Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Science 3 April 1998:
Vol. 280. no. 5360, pp. 77 - 81
DOI: 10.1126/science.280.5360.77
Prev | Table of Contents | Next

Research Articles

Classical Conditioning and Brain Systems: The Role of Awareness

Robert E. Clark, Larry R. Squire *

Classical conditioning of the eye-blink response, perhaps the best studied example of associative learning in vertebrates, is relatively automatic and reflexive, and with the standard procedure (simple delay conditioning), it is intact in animals with hippocampal lesions. In delay conditioning, a tone [the conditioned stimulus (CS)] is presented just before an air puff to the eye [the unconditioned stimulus (US)]. The US is then presented, and the two stimuli coterminate. In trace conditioning, a variant of the standard paradigm, a short interval (500 to 1000 ms) is interposed between the offset of the CS and the onset of the US. Animals with hippocampal lesions fail to acquire trace conditioning. Amnesic patients with damage to the hippocampal formation and normal volunteers were tested on two versions of delay conditioning and two versions of trace conditioning and then assessed for the extent to which they became aware of the temporal relationship between the CS and the US. Amnesic patients acquired delay conditioning at a normal rate but failed to acquire trace conditioning. For normal volunteers, awareness was unrelated to successful delay conditioning but was a prerequisite for successful trace conditioning. Trace conditioning is hippocampus dependent because, as in other tasks of declarative memory, conscious knowledge must be acquired across the training session. Trace conditioning may provide a means for studying awareness in nonhuman animals, in the context of current ideas about multiple memory systems and the function of the hippocampus.

R. E. Clark is in the Department of Psychiatry, University of California, San Diego, La Jolla, CA 92093, USA. L. R. Squire is at the Veterans Affairs Medical Center, San Diego, CA 92161, USA, and Departments of Psychiatry and Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
*   To whom correspondence should be addressed.

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
A Cholinergic-Dependent Role for the Entorhinal Cortex in Trace Fear Conditioning.
F. Esclassan, E. Coutureau, G. Di Scala, and A. R. Marchand (2009)
J. Neurosci. 29, 8087-8093
   Abstract »    Full Text »    PDF »
Interactions between prefrontal cortex and cerebellum revealed by trace eyelid conditioning.
B. E. Kalmbach, T. Ohyama, J. C. Kreider, F. Riusech, and M. D. Mauk (2009)
Learn. Mem. 16, 86-95
   Abstract »    Full Text »    PDF »
Role of the phosphoinositide 3-kinase-Akt-mammalian target of the rapamycin signaling pathway in long-term potentiation and trace fear conditioning memory in rat medial prefrontal cortex.
L. Sui, J. Wang, and B.-M. Li (2008)
Learn. Mem. 15, 762-776
   Abstract »    Full Text »    PDF »
Involvement of the mGluR1 Receptor in Hippocampal Synaptic Plasticity and Associative Learning in Behaving Mice.
C. Gil-Sanz, J. M. Delgado-Garcia, A. Fairen, and A. Gruart (2008)
Cereb Cortex 18, 1653-1663
   Abstract »    Full Text »    PDF »
Neural substrates underlying human delay and trace eyeblink conditioning.
D. T. Cheng, J. F. Disterhoft, J. M. Power, D. A. Ellis, and J. E. Desmond (2008)
PNAS 105, 8108-8113
   Abstract »    Full Text »    PDF »
Contextual specificity of extinction of delay but not trace eyeblink conditioning in humans.
C. Grillon, R. P. Alvarez, L. Johnson, and C. Chavis (2008)
Learn. Mem. 15, 387-389
   Abstract »    Full Text »    PDF »
Hippocampal differentiation without recognition: An fMRI analysis of the contextual cueing task.
A. J. Greene, W. L. Gross, C. L. Elsinger, and S. M. Rao (2007)
Learn. Mem. 14, 548-553
   Abstract »    Full Text »    PDF »
Tracking Short-Term Auditory Cortical Plasticity during Classical Conditioning Using Frequency-Tagged Stimuli.
N. Weisz, B. Kostadinov, K. Dohrmann, T. Hartmann, and W. Schlee (2007)
Cereb Cortex 17, 1867-1876
   Abstract »    Full Text »    PDF »
Reduction of Trace but Not Delay Eyeblink Conditioning in Panic Disorder.
C. Grillon, S. Lissek, D. McDowell, J. Levenson, and D. S. Pine (2007)
Am J Psychiatry 164, 283-289
   Abstract »    Full Text »    PDF »
Cortical barrel lesions impair whisker-CS trace eyeblink conditioning.
R. Galvez, A. P. Weible, and J. F. Disterhoft (2007)
Learn. Mem. 14, 94-100
   Abstract »    Full Text »    PDF »
The Ferrier Lecture 1998 The molecular biology of consciousness investigated with genetically modified mice.
J.-P. Changeux (2006)
Phil Trans R Soc B 361, 2239-2259
   Abstract »    Full Text »    PDF »
Experience-Dependent Eye Movements, Awareness, and Hippocampus-Dependent Memory..
C. N. Smith, R. O. Hopkins, and L. R. Squire (2006)
J. Neurosci. 26, 11304-11312
   Abstract »    Full Text »    PDF »
Enhanced Presynaptic Neurotransmitter Release in the Anterior Cingulate Cortex of Mice with Chronic Pain..
M.-G. Zhao, S. W Ko, L.-J. Wu, H. Toyoda, H. Xu, J. Quan, J. Li, Y. Jia, M. Ren, Z. C. Xu, et al. (2006)
J. Neurosci. 26, 8923-8930
   Abstract »    Full Text »    PDF »
Trace conditioning and the hippocampus: the importance of contiguity..
D. A. Bangasser, D. E. Waxler, J. Santollo, and T. J. Shors (2006)
J. Neurosci. 26, 8702-8706
   Abstract »    Full Text »    PDF »
Microstimulation of the somatosensory cortex can substitute for vibrissa stimulation during Pavlovian conditioning.
R. Leal-Campanario, J. M. Delgado-Garcia, and A. Gruart (2006)
PNAS 103, 10052-10057
   Abstract »    Full Text »    PDF »
Hippocampal CA3 NMDA Receptors Are Crucial for Adaptive Timing of Trace Eyeblink Conditioned Response.
Y. Kishimoto, K. Nakazawa, S. Tonegawa, Y. Kirino, and M. Kano (2006)
J. Neurosci. 26, 1562-1570
   Abstract »    Full Text »    PDF »
Involvement of the CA3-CA1 Synapse in the Acquisition of Associative Learning in Behaving Mice.
A. Gruart, M. D. Munoz, and J. M. Delgado-Garcia (2006)
J. Neurosci. 26, 1077-1087
   Abstract »    Full Text »    PDF »
Fear Conditioning following Unilateral Temporal Lobectomy: Dissociation of Conditioned Startle Potentiation and Autonomic Learning.
A. I. Weike, A. O. Hamm, H. T. Schupp, U. Runge, H. W. S. Schroeder, and C. Kessler (2005)
J. Neurosci. 25, 11117-11124
   Abstract »    Full Text »    PDF »
The neural correlates of implicit and explicit sequence learning: Interacting networks revealed by the process dissociation procedure.
A. Destrebecqz, P. Peigneux, S. Laureys, C. Degueldre, G. Del Fiore, J. Aerts, A. Luxen, M. Van Der Linden, A. Cleeremans, and P. Maquet (2005)
Learn. Mem. 12, 480-490
   Abstract »    Full Text »    PDF »
Deficits in Trace Fear Memory and Long-Term Potentiation in a Mouse Model for Fragile X Syndrome.
M.-G. Zhao, H. Toyoda, S. W. Ko, H.-K. Ding, L.-J. Wu, and M. Zhuo (2005)
J. Neurosci. 25, 7385-7392
   Abstract »    Full Text »    PDF »
What is the function of the claustrum?.
F. C Crick and C. Koch (2005)
Phil Trans R Soc B 360, 1271-1279
   Abstract »    Full Text »    PDF »
Cognitive Processes in Extinction.
P. F. Lovibond (2004)
Learn. Mem. 11, 495-500
   Abstract »    Full Text »    PDF »
A Role for Prefrontal Cortex in Memory Storage for Trace Fear Conditioning.
J. D. Runyan, A. N. Moore, and P. K. Dash (2004)
J. Neurosci. 24, 1288-1295
   Abstract »    Full Text »    PDF »
Neural Substrates Mediating Human Delay and Trace Fear Conditioning.
D. C. Knight, D. T. Cheng, C. N. Smith, E. A. Stein, and F. J. Helmstetter (2004)
J. Neurosci. 24, 218-228
   Abstract »    Full Text »    PDF »
Galantamine Facilitates Acquisition of a Trace-Conditioned Eyeblink Response in Healthy, Young Rabbits.
B. B. Simon, B. Knuckley, and D. A. Powell (2004)
Learn. Mem. 11, 116-122
   Abstract »    Full Text »    PDF »
Expression of conditional fear with and without awareness.
D. C. Knight, H. T. Nguyen, and P. A. Bandettini (2003)
PNAS 100, 15280-15283
   Abstract »    Full Text »    PDF »
Brain-Derived Neurotrophic Factor-Induced Gene Expression Reveals Novel Actions of VGF in Hippocampal Synaptic Plasticity.
J. Alder, S. Thakker-Varia, D. A. Bangasser, M. Kuroiwa, M. R. Plummer, T. J. Shors, and I. B. Black (2003)
J. Neurosci. 23, 10800-10808
   Abstract »    Full Text »    PDF »
Neural Substrates of Eyeblink Conditioning: Acquisition and Retention.
K. M. Christian and R. F. Thompson (2003)
Learn. Mem. 10, 427-455
   Abstract »    Full Text »    PDF »
Trace but not delay fear conditioning requires attention and the anterior cingulate cortex.
C. J. Han, C. M. O'Tuathaigh, L. van Trigt, J. J. Quinn, M. S. Fanselow, R. Mongeau, C. Koch, and D. J. Anderson (2003)
PNAS 100, 13087-13092
   Abstract »    Full Text »    PDF »
Role of the Serotonin 5-HT2A Receptor in Learning.
J. A. Harvey (2003)
Learn. Mem. 10, 355-362
   Abstract »    Full Text »    PDF »
Functional Connectivity of the Medial Temporal Lobe Relates to Learning and Awareness.
A. R. McIntosh, M. N. Rajah, and N. J. Lobaugh (2003)
J. Neurosci. 23, 6520-6528
   Abstract »    Full Text »    PDF »
Role of the hippocampal system in associative learning beyond the spatial domain.
P. J. Brasted, T. J. Bussey, E. A. Murray, and S. P. Wise (2003)
Brain 126, 1202-1223
   Abstract »    Full Text »    PDF »
Working memory and fear conditioning.
R. M. Carter, C. Hofstotter, N. Tsuchiya, and C. Koch (2003)
PNAS 100, 1399-1404
   Abstract »    Full Text »    PDF »
Associative Memory Formation Increases the Observation of Dendritic Spines in the Hippocampus.
B. Leuner, J. Falduto, and T. J. Shors (2003)
J. Neurosci. 23, 659-665
   Abstract »    Full Text »    PDF »
Testosterone in utero and at birth dictates how stressful experience will affect learning in adulthood.
T. J. Shors and G. Miesegaes (2002)
PNAS 99, 13955-13960
   Abstract »    Full Text »    PDF »
Disorders of memory.
M. D. Kopelman (2002)
Brain 125, 2152-2190
   Abstract »    Full Text »    PDF »
Hippocampal Pyramidal Cell Activity Encodes Conditioned Stimulus Predictive Value During Classical Conditioning in Alert Cats.
A. Munera, A. Gruart, M. D. Munoz, R. Fernandez-Mas, and J. M. Delgado-Garcia (2001)
J Neurophysiol 86, 2571-2582
   Abstract »    Full Text »    PDF »
Sex Differences and Opposite Effects of Stress on Dendritic Spine Density in the Male Versus Female Hippocampus.
T. J. Shors, C. Chua, and J. Falduto (2001)
J. Neurosci. 21, 6292-6297
   Abstract »    Full Text »    PDF »
Consciousness.
A. Zeman (2001)
Brain 124, 1263-1289
   Abstract »    Full Text »    PDF »
Rhesus monkeys know when they remember.
R. R. Hampton (2001)
PNAS
   Abstract »    Full Text »
Learning- and Expectation-Related Changes in the Human Brain During Motor Learning.
N. Ramnani, I. Toni, O. Josephs, J. Ashburner, and R. E. Passingham (2000)
J Neurophysiol 84, 3026-3035
   Abstract »    Full Text »    PDF »
Parallel Acquisition of Awareness and Trace Eyeblink Classical Conditioning.
J. R. Manns, R. E. Clark, and L. R. Squire (2000)
Learn. Mem. 7, 267-272
   Abstract »    Full Text »
Functional Connectivity in the Thalamus and Hippocampus Studied with Functional MR Imaging.
T. Stein, C. Moritz, M. Quigley, D. Cordes, V. Haughton, and E. Meyerand (2000)
AJNR Am. J. Neuroradiol. 21, 1397-1401
   Abstract »    Full Text »
Learning Performance of Normal and Mutant Drosophila after Repeated Conditioning Trials with Discrete Stimuli.
C. D. O. Beck, B. Schroeder, and R. L. Davis (2000)
J. Neurosci. 20, 2944-2953
   Abstract »    Full Text »    PDF »
Psychobiology and Social Psychology: Past, Present, and Future.
G. G. Berntson and J. T. Cacioppo (2000)
Personality and Social Psychology Review 4, 3-15
   Abstract »    PDF »
Amygdala-Hippocampal Involvement in Human Aversive Trace Conditioning Revealed through Event-Related Functional Magnetic Resonance Imaging.
C. Buchel, R. J. Dolan, J. L. Armony, and K. J. Friston (1999)
J. Neurosci. 19, 10869-10876
   Abstract »    Full Text »    PDF »
Learning in Parkinson's disease: eyeblink conditioning, declarative learning, and procedural learning.
M. Sommer, J. Grafman, K. Clark, and M. Hallett (1999)
J. Neurol. Neurosurg. Psychiatry 67, 27-34
   Abstract »    Full Text »
Interactions of Prefrontal Cortex in Relation to Awareness in Sensory Learning.
A. R. McIntosh, M. N. Rajah, and N. J. Lobaugh (1999)
Science 284, 1531-1533
   Abstract »    Full Text »
Hippocampal neurogenesis in adult Old World primates.
E. Gould, A. J. Reeves, M. Fallah, P. Tanapat, C. G. Gross, and E. Fuchs (1999)
PNAS 96, 5263-5267
   Abstract »    Full Text »    PDF »
Rhesus monkeys know when they remember.
R. R. Hampton (2001)
PNAS 98, 5359-5362
   Abstract »    Full Text »    PDF »


To Advertise     Find Products

Science. ISSN 0036-8075 (print), 1095-9203 (online)