A cellular mechanism of classical conditioning in Aplysia.

The defensive siphon and gill withdrawal of Aplysia is a simple reflex, mediated by a well-defined neural circuit, that exhibits sensitization in response to strong stimulation of the tail. The siphon withdrawal reflex also exhibits classical conditioning when a weak stimulus to the siphon or mantle shelf (the conditioned stimulus or CS) is paired with a shock to the tail (the unconditioned stimulus or US). Cellular studies indicate that the mechanism of this conditioning shares aspects of the mechanism of sensitization of the reflex: presynaptic facilitation due to a cAMP-mediated decrease in K+ current and consequent broadening of action potentials in the sensory neurones. Thus, tail shock (the US) produces greater facilitation of the monosynaptic EPSP from a sensory to a motor neurone if the shock is immediately preceded by spike activity in the sensory neurone than if it occurs without spike activity (sensitization), or if the shock and spike activity are presented in a specifically unpaired pattern. This activity-dependent amplification of facilitation involves a greater broadening of action potentials in paired than in unpaired sensory neurones and appears to be due to a greater depression of the same serotonin- and cAMP-sensitive K+ current involved in sensitization. These results indicate that a mechanism of classical conditioning of the withdrawal reflex is an elaboration of the mechanism underlying sensitization. By analogy, the mechanisms of higher-order features of learning, such as the effect of contingency, may be built from combinations of the molecular mechanisms of these simple forms of learning.

[1]  K. Lashley.  Brain Mechanisms and Intelligence: A Quantitative Study of Injuries to the Brain , 1965 .

[2]  S. Kaplan.  The Physiology of Thought , 1950 .

[3]  G. Horridge,et al.  Learning of Leg Position by Headless Insects , 1962, Nature.

[4]  W. Spencer,et al.  Response decrement of the flexion reflex in the acute spinal cat and transient restoration by strong stimuli. , 1966, Journal of neurophysiology.

[5]  L. Kamin.  Predictability, surprise, attention, and conditioning , 1967 .

[6]  R. Rescorla.  Pavlovian conditioning and its proper control procedures. , 1967, Psychological review.

[7]  E. Kandel,et al.  MORPHOLOGICAL AND FUNCTIONAL PROPERTIES OF IDENTIFIED NEURONS IN THE ABDOMINAL GANGLION OF APLYSIA CALIFORNICA , 1967 .

[8]  R. Rescorla.  Probability of shock in the presence and absence of CS in fear conditioning. , 1968, Journal of comparative and physiological psychology.

[9]  C. Woody,et al.  Changes in evoked responses from facial nucleus of cat with conditioning and extinction of an eye blink. , 1969, Journal of neurophysiology.

[10]  F. Krasne,et al.  Excitation and habituation of the crayfish escape reflex: the depolarizing response in lateral giant fibres of the isolated abdomen. , 1969, The Journal of experimental biology.

[11]  D. Cohen.  Development of a vertebrate experimental model for cellular neurophysiologic studies of learning , 1969, Conditional Reflex.

[12]  Irving Kupfermann,et al.  Neuronal Correlates of Habituation and Dishabituation of the Gill-Withdrawal Reflex in Aplysia , 1970, Science.

[13]  E R Kandel,et al.  Neuronal Mechanisms of Habituation and Dishabituation of the Gill-Withdrawal Reflex in Aplysia , 1970, Science.

[14]  E. Kandel,et al.  Habituation and Dishabituation of the GM-Withdrawal Reflex in Aplysia , 1970, Science.

[15]  Eric R. Kandel,et al.  Long-Term Habituation of a Defensive Withdrawal Reflex in Aplysia , 1972, Science.

[16]  R. Zucker.  Crayfish escape behavior and central synapses. II. Physiological mechanisms underlying behavioral habituation. , 1972, Journal of neurophysiology.

[17]  Eric R. Kandel,et al.  Long-Term Sensitization of a Defensive Withdrawal Reflex in Aplysia , 1973, Science.

[18]  W. Harris,et al.  Conditioned behavior in Drosophila melanogaster. , 1974, Proceedings of the National Academy of Sciences of the United States of America.

[19]  G. Mpitsos,et al.  Learning: rapid aversive conditioning in the gastropod mollusk Pleurobranchaea. , 1975, Science.

[20]  A. Gelperin.  Rapid food-aversion learning by a terrestrial mollusk. , 1975, Science.

[21]  E. Kandel,et al.  Presynaptic facilitation as a mechanism for behavioral sensitization in Aplysia. , 1976, Science.

[22]  R. F. Thompson,et al.  The search for the engram. , 1976, The American psychologist.

[23]  E R Kandel,et al.  Synaptic facilitation and behavioral sensitization in Aplysia: possible role of serotonin and cyclic AMP. , 1976, Science.

[24]  Y. Jan,et al.  dunce, a mutant of Drosophila deficient in learning. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[25]  E. Kandel,et al.  Presynaptic modulation of voltage-dependent Ca2+ current: mechanism for behavioral sensitization in Aplysia californica. , 1978, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. Crow,et al.  Retention of an associative behavioral change in Hermissenda. , 1978, Science.

[27]  C. D. Woody,et al.  Effects of acetylcholine and cyclic GMP on input resistance of cortical neurons in awake cats , 1978, Brain Research.

[28]  M. M. Patterson,et al.  Neuronal unit activity in the abducens nucleus during classical conditioning of the nictitating membrane response in the rabbit (Oryctolagus cuniculus). , 1979, Journal of comparative and physiological psychology.

[29]  E. Kandel,et al.  Classical conditioning in Aplysia californica. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[30]  E. Kandel,et al.  Intracellular injection of t he catalytic subunit of cyclic AMP-dependent protein kinase simulates facilitation of transmitter release underlying behavioral sensitization in Aplysia. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[31]  D. Alkon,et al.  Associative Behavioral Modification in Hermissenda: Cellular Correlates , 1980, Science.

[32]  E. Kandel,et al.  Mechanism of calcium current modulation underlying presynaptic facilitation and behavioral sensitization in Aplysia. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[33]  C. Woody,et al.  Long-term changes in excitability of cortical neurons after Pavlovian conditioning and extinction. , 1980, Journal of neurophysiology.

[34]  R. Hawkins.  Interneurons involved in mediation and modulation of gill-withdrawal reflex in Aplysia. III. Identified facilitating neurons increase Ca2+ current in sensory neurons. , 1981, Journal of neurophysiology.

[35]  E. Kandel,et al.  Classical conditioning in a simple withdrawal reflex in Aplysia californica , 1981, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[36]  D. Alkon,et al.  Change in a specific phosphoprotein band following associative learning in Hermissenda , 1981, Nature.

[37]  D. Cohen,et al.  Modification of the discharge of vagal cardiac neurons during learned heart rate change. , 1981, Science.

[38]  E. Kandel,et al.  Interneurons involved in mediation and modulation of gill-withdrawal reflex in Aplysia. II. Identified neurons produce heterosynaptic facilitation contributing to behavioral sensitization. , 1981, Journal of neurophysiology.

[39]  E. Kandel,et al.  Interneurons involved in mediation and modulation of gill-withdrawal reflex in Aplysia. IV. Morphological basis of presynaptic facilitation. , 1981, Journal of neurophysiology.

[40]  C. Sahley,et al.  The in vitro Classical Conditioning of the Gill Withdrawal Reflex of Aplysia californica. , 1981, Science.

[41]  Ronald L. Davis,et al.  Defect in cyclic AMP phosphodiesterase due to the dunce mutation of learning in Drosophila melanogaster , 1981, Nature.

[42]  D. Alkon,et al.  Primary changes of membrane currents during retention of associative learning. , 1982, Science.

[43]  E. Kandel,et al.  Facilitatory transmitter causes a selective and prolonged increase in adenosine 3':5'-monophosphate in sensory neurons mediating the gill and siphon withdrawal reflex in Aplysia , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[44]  E. Kandel,et al.  Inhibitor of adenosine 3':5'-monophosphate-dependent protein kinase blocks presynaptic facilitation in Aplysia , 1982, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[45]  W. Quinn,et al.  Three Drosophila mutations that block associative learning also affect habituation and sensitization. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[46]  E R Kandel,et al.  Serotonin modulates a specific potassium current in the sensory neurons that show presynaptic facilitation in Aplysia. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[47]  E. Kandel,et al.  Molecular biology of learning: modulation of transmitter release. , 1982, Science.

[48]  E. Kandel,et al.  Serotonin and cyclic AMP close single K+ channels in Aplysia sensory neurones , 1982, Nature.

[49]  R. Hawkins,et al.  Uptake of [3H]serotonin in the abdominal ganglion ofAplysia california. Further studies on the morphological and biochemical basis of presynaptic facilitation , 1983, Brain Research.

[50]  E. Kandel,et al.  A cellular mechanism of classical conditioning in Aplysia: activity-dependent amplification of presynaptic facilitation. , 1983, Science.

[51]  J. Byrne,et al.  Associative conditioning of single sensory neurons suggests a cellular mechanism for learning. , 1983, Science.

[52]  C. Breen,et al.  Octopamine—a neurohormone with presynaptic activity-dependent effects at crayfish neuromuscular junctions , 1983, Nature.

[53]  C. H. Bailey,et al.  Morphological basis of long-term habituation and sensitization in Aplysia. , 1983, Science.

[54]  Y. Dudai,et al.  Abnormal activity of adenylate cyclase in the Drosophila memory mutant rutabaga , 1983, Neuroscience Letters.

[55]  D. Alkon,et al.  Protein kinase injection reduces voltage-dependent potassium currents. , 1983, Science.

[56]  E. Kandel,et al.  Differential classical conditioning of a defensive withdrawal reflex in Aplysia californica. , 1983, Science.

[57]  E. Kandel,et al.  Classical conditioning and sensitization share aspects of the same molecular cascade in Aplysia. , 1983, Cold Spring Harbor symposia on quantitative biology.

[58]  E. Kandel,et al.  Is there a cell-biological alphabet for simple forms of learning? , 1984, Psychological review.

[59]  E. Kandel,et al.  A test of Hebb's postulate at identified synapses which mediate classical conditioning in Aplysia , 1984, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[60]  M. Livingstone,et al.  Loss of calcium/calmodulin responsiveness in adenylate cyclase of rutabaga, a Drosophila learning mutant , 1984, Cell.

[61]  J. Byrne,et al.  Associative conditioning analog selectively increases cAMP levels of tail sensory neurons in Aplysia. , 1985, Proceedings of the National Academy of Sciences of the United States of America.