Selecting danger signals: dissociable roles of nucleus accumbens shell and core glutamate in predictive fear learning

Abstract

Conditioned stimuli (CSs) vary in their reliability as predictors of danger. Animals must therefore select among CSs those that are appropriate to enter into an association with the aversive unconditioned stimulus (US). The actions of prediction error instruct this stimulus selection so that when prediction error is large, attention to the CS is maintained and learning occurs but when prediction is small attention to the CS is withdrawn and learning is prevented. Here we studied the role of glutamate acting at rat nucleus accumbens shell (AcbSh) and core (AcbC) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in this selection of danger signals. Using associative blocking and unblocking designs in rats, we show that antagonizing AcbSh AMPA receptors via infusions of 2,3-dihydroxy-6-nitro-7-sulphamoyl-benzo[f]quinoxaline-2,3-dione (NBQX; 0.5 μg) prevents the unblocking of fear learning, whereas antagonizing AcbC AMPA receptors via infusions of NBQX (0.5 μg) prevents both the blocking and unblocking of fear learning. These results identify dissociable but complementary roles for AcbSh and AcbC glutamate acting at AMPA receptors in selecting danger signals: AcbSh AMPA receptors upregulate attention and learning to CSs that signal surprising USs, whereas AcbC AMPA receptors encode the predicted outcome of each trial.

The nucleus accumbens shell in reinstatement and extinction of drug seeking

“…Finally, in the rostrocaudal plane, disrupting glutamatergic neurotransmission via infusions of an AMPA/Kainate receptor antagonist generates appetitively motivated behaviors (e.g., ingestion) in the rostral medial AcbSh but aversively motivated behaviors (e.g., defensive treading) in the caudal medial AcbSh (Reynolds & Berridge, , ). Interestingly, these rostrocaudal variations in valence are dopamine‐dependent (Faure et al ., ), consistent with other findings implicating AcbSh glutamate and dopamine neurotransmission in aspects of aversive learning and motivation (Li & McNally, ,b).…”

Brain mechanisms controlling Pavlovian fear conditioning.

“…The effects of Acb AMPA manipulations can be explained formally by supposing that poorer predictors are associated with greater signaling via Acb AMPA receptors than better predictors, so that signaling via Acb AMPA receptors is inversely related to ∑V in the Pearce-Hall model. We (S. S. Y. Li & McNally, 2015b) conducted a variety of simulations of this action using the Pearce-Kaye-Hall model (Pearce, Kaye, & Hall, 1982) and confirmed that it would yield these experimental results.…”

“…We (S. S. Y. Li & McNally, 2015b) conducted a variety of simulations of this action using the Pearce-Kaye-Hall model (Pearce, Kaye, & Hall, 1982) and confirmed that it would yield these experimental results.…”

“…Antagonizing Acb AMPA receptors prior to Stage II training prevented unblocking of fear learning and also prevented blocking of fear learning but had no effect on de novo fear learning in controls (S. S. Y. Li & McNally, 2015b). That is, the same manipulation during the same CS-US training prevented learning in response to prediction error (unblocking) but restored learning when there was no or little prediction error (blocking).…”

“…Animals that received the 1mA shock in Stages I and II showed blocking, whereas animals that received an upshift in US magnitude from 0.6mA in Stage I to 1 mA in Stage II showed unblocking. Antagonizing Acb AMPA receptors prior to Stage II training prevented unblocking of fear learning and also prevented blocking of fear learning but had no effect on de novo fear learning in controls (S. S. Y. Li & McNally, 2015b).…”