Role of the basolateral amygdala and NMDA receptors in the acquisition and extinction of higher-order conditioned fear

摘要

Activation of N-methyl-D-aspartate receptors (NMDAr) in the basolateral complex of the amygdala (BLA) is crucial for the acquisition and extinction of Pavlovian first-order fear. It is unknown whether these substrates also mediate higher-order fear. Higher-order fear has been observed using two procedures. In second-order conditioning, pairings of a tone (S1) and shock are followed by pairings of a light (S2) and the tone (S1); in sensory preconditioning, pairings of a light (S2) and tone (S1) are followed by pairings of the tone (S1) and shock. In each procedure, test presentations of the light alone elicit fear responses which extinguish across such presentations. This thesis examined whether activation of NMDAr in the BLA is necessary for the acquisition and extinction of higher-order fear. Inactivation of the BLA via infusion of the GABAA agonist muscimol, systemic injection of the NMDAr antagonist MK-801, and BLA infusion of the NMDAr NR2B subunit selective antagonist ifenprodil, disrupted acquisition and extinction of second-order fear. Extinction of sensory preconditioned fear was impaired by BLA infusion of muscimol or ifenprodil and by systemic MK-801. Acquisition of the neutral S2-S1 association and extinction of this association before conditioning of S1 was impaired by MK-801 but not by BLA infusion of muscimol. The final experiment examined the role of the perirhinal cortex (PRh) in the acquisition of higher-order fear. Muscimol inactivation of the PRh prior to S2-S1 pairings blocked sensory preconditioning but not second-order conditioning. These findings can be summarised as follows. First, activation of BLA NMDAr is necessary for the acquisition and extinction of second-order fear. Second, the acquisition and pre-extinction of sensory preconditioning requires NMDAr activity but not BLA activation. Third, once the fear circuit is engaged, learning to inhibit sensory preconditioned fear becomes dependent on BLA NMDAr activation. Finally, the PRh is necessary for the acquisition of an association between two neutral stimuli but not between a neutral stimulus and a learned danger signal. These findings are consistent with current views of amygdala function. They are also consistent with the claim that the contents of second-order conditioning and sensory preconditioning differ, the former involving associations between S2 and the fear responses elicited by S1 and the latter consisting in associations between the sensory properties of S2 and S1.