranel D., Damasio H., Adolphs R., Rockland C., Damasio A. R. Double dissociation of conditioning and declarative knowledge relative to the amygdala and hippocampus in humans. Science. 1995 Aug 25;269(5227):1115–1118. doi: 10.1126/science.7652558. [DOI] [PubMed] [Google Scholar]
- Blanchard R. J., Blanchard D. C. Passive and active reactions to fear-eliciting stimuli. J Comp Physiol Psychol. 1969 May;68(1):129–135. doi: 10.1037/h0027676. [DOI] [PubMed] [Google Scholar]
- Bliss T. V., Collingridge G. L. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993 Jan 7;361(6407):31–39. doi: 10.1038/361031a0. [DOI] [PubMed] [Google Scholar]
- Bordi F., LeDoux J. E. Response properties of single units in areas of rat auditory thalamus that project to the amygdala. I. Acoustic discharge patterns and frequency receptive fields. Exp Brain Res. 1994;98(2):261–274. doi: 10.1007/BF00228414. [DOI] [PubMed] [Google Scholar]
- Bordi F., LeDoux J. E. Response properties of single units in areas of rat auditory thalamus that project to the amygdala. II. Cells receiving convergent auditory and somatosensory inputs and cells antidromically activated by amygdala stimulation. Exp Brain Res. 1994;98(2):275–286. doi: 10.1007/BF00228415. [DOI] [PubMed] [Google Scholar]
- Bordi F., LeDoux J. Sensory tuning beyond the sensory system: an initial analysis of auditory response properties of neurons in the lateral amygdaloid nucleus and overlying areas of the striatum. J Neurosci. 1992 Jul;12(7):2493–2503. doi: 10.1523/JNEUROSCI.12-07-02493.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Campeau S., Davis M. Involvement of subcortical and cortical afferents to the lateral nucleus of the amygdala in fear conditioning measured with fear-potentiated startle in rats trained concurrently with auditory and visual conditioned stimuli. J Neurosci. 1995 Mar;15(3 Pt 2):2312–2327. doi: 10.1523/JNEUROSCI.15-03-02312.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Chapman P. F., Kairiss E. W., Keenan C. L., Brown T. H. Long-term synaptic potentiation in the amygdala. Synapse. 1990;6(3):271–278. doi: 10.1002/syn.890060306. [DOI] [PubMed] [Google Scholar]
- Clugnet M. C., LeDoux J. E. Synaptic plasticity in fear conditioning circuits: induction of LTP in the lateral nucleus of the amygdala by stimulation of the medial geniculate body. J Neurosci. 1990 Aug;10(8):2818–2824. doi: 10.1523/JNEUROSCI.10-08-02818.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cohen D. H., Randall D. C. Classical conditioning of cardiovascular responses. Annu Rev Physiol. 1984;46:187–197. doi: 10.1146/annurev.ph.46.030184.001155. [DOI] [PubMed] [Google Scholar]
- Cotman C. W., Monaghan D. T., Ganong A. H. Excitatory amino acid neurotransmission: NMDA receptors and Hebb-type synaptic plasticity. Annu Rev Neurosci. 1988;11:61–80. doi: 10.1146/annurev.ne.11.030188.000425. [DOI] [PubMed] [Google Scholar]
- Damasio H., Grabowski T., Frank R., Galaburda A. M., Damasio A. R. The return of Phineas Gage: clues about the brain from the skull of a famous patient. Science. 1994 May 20;264(5162):1102–1105. doi: 10.1126/science.8178168. [DOI] [PubMed] [Google Scholar]
- Davis M. The role of the amygdala in fear-potentiated startle: implications for animal models of anxiety. Trends Pharmacol Sci. 1992 Jan;13(1):35–41. doi: 10.1016/0165-6147(92)90014-w. [DOI] [PubMed] [Google Scholar]
- Diamond D. M., Rose G. M. Stress impairs LTP and hippocampal-dependent memory. Ann N Y Acad Sci. 1994 Nov 30;746:411–414. doi: 10.1111/j.1749-6632.1994.tb39271.x. [DOI] [PubMed] [Google Scholar]
- Eichenbaum H., Otto T., Cohen N. J. The hippocampus--what does it do? Behav Neural Biol. 1992 Jan;57(1):2–36. doi: 10.1016/0163-1047(92)90724-i. [DOI] [PubMed] [Google Scholar]
- Fanselow M. S., Kim J. J. Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala. Behav Neurosci. 1994 Feb;108(1):210–212. doi: 10.1037//0735-7044.108.1.210. [DOI] [PubMed] [Google Scholar]
- Fanselow M. S., Kim J. J. Acquisition of contextual Pavlovian fear conditioning is blocked by application of an NMDA receptor antagonist D,L-2-amino-5-phosphonovaleric acid to the basolateral amygdala. Behav Neurosci. 1994 Feb;108(1):210–212. doi: 10.1037//0735-7044.108.1.210. [DOI] [PubMed] [Google Scholar]
- Farb C. R., Aoki C., Ledoux J. E. Differential localization of NMDA and AMPA receptor subunits in the lateral and basal nuclei of the amygdala: a light and electron microscopic study. J Comp Neurol. 1995 Nov 6;362(1):86–108. doi: 10.1002/cne.903620106. [DOI] [PubMed] [Google Scholar]
- Helmstetter F. J. The amygdala is essential for the expression of conditional hypoalgesia. Behav Neurosci. 1992 Jun;106(3):518–528. doi: 10.1037//0735-7044.106.3.518. [DOI] [PubMed] [Google Scholar]
- Jacobs W. J., Nadel L. Stress-induced recovery of fears and phobias. Psychol Rev. 1985 Oct;92(4):512–531. [PubMed] [Google Scholar]
- 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 bradycardiac conditioning to acoustic conditioned stimuli in rabbits. Brain Res. 1987 Jun 2;412(2):285–294. doi: 10.1016/0006-8993(87)91135-8. [DOI] [PubMed] [Google Scholar]
- Kim J. J., Fanselow M. S. Modality-specific retrograde amnesia of fear. Science. 1992 May 1;256(5057):675–677. doi: 10.1126/science.1585183. [DOI] [PubMed] [Google Scholar]
- LaBar K. S., LeDoux J. E., Spencer D. D., Phelps E. A. Impaired fear conditioning following unilateral temporal lobectomy in humans. J Neurosci. 1995 Oct;15(10):6846–6855. doi: 10.1523/JNEUROSCI.15-10-06846.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LeDoux J. E. Brain mechanisms of emotion and emotional learning. Curr Opin Neurobiol. 1992 Apr;2(2):191–197. doi: 10.1016/0959-4388(92)90011-9. [DOI] [PubMed] [Google Scholar]
- LeDoux J. E., Cicchetti P., Xagoraris A., Romanski L. M. The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning. J Neurosci. 1990 Apr;10(4):1062–1069. doi: 10.1523/JNEUROSCI.10-04-01062.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LeDoux J. E. Emotion, memory and the brain. Sci Am. 1994 Jun;270(6):50–57. doi: 10.1038/scientificamerican0694-50. [DOI] [PubMed] [Google Scholar]
- LeDoux J. E. Emotion: clues from the brain. Annu Rev Psychol. 1995;46:209–235. doi: 10.1146/annurev.ps.46.020195.001233. [DOI] [PubMed] [Google Scholar]
- LeDoux J. E., Farb C. R., Milner T. A. Ultrastructure and synaptic associations of auditory thalamo-amygdala projections in the rat. Exp Brain Res. 1991;85(3):577–586. doi: 10.1007/BF00231742. [DOI] [PubMed] [Google Scholar]
- LeDoux J. E., Farb C. R. Neurons of the acoustic thalamus that project to the amygdala contain glutamate. Neurosci Lett. 1991 Dec 16;134(1):145–149. doi: 10.1016/0304-3940(91)90527-z. [DOI] [PubMed] [Google Scholar]
- LeDoux J. E., Farb C. R., Romanski L. M. Overlapping projections to the amygdala and striatum from auditory processing areas of the thalamus and cortex. Neurosci Lett. 1991 Dec 16;134(1):139–144. doi: 10.1016/0304-3940(91)90526-y. [DOI] [PubMed] [Google Scholar]
- LeDoux J. E., Farb C., Ruggiero D. A. Topographic organization of neurons in the acoustic thalamus that project to the amygdala. J Neurosci. 1990 Apr;10(4):1043–1054. doi: 10.1523/JNEUROSCI.10-04-01043.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
- LeDoux J. E., Sakaguchi A., Reis D. J. Subcortical efferent projections of the medial geniculate nucleus mediate emotional responses conditioned to acoustic stimuli. J Neurosci. 1984 Mar;4(3):683–698. doi: 10.1523/JNEUROSCI.04-03-00683.1984. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Li X. F., Phillips R., LeDoux J. E. NMDA and non-NMDA receptors contribute to synaptic transmission between the medial geniculate body and the lateral nucleus of the amygdala. Exp Brain Res. 1995;105(1):87–100. doi: 10.1007/BF00242185. [DOI] [PubMed] [Google Scholar]
- Li X. F., Stutzmann G. E., LeDoux J. E. Convergent but temporally separated inputs to lateral amygdala neurons from the auditory thalamus and auditory cortex use different postsynaptic receptors: in vivo intracellular and extracellular recordings in fear conditioning pathways. Learn Mem. 1996 Sep-Oct;3(2-3):229–242. doi: 10.1101/lm.3.2-3.229. [DOI] [PubMed] [Google Scholar]
- Madison D. V., Malenka R. C., Nicoll R. A. Mechanisms underlying long-term potentiation of synaptic transmission. Annu Rev Neurosci. 1991;14:379–397. doi: 10.1146/annurev.ne.14.030191.002115. [DOI] [PubMed] [Google Scholar]
- Malenka R. C., Nicoll R. A. NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms. Trends Neurosci. 1993 Dec;16(12):521–527. doi: 10.1016/0166-2236(93)90197-t. [DOI] [PubMed] [Google Scholar]
- Maren S., Fanselow M. S. Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo. J Neurosci. 1995 Nov;15(11):7548–7564. doi: 10.1523/JNEUROSCI.15-11-07548.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mason J. W. A review of psychoendocrine research on the sympathetic-adrenal medullary system. Psychosom Med. 1968 Sep-Oct;30(5 Suppl):631–653. doi: 10.1097/00006842-196809000-00022. [DOI] [PubMed] [Google Scholar]
- McEwen B. S., Sapolsky R. M. Stress and cognitive function. Curr Opin Neurobiol. 1995 Apr;5(2):205–216. doi: 10.1016/0959-4388(95)80028-x. [DOI] [PubMed] [Google Scholar]
- Miserendino M. J., Sananes C. B., Melia K. R., Davis M. Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala. Nature. 1990 Jun 21;345(6277):716–718. doi: 10.1038/345716a0. [DOI] [PubMed] [Google Scholar]
- Morgan M. A., Romanski L. M., LeDoux J. E. Extinction of emotional learning: contribution of medial prefrontal cortex. Neurosci Lett. 1993 Nov 26;163(1):109–113. doi: 10.1016/0304-3940(93)90241-c. [DOI] [PubMed] [Google Scholar]
- Phillips R. G., LeDoux J. E. Differential contribution of amygdala and hippocampus to cued and contextual fear conditioning. Behav Neurosci. 1992 Apr;106(2):274–285. doi: 10.1037//0735-7044.106.2.274. [DOI] [PubMed] [Google Scholar]
- Pitkänen A., Stefanacci L., Farb C. R., Go G. G., LeDoux J. E., Amaral D. G. Intrinsic connections of the rat amygdaloid complex: projections originating in the lateral nucleus. J Comp Neurol. 1995 May 29;356(2):288–310. doi: 10.1002/cne.903560211. [DOI] [PubMed] [Google Scholar]
- 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. 1995 Nov;15(5):1029–1039. doi: 10.1016/0896-6273(95)90092-6. [DOI] [PubMed] [Google Scholar]
- Rogan M. T., LeDoux J. E. LTP is accompanied by commensurate enhancement of auditory-evoked responses in a fear conditioning circuit. Neuron. 1995 Jul;15(1):127–136. doi: 10.1016/0896-6273(95)90070-5. [DOI] [PubMed] [Google Scholar]
- Romanski L. M., LeDoux J. E. Equipotentiality of thalamo-amygdala and thalamo-cortico-amygdala circuits in auditory fear conditioning. J Neurosci. 1992 Nov;12(11):4501–4509. doi: 10.1523/JNEUROSCI.12-11-04501.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 1993 Nov-Dec;3(6):515–532. doi: 10.1093/cercor/3.6.515. [DOI] [PubMed] [Google Scholar]
- Savander V., Go C. G., Ledoux J. E., Pitkänen A. Intrinsic connections of the rat amygdaloid complex: projections originating in the accessory basal nucleus. J Comp Neurol. 1996 Oct 14;374(2):291–313. doi: 10.1002/(SICI)1096-9861(19961014)374:2<291::AID-CNE10>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
- Selden N. R., Everitt B. J., Jarrard L. E., Robbins T. W. Complementary roles for the amygdala and hippocampus in aversive conditioning to explicit and contextual cues. Neuroscience. 1991;42(2):335–350. doi: 10.1016/0306-4522(91)90379-3. [DOI] [PubMed] [Google Scholar]
- Smith O. A., Astley C. A., DeVito J. L., Stein J. M., Walsh K. E. Functional analysis of hypothalamic control of the cardiovascular responses accompanying emotional behavior. Fed Proc. 1980 Jun;39(8):2487–2494. [PubMed] [Google Scholar]
- Squire L. R., Knowlton B., Musen G. The structure and organization of memory. Annu Rev Psychol. 1993;44:453–495. doi: 10.1146/annurev.ps.44.020193.002321. [DOI] [PubMed] [Google Scholar]
- Uwano T., Nishijo H., Ono T., Tamura R. Neuronal responsiveness to various sensory stimuli, and associative learning in the rat amygdala. Neuroscience. 1995 Sep;68(2):339–361. doi: 10.1016/0306-4522(95)00125-3. [DOI] [PubMed] [Google Scholar]
- 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. 1991 Aug;54(2):89–95. doi: 10.1159/000125856. [DOI] [PubMed] [Google Scholar]
- Watkins L. R., Mayer D. J. Organization of endogenous opiate and nonopiate pain control systems. Science. 1982 Jun 11;216(4551):1185–1192. doi: 10.1126/science.6281891. [DOI] [PubMed] [Google Scholar]
- Weisz D. J., Harden D. G., Xiang Z. Effects of amygdala lesions on reflex facilitation and conditioned response acquisition during nictitating membrane response conditioning in rabbit. Behav Neurosci. 1992 Apr;106(2):262–273. doi: 10.1037//0735-7044.106.2.262. [DOI] [PubMed] [Google Scholar]