Classical conditioning and brain systems: The role of awareness

Science

Volumn 280, Issue 5360, 1998, Pages 77-81

  Clark, Robert E ^a   Squire, Larry R ^b,c  

^a UNIVERSITY OF CALIFORNIA   (United States)

^b VA SAN DIEGO HEALTHCARE SYSTEM   (United States)

^c UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

AMNESIA; ANIMAL BEHAVIOR; ARTICLE; AWARENESS; BRAIN INJURY; CONDITIONED REFLEX; EYELID REFLEX; HIPPOCAMPUS; HUMAN; MEMORY; NONHUMAN; PRIORITY JOURNAL; STATE DEPENDENT LEARNING;

AGED; AMNESIA; AWARENESS; BLINKING; CEREBELLUM; CONDITIONING, CLASSICAL; FEMALE; HIPPOCAMPUS; HUMANS; LEARNING; MALE; MEMORY; MIDDLE AGED; NEOCORTEX;

ANIMALIA; HIPPOCAMPUS HIPPOCAMPUS; NEPTUNIA; VERTEBRATA;

EID: 0032478637     PISSN: 00368075     EISSN: None     Source Type: Journal    
DOI: 10.1126/science.280.5360.77     Document Type: Article

References (63)

1. L. R. Squire, Annu. Rev. Neurosci. 5, 241 (1982); N. Cohen, in Neuropsychology of Memory, L. R. Squire and N. Butters, Eds. (Guilford, New York, 1984), pp. 83-103; M. Mishkin and H. L. Petri, in ibid., pp. 287-296; R. J. McDonald and N. M. White, Behav. Neurosci. 107, 3 (1993); D. L. Schacter and E. Tulving, Memory Systems 1994 (MIT Press, Cambridge, MA, 1994); L. R. Squire and B. J. Knowlton, in The Cognitive Neurosciences, M. Gazzaniga, Ed. (MIT Press, Cambridge, MA, 1994), pp. 825-838.
2. L. R. Squire, Annu. Rev. Neurosci. 5, 241 (1982); N. Cohen, in Neuropsychology of Memory, L. R. Squire and N. Butters, Eds. (Guilford, New York, 1984), pp. 83-103; M. Mishkin and H. L. Petri, in ibid., pp. 287-296; R. J. McDonald and N. M. White, Behav. Neurosci. 107, 3 (1993); D. L. Schacter and E. Tulving, Memory Systems 1994 (MIT Press, Cambridge, MA, 1994); L. R. Squire and B. J. Knowlton, in The Cognitive Neurosciences, M. Gazzaniga, Ed. (MIT Press, Cambridge, MA, 1994), pp. 825-838.
3. L. R. Squire, Annu. Rev. Neurosci. 5, 241 (1982); N. Cohen, in Neuropsychology of Memory, L. R. Squire and N. Butters, Eds. (Guilford, New York, 1984), pp. 83-103; M. Mishkin and H. L. Petri, in ibid., pp. 287-296; R. J. McDonald and N. M. White, Behav. Neurosci. 107, 3 (1993); D. L. Schacter and E. Tulving, Memory Systems 1994 (MIT Press, Cambridge, MA, 1994); L. R. Squire and B. J. Knowlton, in The Cognitive Neurosciences, M. Gazzaniga, Ed. (MIT Press, Cambridge, MA, 1994), pp. 825-838.
4. L. R. Squire, Annu. Rev. Neurosci. 5, 241 (1982); N. Cohen, in Neuropsychology of Memory, L. R. Squire and N. Butters, Eds. (Guilford, New York, 1984), pp. 83-103; M. Mishkin and H. L. Petri, in ibid., pp. 287-296; R. J. McDonald and N. M. White, Behav. Neurosci. 107, 3 (1993); D. L. Schacter and E. Tulving, Memory Systems 1994 (MIT Press, Cambridge, MA, 1994); L. R. Squire and B. J. Knowlton, in The Cognitive Neurosciences, M. Gazzaniga, Ed. (MIT Press, Cambridge, MA, 1994), pp. 825-838.
5. L. R. Squire, Annu. Rev. Neurosci. 5, 241 (1982); N. Cohen, in Neuropsychology of Memory, L. R. Squire and N. Butters, Eds. (Guilford, New York, 1984), pp. 83-103; M. Mishkin and H. L. Petri, in ibid., pp. 287-296; R. J. McDonald and N. M. White, Behav. Neurosci. 107, 3 (1993); D. L. Schacter and E. Tulving, Memory Systems 1994 (MIT Press, Cambridge, MA, 1994); L. R. Squire and B. J. Knowlton, in The Cognitive Neurosciences, M. Gazzaniga, Ed. (MIT Press, Cambridge, MA, 1994), pp. 825-838.
6. L. R. Squire, Annu. Rev. Neurosci. 5, 241 (1982); N. Cohen, in Neuropsychology of Memory, L. R. Squire and N. Butters, Eds. (Guilford, New York, 1984), pp. 83-103; M. Mishkin and H. L. Petri, in ibid., pp. 287-296; R. J. McDonald and N. M. White, Behav. Neurosci. 107, 3 (1993); D. L. Schacter and E. Tulving, Memory Systems 1994 (MIT Press, Cambridge, MA, 1994); L. R. Squire and B. J. Knowlton, in The Cognitive Neurosciences, M. Gazzaniga, Ed. (MIT Press, Cambridge, MA, 1994), pp. 825-838.
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10. Classical conditioning has been demonstrated in several invertebrate [T. J. Carew and C. L. Sahley, Annu. Rev. Neurosci. 9, 435 (1986)]
11. and vertebrate species [I. Gormezano, N. Schneiderman, E. Deaux, I. Fuentes, Science 138, 33 (1962);
12. I. Gormezano, W. F. Prokasy, R. F. Thompson, Eds., Classical Conditioning (Erlbaum, Hillsdale, NJ, 1987)].
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19. L. Weiskrantz and E. K. Warrington, Neuropsychologia 17, 187 (1979); I. Daum, S. Channon, A. G. M. Canavan, J. Neurol. Neurosurg. Psychiatry 52, 47 (1989); I. Daum and H. Ackermann, Int. J. Neurosci. 75, 153 (1994); J.D.E. Gabrieli et al., Behav. Neurosci. 109, 819 (1995).
20. L. Weiskrantz and E. K. Warrington, Neuropsychologia 17, 187 (1979); I. Daum, S. Channon, A. G. M. Canavan, J. Neurol. Neurosurg. Psychiatry 52, 47 (1989); I. Daum and H. Ackermann, Int. J. Neurosci. 75, 153 (1994); J.D.E. Gabrieli et al., Behav. Neurosci. 109, 819 (1995).
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22. Impaired delay conditioning in one amnesic patient may have been due to the reported atrophy of the cerebellar vermis and hemispheres [D. S. Woodruff-Pak, Behav. Neurosci. 107, 911 (1993)]. Two amnesic patients who had previously acquired delay conditioning subsequently exhibited little if any acquisition of trace conditioning, although during training they did achieve a string of eight CRs in nine consecutive trials.
23. I. P. Pavlov, Conditioned Reflexes (Oxford Univ. Press, London, 1927).
24. +-only (single cue) procedure were used [R. McGlinchey-Berroth, M. C. Carrillo, J. D. E. Gabrieli, C. M. Brawn, J. F. Disterhoft, Behav. Neurosci. 111, 873 (1997)]. Some acquisition occurred with trace intervals of 500 or 750 ms, but no acquisition was detectable with a 1000-ms trace interval.
25. Rabbits with hippocampal lesions are impaired at trace conditioning [P. R. Solomon, E. R. Vander Schaaf, R. F. Thompson, D. J. Weisz, Behav. Neurosci. 100, 729 (1986); J. R. Moyer, R. A. Deyo, J. F. Disterhoft, ibid. 104, 243 (1990)].
26. Rabbits with hippocampal lesions are impaired at trace conditioning [P. R. Solomon, E. R. Vander Schaaf, R. F. Thompson, D. J. Weisz, Behav. Neurosci. 100, 729 (1986); J. R. Moyer, R. A. Deyo, J. F. Disterhoft, ibid. 104, 243 (1990)].
27. Trace conditioning was impaired in rabbits when the lesion was made 1 day, but not 30 days, after conditioning [J. J. Kim, R. E. Clark, R. F. Thompson, Behav. Neurosci. 109, 195 (1995)]. This temporal gradient of retrograde amnesia is characteristic of tasks that depend on the hippocampus.
28. Amnesic patients have fully intact immediate memory [A. D. Baddeley and E. K. Warrington, J. Verb. Learn. Verb. Behav. 9, 176 (1970); D. A. Drachman and J. Arbit, Arch. Neurol. 15, 52 (1966); C. B. Cave and L. R. Squire, Hippocampus 2, 151 (1992)]. Even severely amnesic patients can retain small amounts of material in memory for a few seconds and sometimes up to a minute or more if they are not distracted [B. Milner, in Amnesia, C. W. M. Whitty and O. L. Zangwill, Eds. (Butterworths, London, 1966), pp. 109-133].
29. Amnesic patients have fully intact immediate memory [A. D. Baddeley and E. K. Warrington, J. Verb. Learn. Verb. Behav. 9, 176 (1970); D. A. Drachman and J. Arbit, Arch. Neurol. 15, 52 (1966); C. B. Cave and L. R. Squire, Hippocampus 2, 151 (1992)]. Even severely amnesic patients can retain small amounts of material in memory for a few seconds and sometimes up to a minute or more if they are not distracted [B. Milner, in Amnesia, C. W. M. Whitty and O. L. Zangwill, Eds. (Butterworths, London, 1966), pp. 109-133].
30. Amnesic patients have fully intact immediate memory [A. D. Baddeley and E. K. Warrington, J. Verb. Learn. Verb. Behav. 9, 176 (1970); D. A. Drachman and J. Arbit, Arch. Neurol. 15, 52 (1966); C. B. Cave and L. R. Squire, Hippocampus 2, 151 (1992)]. Even severely amnesic patients can retain small amounts of material in memory for a few seconds and sometimes up to a minute or more if they are not distracted [B. Milner, in Amnesia, C. W. M. Whitty and O. L. Zangwill, Eds. (Butterworths, London, 1966), pp. 109-133].
31. Amnesic patients have fully intact immediate memory [A. D. Baddeley and E. K. Warrington, J. Verb. Learn. Verb. Behav. 9, 176 (1970); D. A. Drachman and J. Arbit, Arch. Neurol. 15, 52 (1966); C. B. Cave and L. R. Squire, Hippocampus 2, 151 (1992)]. Even severely amnesic patients can retain small amounts of material in memory for a few seconds and sometimes up to a minute or more if they are not distracted [B. Milner, in Amnesia, C. W. M. Whitty and O. L. Zangwill, Eds. (Butterworths, London, 1966), pp. 109-133].
32. Delay conditioning in humans can occur without individuals becoming aware of the relationship between the CS and the US [E. R. Hilgard and L. G. Humphreys, J. Gen. Psychol. 19, 111 (1938); K. W. Spence and J. Taylor, J. Exp. Psychol. 42, 183 (1951); 29, 30]. One review concluded that "very careful intensive, in-depth interviewing in the 1940s revealed clearly that there was little relationship between the subject's reported awareness and his conditioning [eye blink] performance" [D. A. Grant, Psychophysiology 10, 75 (1973), p. 75]. Four amnesic patients (three men and one woman) were tested (A.B., P.H., L.J., and E.P.). Bilateral damage to the hippocampal formation was confirmed by magnetic resonance imaging for three of the four patients [L. R. Squire, D. G. Amaral, G. A. Press, J. Neurosci. 10, 3106 (1990); J. Polich and L. R. Squire, Electroencephalogr. Clin. Neurophysiol. 86, 408 (1993); L. R. Squire and B. J. Knowlton, Proc. Natl. Acad. Sci. U.S.A. 92, 12470 (1995)]. The remaining patient (A.B.) was suspected to have hippocampal formation damage on the basis of etiology (anoxia). The patients averaged 67.5 years of age (range, 60 to 75 years) with an average of 15.6 years of education. They averaged 105.0 on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; mean subscale scores = 20.5 for information and 51.8 for vocabulary), and they averaged 100.8, 67.7, 74.3, 65.3, and 53.3 on the five indices of the Wechsler Memory Scale-Revised (attention concentration, verbal memory, nonverbal memory, general memory, and delayed memory, respectively). These scores have a mean of 100 in the normal population (SD = 15). For additional information about the four patients, see S. B. Hamann and L. R. Squire, Behav. Neurosci. 111, 850 (1997); ibid. 109, 1027 (1995).
33. Delay conditioning in humans can occur without individuals becoming aware of the relationship between the CS and the US [E. R. Hilgard and L. G. Humphreys, J. Gen. Psychol. 19, 111 (1938); K. W. Spence and J. Taylor, J. Exp. Psychol. 42, 183 (1951); 29, 30]. One review concluded that "very careful intensive, in-depth interviewing in the 1940s revealed clearly that there was little relationship between the subject's reported awareness and his conditioning [eye blink] performance" [D. A. Grant, Psychophysiology 10, 75 (1973), p. 75]. Four amnesic patients (three men and one woman) were tested (A.B., P.H., L.J., and E.P.). Bilateral damage to the hippocampal formation was confirmed by magnetic resonance imaging for three of the four patients [L. R. Squire, D. G. Amaral, G. A. Press, J. Neurosci. 10, 3106 (1990); J. Polich and L. R. Squire, Electroencephalogr. Clin. Neurophysiol. 86, 408 (1993); L. R. Squire and B. J. Knowlton, Proc. Natl. Acad. Sci. U.S.A. 92, 12470 (1995)]. The remaining patient (A.B.) was suspected to have hippocampal formation damage on the basis of etiology (anoxia). The patients averaged 67.5 years of age (range, 60 to 75 years) with an average of 15.6 years of education. They averaged 105.0 on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; mean subscale scores = 20.5 for information and 51.8 for vocabulary), and they averaged 100.8, 67.7, 74.3, 65.3, and 53.3 on the five indices of the Wechsler Memory Scale-Revised (attention concentration, verbal memory, nonverbal memory, general memory, and delayed memory, respectively). These scores have a mean of 100 in the normal population (SD = 15). For additional information about the four patients, see S. B. Hamann and L. R. Squire, Behav. Neurosci. 111, 850 (1997); ibid. 109, 1027 (1995).
34. Delay conditioning in humans can occur without individuals becoming aware of the relationship between the CS and the US [E. R. Hilgard and L. G. Humphreys, J. Gen. Psychol. 19, 111 (1938); K. W. Spence and J. Taylor, J. Exp. Psychol. 42, 183 (1951); 29, 30]. One review concluded that "very careful intensive, in-depth interviewing in the 1940s revealed clearly that there was little relationship between the subject's reported awareness and his conditioning [eye blink] performance" [D. A. Grant, Psychophysiology 10, 75 (1973), p. 75]. Four amnesic patients (three men and one woman) were tested (A.B., P.H., L.J., and E.P.). Bilateral damage to the hippocampal formation was confirmed by magnetic resonance imaging for three of the four patients [L. R. Squire, D. G. Amaral, G. A. Press, J. Neurosci. 10, 3106 (1990); J. Polich and L. R. Squire, Electroencephalogr. Clin. Neurophysiol. 86, 408 (1993); L. R. Squire and B. J. Knowlton, Proc. Natl. Acad. Sci. U.S.A. 92, 12470 (1995)]. The remaining patient (A.B.) was suspected to have hippocampal formation damage on the basis of etiology (anoxia). The patients averaged 67.5 years of age (range, 60 to 75 years) with an average of 15.6 years of education. They averaged 105.0 on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; mean subscale scores = 20.5 for information and 51.8 for vocabulary), and they averaged 100.8, 67.7, 74.3, 65.3, and 53.3 on the five indices of the Wechsler Memory Scale-Revised (attention concentration, verbal memory, nonverbal memory, general memory, and delayed memory, respectively). These scores have a mean of 100 in the normal population (SD = 15). For additional information about the four patients, see S. B. Hamann and L. R. Squire, Behav. Neurosci. 111, 850 (1997); ibid. 109, 1027 (1995).
35. Delay conditioning in humans can occur without individuals becoming aware of the relationship between the CS and the US [E. R. Hilgard and L. G. Humphreys, J. Gen. Psychol. 19, 111 (1938); K. W. Spence and J. Taylor, J. Exp. Psychol. 42, 183 (1951); 29, 30]. One review concluded that "very careful intensive, in-depth interviewing in the 1940s revealed clearly that there was little relationship between the subject's reported awareness and his conditioning [eye blink] performance" [D. A. Grant, Psychophysiology 10, 75 (1973), p. 75]. Four amnesic patients (three men and one woman) were tested (A.B., P.H., L.J., and E.P.). Bilateral damage to the hippocampal formation was confirmed by magnetic resonance imaging for three of the four patients [L. R. Squire, D. G. Amaral, G. A. Press, J. Neurosci. 10, 3106 (1990); J. Polich and L. R. Squire, Electroencephalogr. Clin. Neurophysiol. 86, 408 (1993); L. R. Squire and B. J. Knowlton, Proc. Natl. Acad. Sci. U.S.A. 92, 12470 (1995)]. The remaining patient (A.B.) was suspected to have hippocampal formation damage on the basis of etiology (anoxia). The patients averaged 67.5 years of age (range, 60 to 75 years) with an average of 15.6 years of education. They averaged 105.0 on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; mean subscale scores = 20.5 for information and 51.8 for vocabulary), and they averaged 100.8, 67.7, 74.3, 65.3, and 53.3 on the five indices of the Wechsler Memory Scale-Revised (attention concentration, verbal memory, nonverbal memory, general memory, and delayed memory, respectively). These scores have a mean of 100 in the normal population (SD = 15). For additional information about the four patients, see S. B. Hamann and L. R. Squire, Behav. Neurosci. 111, 850 (1997); ibid. 109, 1027 (1995).
36. Delay conditioning in humans can occur without individuals becoming aware of the relationship between the CS and the US [E. R. Hilgard and L. G. Humphreys, J. Gen. Psychol. 19, 111 (1938); K. W. Spence and J. Taylor, J. Exp. Psychol. 42, 183 (1951); 29, 30]. One review concluded that "very careful intensive, in-depth interviewing in the 1940s revealed clearly that there was little relationship between the subject's reported awareness and his conditioning [eye blink] performance" [D. A. Grant, Psychophysiology 10, 75 (1973), p. 75]. Four amnesic patients (three men and one woman) were tested (A.B., P.H., L.J., and E.P.). Bilateral damage to the hippocampal formation was confirmed by magnetic resonance imaging for three of the four patients [L. R. Squire, D. G. Amaral, G. A. Press, J. Neurosci. 10, 3106 (1990); J. Polich and L. R. Squire, Electroencephalogr. Clin. Neurophysiol. 86, 408 (1993); L. R. Squire and B. J. Knowlton, Proc. Natl. Acad. Sci. U.S.A. 92, 12470 (1995)]. The remaining patient (A.B.) was suspected to have hippocampal formation damage on the basis of etiology (anoxia). The patients averaged 67.5 years of age (range, 60 to 75 years) with an average of 15.6 years of education. They averaged 105.0 on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; mean subscale scores = 20.5 for information and 51.8 for vocabulary), and they averaged 100.8, 67.7, 74.3, 65.3, and 53.3 on the five indices of the Wechsler Memory Scale-Revised (attention concentration, verbal memory, nonverbal memory, general memory, and delayed memory, respectively). These scores have a mean of 100 in the normal population (SD = 15). For additional information about the four patients, see S. B. Hamann and L. R. Squire, Behav. Neurosci. 111, 850 (1997); ibid. 109, 1027 (1995).
37. Delay conditioning in humans can occur without individuals becoming aware of the relationship between the CS and the US [E. R. Hilgard and L. G. Humphreys, J. Gen. Psychol. 19, 111 (1938); K. W. Spence and J. Taylor, J. Exp. Psychol. 42, 183 (1951); 29, 30]. One review concluded that "very careful intensive, in-depth interviewing in the 1940s revealed clearly that there was little relationship between the subject's reported awareness and his conditioning [eye blink] performance" [D. A. Grant, Psychophysiology 10, 75 (1973), p. 75]. Four amnesic patients (three men and one woman) were tested (A.B., P.H., L.J., and E.P.). Bilateral damage to the hippocampal formation was confirmed by magnetic resonance imaging for three of the four patients [L. R. Squire, D. G. Amaral, G. A. Press, J. Neurosci. 10, 3106 (1990); J. Polich and L. R. Squire, Electroencephalogr. Clin. Neurophysiol. 86, 408 (1993); L. R. Squire and B. J. Knowlton, Proc. Natl. Acad. Sci. U.S.A. 92, 12470 (1995)]. The remaining patient (A.B.) was suspected to have hippocampal formation damage on the basis of etiology (anoxia). The patients averaged 67.5 years of age (range, 60 to 75 years) with an average of 15.6 years of education. They averaged 105.0 on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; mean subscale scores = 20.5 for information and 51.8 for vocabulary), and they averaged 100.8, 67.7, 74.3, 65.3, and 53.3 on the five indices of the Wechsler Memory Scale-Revised (attention concentration, verbal memory, nonverbal memory, general memory, and delayed memory, respectively). These scores have a mean of 100 in the normal population (SD = 15). For additional information about the four patients, see S. B. Hamann and L. R. Squire, Behav. Neurosci. 111, 850 (1997); ibid. 109, 1027 (1995).
38. Delay conditioning in humans can occur without individuals becoming aware of the relationship between the CS and the US [E. R. Hilgard and L. G. Humphreys, J. Gen. Psychol. 19, 111 (1938); K. W. Spence and J. Taylor, J. Exp. Psychol. 42, 183 (1951); 29, 30]. One review concluded that "very careful intensive, in-depth interviewing in the 1940s revealed clearly that there was little relationship between the subject's reported awareness and his conditioning [eye blink] performance" [D. A. Grant, Psychophysiology 10, 75 (1973), p. 75]. Four amnesic patients (three men and one woman) were tested (A.B., P.H., L.J., and E.P.). Bilateral damage to the hippocampal formation was confirmed by magnetic resonance imaging for three of the four patients [L. R. Squire, D. G. Amaral, G. A. Press, J. Neurosci. 10, 3106 (1990); J. Polich and L. R. Squire, Electroencephalogr. Clin. Neurophysiol. 86, 408 (1993); L. R. Squire and B. J. Knowlton, Proc. Natl. Acad. Sci. U.S.A. 92, 12470 (1995)]. The remaining patient (A.B.) was suspected to have hippocampal formation damage on the basis of etiology (anoxia). The patients averaged 67.5 years of age (range, 60 to 75 years) with an average of 15.6 years of education. They averaged 105.0 on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; mean subscale scores = 20.5 for information and 51.8 for vocabulary), and they averaged 100.8, 67.7, 74.3, 65.3, and 53.3 on the five indices of the Wechsler Memory Scale-Revised (attention concentration, verbal memory, nonverbal memory, general memory, and delayed memory, respectively). These scores have a mean of 100 in the normal population (SD = 15). For additional information about the four patients, see S. B. Hamann and L. R. Squire, Behav. Neurosci. 111, 850 (1997); ibid. 109, 1027 (1995).
39. Delay conditioning in humans can occur without individuals becoming aware of the relationship between the CS and the US [E. R. Hilgard and L. G. Humphreys, J. Gen. Psychol. 19, 111 (1938); K. W. Spence and J. Taylor, J. Exp. Psychol. 42, 183 (1951); 29, 30]. One review concluded that "very careful intensive, in-depth interviewing in the 1940s revealed clearly that there was little relationship between the subject's reported awareness and his conditioning [eye blink] performance" [D. A. Grant, Psychophysiology 10, 75 (1973), p. 75]. Four amnesic patients (three men and one woman) were tested (A.B., P.H., L.J., and E.P.). Bilateral damage to the hippocampal formation was confirmed by magnetic resonance imaging for three of the four patients [L. R. Squire, D. G. Amaral, G. A. Press, J. Neurosci. 10, 3106 (1990); J. Polich and L. R. Squire, Electroencephalogr. Clin. Neurophysiol. 86, 408 (1993); L. R. Squire and B. J. Knowlton, Proc. Natl. Acad. Sci. U.S.A. 92, 12470 (1995)]. The remaining patient (A.B.) was suspected to have hippocampal formation damage on the basis of etiology (anoxia). The patients averaged 67.5 years of age (range, 60 to 75 years) with an average of 15.6 years of education. They averaged 105.0 on the Wechsler Adult Intelligence Scale-Revised (WAIS-R; mean subscale scores = 20.5 for information and 51.8 for vocabulary), and they averaged 100.8, 67.7, 74.3, 65.3, and 53.3 on the five indices of the Wechsler Memory Scale-Revised (attention concentration, verbal memory, nonverbal memory, general memory, and delayed memory, respectively). These scores have a mean of 100 in the normal population (SD = 15). For additional information about the four patients, see S. B. Hamann and L. R. Squire, Behav. Neurosci. 111, 850 (1997); ibid. 109, 1027 (1995).
40. The 48 controls (21 men and 27 women) averaged 66.9 years of age (range, 59 to 78 years) and 14.5 years of education and scored 20.6 and 53.2 on the information and vocabulary subscales of the WAIS-R respectively. They were assigned to four separate groups, consisting of 10 to 14 individuals in each of four experimental conditions.
41. - were reversed for the second conditioning session. A pair of modified sunglasses held a nozzle for delivering the US (a 3-psi air puff to the left eye) and also held an infrared emitter detector for measuring the eye blink.
42. -, mean score = 2.5 out of 4; P > 0.10). These results agree with previous findings (29, 30). 18. The binomial probability of correctly answering 13 of 17 true or false questions by chance is P = 0.05.
43. +.
44. +.
45. +.
46. +.
47. The amnesic patients also exhibited no awareness of the CS-US relationships when training was continued beyond 120 trials and the test items were given during the intertrial intervals.
48. -), conditioning can proceed relatively automatically. First, amnesic patients do exhibit some learning in the single-cue condition (9). Second, normal participants exhibited conditioning with this procedure, despite a distraction task intended to reduce attention and awareness [M. C. Carillo, J. D. E. Gabrieli, J. F. Disterhoft, Soc. Neurosci. Abstr. 22, 1866 (1996)].
49. + caused by the pretraining instructions. Sensitization waned as participants habituated and became less concerned about the US.
50. L. R. Squire, S. Zola-Morgan, K. S. Chen, Behav. Neurosci. 102, 210 (1988).
51. Lesions of the caudal area of the rabbit medial prefrontal cortex impair trace eye-blink conditioning (M. A. Kronforst-Collins and J. F. Disterhott, Neurobiol. Learn. Mem., in press).
52. D. S. Woodruff-Pak, D. G. Lavond, R. F. Thompson, Brain Res. 348, 249 (1985).
53. H. Eichenbaum, Annu. Rev. Psychol. 48, 547 (1997).
54. D. L. Schacter, J. Clin. Exp. Neuropsychol. 12, 155 (1990).
55. Hippocampal cells in rabbits increase in activity alter the US during the first four to five trials of delay classical eye-blink conditioning [T. W. Berger, B. Alger, R. F. Thompson, Science 192, 483 (1976)]. This rapidly developing activity may be related to detection of the CS-US contingency and to its representation in declarative memory. The increase in activity survives lesions of the cerebellar interpositus nucleus that abolish the CR itself [
56. G. A. Clark, D. A. McCormick, D. G. Lavond, R. F. Thompson, Brain Res. 291, 125 (1984); (31)].
57. Another possible marker of declarative memory that occurs during classical conditioning (tone CS-shock US) is rapidly developing receptive field plasticity in the primary auditory cortex in response to the CS [J. S. Bakin and N. M. Weinberger, Brain Res. 536, 271 (1990)]. These data have been interpreted as stimulus-stimulus learning (declarative), a rapidly acquired association between the CS and the US. Stimulus-response learning (procedural) is a more slowly acquired and precisely timed response specific to the US (
58. N. M. Weinberger, Neurobiol. Learn. Mem., in press). Finally, another marker of declarative memory is that the hippocampus is essential for only a limited time after learning. Three studies of eye-blink conditioning in rabbits support this feature of declarative memory. First, the hippocampus is essential for trace conditioning before and shortly after training, but not 1 month later (11). Second, after trace conditioning, the excitability of CA1 and CA3 hippocampal pyramidal neurons is increased. This increase in excitability peaks 24 hours after conditioning and decays back to baseline within 7 days [
59. J. R. Moyer Jr., L. T. Thompson, J. F. Disterhoft, J. Neurosci. 16, 5536 (1996)]. Third, multiple unit recordings from the hippocampus during delay conditioning show large learning-related activity increases in response to the CS, but this activity diminishes back to baseline within 7 days, even though animals continue to exhibit robust CRs (31).
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63. We thank J. Moore, J. C. Frascino, and J. Zouzounis for assistance. Supported by the Medical Research Service of the Department of Veterans Affairs, National Institute of Mental Health (NIMH) grant 24600, and an NIMH postdoctoral fellowship (R.E.C.).