Memory consolidation of Pavlovian fear conditioning: a cellular and molecular perspective

Pavlovian fear conditioning has emerged as a leading behavioral paradigm for studying the neurobiological basis of learning and memory. Although considerable progress has been made in understanding the neural substrates of fear conditioning at the systems level, until recently little has been learned about the underlying cellular and molecular mechanisms. The success of systems-level work aimed at defining the neuroanatomical pathways underlying fear conditioning, combined with the knowledge accumulated by studies of long-term potentiation (LTP), has recently given way to new insights into the cellular and molecular mechanisms that underlie acquisition and consolidation of fear memories. Collectively, these findings suggest that fear memory consolidation in the amygdala shares essential biochemical features with LTP, and hold promise for understanding the relationship between memory consolidation and synaptic plasticity in the mammalian brain.

[1]  I. Izquierdo,et al.  Post-training intrahippocampal infusion of protein kinase C inhibitors causes amnesia in rats. , 1994, Behavioral and neural biology.

[2]  E R Kandel,et al.  Spatially resolved dynamics of cAMP and protein kinase A subunits in Aplysia sensory neurons. , 1993, Science.

[3]  S. Sara Retrieval and reconsolidation: toward a neurobiology of remembering. , 2000, Learning & memory.

[4]  Joseph E LeDoux,et al.  Synaptic plasticity in fear conditioning circuits: induction of LTP in the lateral nucleus of the amygdala by stimulation of the medial geniculate body , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[5]  U. Müller,et al.  Induction of a Specific Olfactory Memory Leads to a Long-Lasting Activation of Protein Kinase C in the Antennal Lobe of the Honeybee , 1998, The Journal of Neuroscience.

[6]  Eric R. Kandel Genes, synapses, and long‐term memory , 1997 .

[7]  J. David Sweatt,et al.  The MAPK cascade is required for mammalian associative learning , 1998, Nature Neuroscience.

[8]  Joseph E LeDoux Emotion circuits in the brain. , 2009, Annual review of neuroscience.

[9]  D. J. Lewis,et al.  Retrograde Amnesia Produced by Electroconvulsive Shock after Reactivation of a Consolidated Memory Trace , 1968, Science.

[10]  Eric R Kandel,et al.  MAP Kinase Translocates into the Nucleus of the Presynaptic Cell and Is Required for Long-Term Facilitation in Aplysia , 1997, Neuron.

[11]  Joseph E LeDoux,et al.  Somatosensory and auditory convergence in the lateral nucleus of the amygdala. , 1993, Behavioral neuroscience.

[12]  Alcino J. Silva,et al.  Deficient long-term memory in mice with a targeted mutation of the cAMP-responsive element-binding protein , 1994, Cell.

[13]  Joseph E LeDoux,et al.  Memory Consolidation of Auditory Pavlovian Fear Conditioning Requires Protein Synthesis and Protein Kinase A in the Amygdala , 2000, The Journal of Neuroscience.

[14]  J. Sweatt,et al.  A role for the beta isoform of protein kinase C in fear conditioning. , 2000, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[15]  Joseph E LeDoux,et al.  Fear conditioning and LTP in the lateral amygdala are sensitive to the same stimulus contingencies , 2001, Nature Neuroscience.

[16]  Joseph E LeDoux,et al.  Different projections of the central amygdaloid nucleus mediate autonomic and behavioral correlates of conditioned fear , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[17]  J. David Sweatt,et al.  Activation of p42 Mitogen-activated Protein Kinase in Hippocampal Long Term Potentiation* , 1996, The Journal of Biological Chemistry.

[18]  E. Kandel,et al.  cAMP contributes to mossy fiber LTP by initiating both a covalently mediated early phase and macromolecular synthesis-dependent late phase , 1994, Cell.

[19]  Michael Davis,et al.  Blocking of acquisition but not expression of conditioned fear-potentiated startle by NMDA antagonists in the amygdala , 1990, Nature.

[20]  J. David Sweatt,et al.  A Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation* , 1997, The Journal of Biological Chemistry.

[21]  J. D. McGaugh,et al.  Is the Amygdala a Locus of “Conditioned Fear”? Some Questions and Caveats , 1999, Neuron.

[22]  Stefan Strack,et al.  Mechanism and Regulation of Calcium/Calmodulin-dependent Protein Kinase II Targeting to the NR2B Subunit of the N-Methyl-d-aspartate Receptor* , 2000, The Journal of Biological Chemistry.

[23]  W. Abraham,et al.  Immediate early gene transcription and synaptic modulation , 1999, Journal of neuroscience research.

[24]  Joseph E LeDoux,et al.  The Amygdala Modulates Memory Consolidation of Fear-Motivated Inhibitory Avoidance Learning But Not Classical Fear Conditioning , 2000, The Journal of Neuroscience.

[25]  E. Kandel,et al.  A Macromolecular Synthesis-Dependent Late Phase of Long-Term Potentiation Requiring cAMP in the Medial Perforant Pathway of Rat Hippocampal Slices , 1996, The Journal of Neuroscience.

[26]  B. Everitt,et al.  Cellular Imaging of zif268 Expression in the Hippocampus and Amygdala during Contextual and Cued Fear Memory Retrieval: Selective Activation of Hippocampal CA1 Neurons during the Recall of Contextual Memories , 2001, The Journal of Neuroscience.

[27]  M. McKERNAN,et al.  Fear conditioning induces a lasting potentiation of synaptic currents in vitro , 1997, Nature.

[28]  M. Davis,et al.  Involvement of NMDA receptors within the amygdala in short- versus long-term memory for fear conditioning as assessed with fear-potentiated startle. , 2000, Behavioral neuroscience.

[29]  Lawrence M. Grover,et al.  Two components of long-term potentiation induced by different patterns of afferent activation , 1990, Nature.

[30]  Joseph E LeDoux,et al.  The lateral amygdaloid nucleus: sensory interface of the amygdala in fear conditioning , 1990, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  E R Kandel,et al.  Both Protein Kinase A and Mitogen-Activated Protein Kinase Are Required in the Amygdala for the Macromolecular Synthesis-Dependent Late Phase of Long-Term Potentiation , 2000, The Journal of Neuroscience.

[32]  Yy Huang,et al.  Examination of TEA-induced synaptic enhancement in area CA1 of the hippocampus: the role of voltage-dependent Ca2+ channels in the induction of LTP , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[33]  J. Sweatt,et al.  Activation of p 42 Mitogen-activated Protein Kinase in Hippocampal Long Term Potentiation * , 1996 .

[34]  Ralph J. Greenspan,et al.  Inhibition of calcium/calmodulin-dependent protein kinase in drosophila disrupts behavioral plasticity , 1993, Neuron.

[35]  M. Fanselow,et al.  Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: absence of a temporal gradient. , 1996, Behavioral neuroscience.

[36]  R. Nicoll,et al.  Mechanisms underlying long-term potentiation of synaptic transmission. , 1991, Annual review of neuroscience.

[37]  S. Davis,et al.  The MAPK/ERK Cascade Targets Both Elk-1 and cAMP Response Element-Binding Protein to Control Long-Term Potentiation-Dependent Gene Expression in the Dentate Gyrus In Vivo , 2000, The Journal of Neuroscience.

[38]  M. Davis,et al.  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 , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[39]  R. Nicoll,et al.  Long-term potentiation--a decade of progress? , 1999, Science.

[40]  Andrew J. Cole,et al.  Rapid increase of an immediate early gene messenger RNA in hippocampal neurons by synaptic NMDA receptor activation , 1989, Nature.

[41]  I. Izquierdo,et al.  Intrahippocampal or intraamygdala infusion of KN62, a specific inhibitor of calcium/calmodulin-dependent protein kinase II, causes retrograde amnesia in the rat. , 1994, Behavioral and neural biology.

[42]  Michael Davis,et al.  Neurobiology of fear responses: the role of the amygdala. , 1997, The Journal of neuropsychiatry and clinical neurosciences.

[43]  Joseph E LeDoux,et al.  Activation of ERK/MAP Kinase in the Amygdala Is Required for Memory Consolidation of Pavlovian Fear Conditioning , 2000, The Journal of Neuroscience.

[44]  D. Riccio,et al.  Retrograde amnesia for old (reactivated) memory: some anomalous characteristics. , 1979, Science.

[45]  R. Nicoll,et al.  NMDA-receptor-dependent synaptic plasticity: multiple forms and mechanisms , 1993, Trends in Neurosciences.

[46]  Stephen Maren,et al.  Long-term potentiation in the amygdala: a mechanism for emotional learning and memory , 1999, Trends in Neurosciences.

[47]  Joseph E LeDoux,et al.  Different lateral amygdala outputs mediate reactions and actions elicited by a fear-arousing stimulus , 2000, Nature Neuroscience.

[48]  Michela Gallagher,et al.  Amygdala central nucleus lesions: Effect on heart rate conditioning in the rabbit , 1979, Physiology & Behavior.

[49]  L. Squire,et al.  Protein synthesis and memory: a review. , 1984, Psychological bulletin.

[50]  E. Kandel,et al.  Effects of cAMP simulate a late stage of LTP in hippocampal CA1 neurons. , 1993, Science.

[51]  Edwin J. Weeber,et al.  A Role for the β Isoform of Protein Kinase C in Fear Conditioning , 2000, The Journal of Neuroscience.

[52]  G. Collingridge,et al.  Excitatory amino acids in synaptic transmission in the Schaffer collateral‐commissural pathway of the rat hippocampus. , 1983, The Journal of physiology.

[53]  Scott T. Wong,et al.  Cross Talk between ERK and PKA Is Required for Ca2+ Stimulation of CREB-Dependent Transcription and ERK Nuclear Translocation , 1998, Neuron.

[54]  F. Helmstetter,et al.  Acquisition of fear conditioning in rats requires the synthesis of mRNA in the amygdala. , 1999, Behavioral neuroscience.

[55]  E R Kandel,et al.  Different training procedures recruit either one or two critical periods for contextual memory consolidation, each of which requires protein synthesis and PKA. , 1998, Learning & memory.

[56]  Stephen Maren,et al.  Auditory fear conditioning increases CS‐elicited spike firing in lateral amygdala neurons even after extensive overtraining , 2000, The European journal of neuroscience.

[57]  H. T. Blair,et al.  Synaptic plasticity in the lateral amygdala: a cellular hypothesis of fear conditioning. , 2001, Learning & memory.

[58]  M. Davis,et al.  Intra-amygdala infusion of the N-methyl-D-aspartate receptor antagonist AP5 blocks acquisition but not expression of fear-potentiated startle to an auditory conditioned stimulus. , 1992, Behavioral neuroscience.

[59]  E R Kandel,et al.  A Molecular Switch for the Consolidation of Long‐Term Memory: cAMP‐Inducible Gene Expression , 1995, Annals of the New York Academy of Sciences.

[60]  Joseph E LeDoux,et al.  Damage to the lateral and central, but not other, amygdaloid nuclei prevents the acquisition of auditory fear conditioning. , 2001, Learning & memory.

[61]  M. Fanselow,et al.  N-methyl-D-aspartate receptor antagonist APV blocks acquisition but not expression of fear conditioning. , 1991, Behavioral neuroscience.

[62]  Eric R Kandel,et al.  Postsynaptic Induction and PKA-Dependent Expression of LTP in the Lateral Amygdala , 1998, Neuron.

[63]  E. Kandel,et al.  Recruitment of long-lasting and protein kinase A-dependent long-term potentiation in the CA1 region of hippocampus requires repeated tetanization. , 1994, Learning & memory.

[64]  E. Kandel,et al.  Control of Memory Formation Through Regulated Expression of a CaMKII Transgene , 1996, Science.

[65]  J. Sweatt,et al.  Protected‐Site Phosphorylation of Protein Kinase C in Hippocampal Long‐Term Potentiation , 1998, Journal of neurochemistry.

[66]  Alcino J. Silva,et al.  Impaired spatial learning in alpha-calcium-calmodulin kinase II mutant mice. , 1992, Science.

[67]  J. Rosen,et al.  Specific induction of early growth response gene 1 in the lateral nucleus of the amygdala following contextual fear conditioning in rats , 2000, Neuroscience.

[68]  E. Kandel Genes, synapses and long-term memory , 1995, Journal of the Neurological Sciences.

[69]  M. Fanselow,et al.  Synaptic plasticity in the basolateral amygdala induced by hippocampal formation stimulation in vivo , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[70]  J J Kim,et al.  Acquisition of fear conditioning in rats requires the synthesis of mRNA in the amygdala. , 1999, Behavioral neuroscience.

[71]  Keiko Sato,et al.  Time-Dependent Changes in Neurotrophic Factor mRNA Expression after Kindling and Long-Term Potentiation in Rats , 1998, Brain Research Bulletin.

[72]  Michael S. Fanselow,et al.  Retrograde abolition of conditional fear after excitotoxic lesions in the basolateral amygdala of rats: absence of a temporal gradient. , 1996 .

[73]  R. Tsien,et al.  Inhibition of postsynaptic PKC or CaMKII blocks induction but not expression of LTP. , 1989, Science.

[74]  Sweatt Jd,et al.  Toward a molecular explanation for long-term potentiation. , 1999 .

[75]  T. Soderling,et al.  Postsynaptic protein phosphorylation and LTP , 2000, Trends in Neurosciences.

[76]  Alcino J. Silva,et al.  CREB and memory. , 1998, Annual review of neuroscience.

[77]  S. Akira,et al.  Expressions of CCAAT/Enhancer-binding Proteins β and δ and Their Activities Are Intensified by cAMP Signaling as Well as Ca2+/Calmodulin Kinases Activation in Hippocampal Neurons* , 1998, The Journal of Biological Chemistry.

[78]  K. Harris,et al.  Slices Have More Synapses than Perfusion-Fixed Hippocampus from both Young and Mature Rats , 1999, The Journal of Neuroscience.

[79]  Joseph E LeDoux,et al.  Fear conditioning enhances short-latency auditory responses of lateral amygdala neurons: Parallel recordings in the freely behaving rat , 1995, Neuron.

[80]  E. Kandel,et al.  Requirement of a critical period of transcription for induction of a late phase of LTP. , 1994, Science.

[81]  P. Gluckman,et al.  Brain-derived neurotrophic factor expression after long-term potentiation , 1993, Neuroscience Letters.

[82]  Joseph E LeDoux,et al.  Fear Conditioning Enhances Different Temporal Components of Tone-Evoked Spike Trains in Auditory Cortex and Lateral Amygdala , 1997, Neuron.

[83]  E. Kandel,et al.  Cognitive Neuroscience and the Study of Memory , 1998, Neuron.

[84]  J. Sweatt,et al.  A necessity for MAP kinase activation in mammalian spatial learning. , 1999, Learning & memory.

[85]  Paul W. Frankland,et al.  Impaired learning in mice with abnormal short-lived plasticity , 1996, Current Biology.

[86]  Joseph E LeDoux,et al.  Why We Think Plasticity Underlying Pavlovian Fear Conditioning Occurs in the Basolateral Amygdala , 1999, Neuron.

[87]  J. Sweatt,et al.  Toward a molecular explanation for long-term potentiation. , 1999, Learning & memory.

[88]  B. Kapp,et al.  Effects of electrical stimulation of the amygdaloid central nucleus on neocortical arousal in the rabbit. , 1994, Behavioral neuroscience.

[89]  Christian Hölscher,et al.  Neuronal mechanisms of memory formation : concepts of long-term potentiation and beyond , 2000 .

[90]  Joseph E LeDoux,et al.  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. , 1997, Behavioral neuroscience.

[91]  Joseph E. LeDoux,et al.  LTP is accompanied by commensurate enhancement of auditory-evoked responses in a fear conditioning circuit , 1995, Neuron.

[92]  D. O. Hebb,et al.  The organization of behavior , 1988 .

[93]  M. Fendt,et al.  The neuroanatomical and neurochemical basis of conditioned fear , 1999, Neuroscience & Biobehavioral Reviews.

[94]  K. Nader,et al.  Fear memories require protein synthesis in the amygdala for reconsolidation after retrieval , 2000, Nature.

[95]  J. Sweatt,et al.  Transient Activation of Cyclic AMP-dependent Protein Kinase during Hippocampal Long-term Potentiation* , 1996, The Journal of Biological Chemistry.

[96]  D. Johnston,et al.  A Synaptically Controlled, Associative Signal for Hebbian Plasticity in Hippocampal Neurons , 1997, Science.

[97]  E. Shimizu,et al.  Genetic enhancement of learning and memory in mice , 1999, Nature.

[98]  R. Colbran,et al.  Autophosphorylation-dependent Targeting of Calcium/ Calmodulin-dependent Protein Kinase II by the NR2B Subunit of theN-Methyl- d-aspartate Receptor* , 1998, The Journal of Biological Chemistry.

[99]  E. Kandel,et al.  Genetic Demonstration of a Role for PKA in the Late Phase of LTP and in Hippocampus-Based Long-Term Memory , 1997, Cell.

[100]  Joseph E LeDoux,et al.  Fear conditioning induces associative long-term potentiation in the amygdala , 1997, Nature.

[101]  E. W. Kairiss,et al.  Long‐Term synaptic potentiation in the amygdala , 1990, Synapse.

[102]  Joseph E LeDoux,et al.  L-Type Voltage-Gated Calcium Channels Mediate NMDA-Independent Associative Long-Term Potentiation at Thalamic Input Synapses to the Amygdala , 1999, The Journal of Neuroscience.

[103]  E. Villacres,et al.  Induction of CRE-Mediated Gene Expression by Stimuli That Generate Long-Lasting LTP in Area CA1 of the Hippocampus , 1996, Neuron.

[104]  S. Grant,et al.  A role for the Ras signalling pathway in synaptic transmission and long-term memory , 1997, Nature.

[105]  Sheena A. Josselyn,et al.  Long-Term Memory Is Facilitated by cAMP Response Element-Binding Protein Overexpression in the Amygdala , 2001, The Journal of Neuroscience.

[106]  Joseph E LeDoux,et al.  Memory consolidation for contextual and auditory fear conditioning is dependent on protein synthesis, PKA, and MAP kinase. , 1999, Learning & memory.

[107]  M. Fanselow,et al.  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. , 1994, Behavioral neuroscience.

[108]  Sweatt Jd,et al.  A Requirement for the Mitogen-activated Protein Kinase Cascade in Hippocampal Long Term Potentiation , 1997 .

[109]  Intra-amygdala infusion of the N-methyl-D-aspartate receptor antagonist AP5 blocks acquisition but not expression of fear-potentiated startle to an auditory conditioned stimulus. , 1992, Behavioral neuroscience.

[110]  T. Bliss,et al.  Long‐lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path , 1973, The Journal of physiology.

[111]  Joseph E LeDoux,et al.  Intra-Amygdala Blockade of the NR2B Subunit of the NMDA Receptor Disrupts the Acquisition But Not the Expression of Fear Conditioning , 2001, The Journal of Neuroscience.