PMID- 35410880
OWN - NLM
STAT- MEDLINE
DCOM- 20220527
LR  - 20240401
IS  - 1529-2401 (Electronic)
IS  - 0270-6474 (Print)
IS  - 0270-6474 (Linking)
VI  - 42
IP  - 21
DP  - 2022 May 25
TI  - Prediction Error Determines Whether NMDA Receptors in the Basolateral Amygdala 
      Complex Are Involved in Pavlovian Fear Conditioning.
PG  - 4360-4379
LID - 10.1523/JNEUROSCI.2156-21.2022 [doi]
AB  - 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.
CI  - Copyright (c) 2022 the authors.
FAU - Williams-Spooner, Matthew J
AU  - Williams-Spooner MJ
AUID- ORCID: 0000-0001-9760-465X
AD  - School of Psychology, University of New South Wales, Sydney, New South Wales, 
      Australia 2052.
AD  - Center for Studies in Behavioral Neurobiology, Department of Psychology, 
      Concordia University, Montreal, Quebec, Canada H3G 1M8.
FAU - Delaney, Andrew J
AU  - Delaney AJ
AD  - School of Biomedical Sciences, Charles Sturt University, Orange, New South Wales, 
      Australia 2795.
FAU - Westbrook, R Frederick
AU  - Westbrook RF
AUID- ORCID: 0000-0002-6880-9274
AD  - School of Psychology, University of New South Wales, Sydney, New South Wales, 
      Australia 2052.
FAU - Holmes, Nathan M
AU  - Holmes NM
AUID- ORCID: 0000-0002-0592-2026
AD  - School of Psychology, University of New South Wales, Sydney, New South Wales, 
      Australia 2052 n.holmes@unsw.edu.au.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220411
PL  - United States
TA  - J Neurosci
JT  - The Journal of neuroscience : the official journal of the Society for 
      Neuroscience
JID - 8102140
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Amygdala/physiology
MH  - Animals
MH  - *Basolateral Nuclear Complex/physiology
MH  - Extinction, Psychological/physiology
MH  - Fear/physiology
MH  - Male
MH  - Rats
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
PMC - PMC9145214
OTO - NOTNLM
OT  - NMDA receptor
OT  - basolateral amygdala
OT  - fear conditioning
OT  - higher-order conditioning
OT  - prediction error
OT  - rat
EDAT- 2022/04/13 06:00
MHDA- 2022/05/28 06:00
PMCR- 2022/11/25
CRDT- 2022/04/12 05:29
PHST- 2021/10/27 00:00 [received]
PHST- 2022/03/07 00:00 [revised]
PHST- 2022/03/10 00:00 [accepted]
PHST- 2022/04/13 06:00 [pubmed]
PHST- 2022/05/28 06:00 [medline]
PHST- 2022/04/12 05:29 [entrez]
PHST- 2022/11/25 00:00 [pmc-release]
AID - JNEUROSCI.2156-21.2022 [pii]
AID - JN-RM-2156-21 [pii]
AID - 10.1523/JNEUROSCI.2156-21.2022 [doi]
PST - ppublish
SO  - J Neurosci. 2022 May 25;42(21):4360-4379. doi: 10.1523/JNEUROSCI.2156-21.2022. 
      Epub 2022 Apr 11.