Amygdalar NMDA Receptors Are Critical for the Expression of Multiple Conditioned Fear Responses

There is conflicting evidence regarding the issue of whether NMDA receptors in the basolateral amygdalar complex (BLA) are critically involved in the expression of conditioned fear. This matter was addressed by infusing the rat BLA withd,l-2-amino-5-phosphonovaleric acid (APV), a competitive NMDA receptor antagonist. APV infusion into the BLA was reported to block the expression of conditioned fear when measured by freezing but not when measured by fear-potentiated startle response to a loud noise. To examine this issue further, here we used multiple indices of conditioned fear, including analgesia, 22 kHz ultrasonic vocalization (USV), defecation, and freezing. Rats with bilateral BLA cannula implants underwent fear conditioning consisting of 10 tone–footshock pairings. Before context and tone fear-retention tests, animals received intra-BLA infusions with APV (2.5 μg/side) or artificial CSF. Both tone and context tests demonstrated that the expression of conditioned freezing, USV, defecation, and analgesia were significantly impaired by intra-amygdalar infusions of APV. In a second set of experiments, intra-BLA infusions of APV markedly impaired the normal expression of postshock fear responses during training, as measured by freezing, USV, and defecation. Immediate postshock fear expression was predictive of subsequent fear retention to the tone and context when the animals were not infused. These results are consistent with the hypothesis that amygdalar NMDA receptors participate in normal synaptic transmission and therefore the overall functioning of the amygdala.

[1]  Joseph E LeDoux.  Emotion Circuits in the Brain , 2000 .

[2]  S. Kelso,et al.  Differential conditioning of associative synaptic enhancement in hippocampal brain slices. , 1986, Science.

[3]  M. Fanselow,et al.  N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats , 1996 .

[4]  S. Kelso,et al.  Hebbian synapses in hippocampus. , 1986, Proceedings of the National Academy of Sciences of the United States of America.

[5]  C. Shatz.  Impulse activity and the patterning of connections during cns development , 1990, Neuron.

[6]  Conditioned Enhancement of the Early Component of the Rat Eyeblink Reflex , 1996, Neurobiology of Learning and Memory.

[7]  Jonathan C. Gewirtz,et al.  Second-order fear conditioning prevented by blocking NMDA receptors in amygdala , 1997, Nature.

[8]  E. W. Kairiss,et al.  Hebbian synapses: biophysical mechanisms and algorithms. , 1990, Annual review of neuroscience.

[9]  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.

[10]  M. Fanselow,et al.  The Amygdala and Fear Conditioning: Has the Nut Been Cracked? , 1996, Neuron.

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

[12]  R. Morris,et al.  Hippocampal synaptic plasticity and NMDA receptors: a role in information storage? , 1990, Philosophical transactions of the Royal Society of London. Series B, Biological sciences.

[13]  Michael Davis,et al.  Extinction of fear-potentiated startle: blockade by infusion of an NMDA antagonist into the amygdala , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

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

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

[16]  E. W. Kairiss,et al.  Long-Term Potentiation in Two Synaptic Systems of the Hippocampal Brain Slice , 1989 .

[17]  P. Chapman,et al.  Induction of long‐term potentiation in the basolateral amygdala does not depend on NMDA receptor activation , 1992, Synapse.

[18]  F. Attneave,et al.  The Organization of Behavior: A Neuropsychological Theory , 1949 .

[19]  M. Fanselow,et al.  N-methyl-D-aspartate receptors in the basolateral amygdala are required for both acquisition and expression of conditional fear in rats. , 1996, Behavioral neuroscience.

[20]  M. Fanselow,et al.  The benzodiazepine inverse agonist DMCM as an unconditional stimulus for fear-induced analgesia: implications for the role of GABAA receptors in fear-related behavior. , 1992, Behavioral neuroscience.

[21]  Michael Davis,et al.  Fear-potentiated startle: A neural and pharmacological analysis , 1993, Behavioural Brain Research.

[22]  D. Johnston,et al.  NMDA-receptor-independent long-term potentiation. , 1992, Annual review of physiology.

[23]  J. D. McGaugh,et al.  Glucocorticoid Receptor Agonist and Antagonist Administration into the Basolateral but Not Central Amygdala Modulates Memory Storage , 1997, Neurobiology of Learning and Memory.

[24]  J. S. Brown,et al.  Conditioned fear as revealed by magnitude of startle response to an auditory stimulus. , 1951, Journal of experimental psychology.

[25]  Hongjoo J. Lee,et al.  Amygdalar NMDA Receptors are Critical for New Fear Learning in Previously Fear-Conditioned Rats , 1998, The Journal of Neuroscience.

[26]  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.

[27]  D C Blanchard,et al.  Crouching as an index of fear. , 1969, Journal of comparative and physiological psychology.

[28]  Joseph E LeDoux,et al.  Distinct populations of NMDA receptors at subcortical and cortical inputs to principal cells of the lateral amygdala. , 1999, Journal of neurophysiology.

[29]  C. Cotman,et al.  Long-term potentiation of guinea pig mossy fiber responses is not blocked by N-methyl d-aspartate antagonists , 1986, Neuroscience Letters.

[30]  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.

[31]  P. Bellgowan,et al.  Lesions of the amygdala block conditional hypoalgesia on the tail flick test , 1993, Brain Research.

[32]  R. Nicoll,et al.  Comparison of two forms of long-term potentiation in single hippocampal neurons. , 1990, Science.

[33]  T. H. Brown,et al.  Associative long-term potentiation in hippocampal slices. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

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

[35]  M. Fendt,et al.  Injections of the NMDA Receptor Antagonist Aminophosphonopentanoic Acid into the Lateral Nucleus of the Amygdala Block the Expression of Fear-Potentiated Startle and Freezing , 2001, The Journal of Neuroscience.

[36]  K D Miller,et al.  Visual responses in adult cat visual cortex depend on N-methyl-D-aspartate receptors. , 1989, Proceedings of the National Academy of Sciences of the United States of America.

[37]  D. C. Blanchard,et al.  Twenty-two kHz alarm cries to presentation of a predator, by laboratory rats living in visible burrow systems , 1991, Physiology & Behavior.

[38]  T. Teyler,et al.  Long-term potentiation. , 1987, Annual review of neuroscience.

[39]  T. Shors,et al.  NMDA receptor antagonism in the lateral/basolateral but not central nucleus of the amygdala prevents the induction of facilitated learning in response to stress. , 1998, Learning & memory.

[40]  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.

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

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