%0 Journal Article %A Matthew J. Williams-Spooner %A Andrew J. Delaney %A R. Frederick Westbrook %A Nathan M. Holmes %T Prediction Error Determines Whether NMDA Receptors in the Basolateral Amygdala Complex Are Involved in Pavlovian Fear Conditioning %D 2022 %R 10.1523/JNEUROSCI.2156-21.2022 %J The Journal of Neuroscience %P 4360-4379 %V 42 %N 21 %X It is widely accepted that activation of NMDA receptors (NMDAR) is necessary for the formation of fear memories in the basolateral amygdala complex (BLA). This acceptance is based on findings that blockade of NMDAR in the BLA disrupts Pavlovian fear conditioning in rodents when initially innocuous stimuli are paired with aversive and unexpected events (surprising foot shock). The present study challenges this acceptance by showing that the involvement of NMDAR in Pavlovian fear conditioning is determined by prediction errors in relation to aversive events. In the initial experiments, male rats received a BLA infusion of the NMDAR antagonist, D-AP5 and were then exposed to pairings of a novel target stimulus and foot shock. This infusion disrupted acquisition of fear to the target when the shock was surprising (experiments 1a, 1b, 2a, 2b, 3a, and 3b) but spared fear to the target when the shock was expected based on the context, time and other stimuli that were present (experiments 1a and 1b). Under the latter circumstances, fear to the target required activation of calcium-permeable AMPAR (CP-AMPA; experiments 4a, 4b, and 4c), which, using electrophysiology, were shown to regulate the activity of interneurons in the BLA (experiment 5). Thus, NMDAR activation is not required for fear conditioning when danger occurs as expected given the context, time and stimuli present, but is required for fear conditioning when danger occurs unexpectedly. These findings are related to current theories of NMDAR function and ways that prediction errors might influence the substrates of fear memory formation in the BLA.SIGNIFICANCE STATEMENT It is widely accepted that NMDA receptors (NMDAR) in the basolateral amygdala complex (BLA) are activated by pairings of a conditioned stimulus (CS) and an aversive unconditioned (US) stimulus, leading to the synaptic changes that underlie formation of a CS-US association. The present findings are significant in showing that this theory is incomplete. When the aversive US is unexpected, animals encode all features of the situation (context, time and stimuli present) as a new fear/threat memory, which is regulated by NMDAR in the BLA. However, when the US is expected based on the context, time and stimuli present, the new fear memory is assimilated into networks that represent those features, which occurs independently of NMDAR activation in the BLA. %U https://www.jneurosci.org/content/jneuro/42/21/4360.full.pdf