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Extinction Learning, Which Consists of the Inhibition of Retrieval, Can Be Learned Without Retrieval

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Extinction Learning, Which Consists of the Inhibition of Retrieval, Can Be Learned Without Retrieval Extinction learning, which consists of the inhibition of retrieval, can be learned without retrieval Jociane de Carvalho Myskiw1, Cristiane Regina Guerino Furini, Bianca Schmidt, Flávia Ferreira, and Ivan Izquierdo1 National Institute of Translational Neuroscience, National Research Council of Brazil, and Memory Center, Brain Institute of Rio Grande do Sul, Pontifical Catholic University of Rio Grande do Sul, 90610-000 Porto Alegre, RS, Brazil Contributed by Ivan Izquierdo, December 9, 2014 (sent for review December 1, 2014) In the present study we test the hypothesis that extinction is not amygdala (BLA) for conditioned taste aversion or into the per- a consequence of retrieval in unreinforced conditioned stimulus irhinal cortex for object recognition (6). In both tasks, the drugs (CS) presentation but the mere perception of the CS in the absence selectively blocked retrieval but spared reconsolidation, suggesting of a conditioned response. Animals with cannulae implanted in that the two neural processes are independent from each other the CA1 region of hippocampus were subjected to extinction of (16, 21). In contrast, a glutamate NMDA receptor antagonist contextual fear conditioning. Muscimol infused intra-CA1 before blocked the reconsolidation of conditioned taste aversion when an extinction training session of contextual fear conditioning (CFC) given into the BLA (21) and that of object recognition when in- blocks retrieval but not consolidation of extinction measured 24 h fused into the perirhinal cortex (16). later. Additionally, this inhibition of retrieval does not affect early In the present study we test the hypothesis that extinction is persistence of extinction when tested 7 d later or its spontaneous not a consequence of retrieval in unreinforced CS presentations recovery after 2 wk. Furthermore, both anisomycin, an inhibitor of (13, 22) but to the mere perception of the CS in the absence of ribosomal protein synthesis, and rapamycin, an inhibitor of extra- a CR. This is important because, depending on the answer, the ribosomal protein synthesis, given into the CA1, impair extinction origin of both postretrieval processes (extinction and perhaps of CFC regardless of whether its retrieval was blocked by muscimol. reconsolidation) will have to be searched for in sensory or Therefore, retrieval performance in the first unreinforced session is sensory-motor rather than in cognitive or behavioral events, and not necessary for the installation, maintenance, or spontaneous the unstabilization of the memory being studied may depend on recovery of extinction of CFC. the former. contextual fear conditioning | fear extinction | hippocampus | retrieval | Results unreinforced conditioned stimulus Effect of Mus Given into the Hippocampus Before or After the Extinction Training Session. Animals received intra-CA1 infusions μ n animal experiments, retrieval can be defined as the behav- of vehicle (Veh) or Mus (0.01 g per side) 10 min before or Iioral expression of recalled memories; the actual performance immediately after the extinction training session (Ext Tr) of of retrieval is usually thought to destabilize memories and trigger CFC, and 24 h later they were subjected to a 3-min extinction A two opposite protein synthesis-dependent processes: reconsoli- retention test (Ext Test) (23). As shown in Fig. 1 , animals that dation (1–7) and extinction (8–13). Reconsolidation is viewed as received Mus into the CA1 before the Ext Tr expressed less a consequence of the labilization of consolidated memories at freezing behavior compared with the Veh-treated animals during the time of the unreinforced retrieval, which renders them open the Ext Tr. However, both groups (Veh and Mus) exhibited to strengthening and updating (3–7, 14–20), whereas extinction is similar levels of freezing during the extinction retention test, in- viewed as a form of learning to inhibit retrieval of original dicating that even in the absence of retrieval, animals that received memory (8–12). Pavlov observed more than a century ago (8) intra-CA1 infusion of Mus were able to learn the extinction of B that extinguished responses can recover spontaneously with the CFC. As can be seen in Fig. 1 , animals that received Mus intra- passage of time, which indicates that extinction does not erase CA1 immediately after the Ext Tr expressed the same freezing memories. This was corroborated and expanded by Konorski (9) behavior in the Ext Test as the Veh group, indicating that Mus and Rescorla (10, 11). does not affect the consolidation of the extinction of CFC. In contextual fear conditioning (CFC), animals learn to asso- The findings on retrieval of the original task are in agreement ciate a context used as a conditioned stimulus (CS) and relatively with those observed by Raybuck and Lattal (24), in which Mus mild foot shocks used as an unconditioned stimulus (US). The given into the hippocampus inhibits the retrieval of other forms ’ conditioned response (CR), usually measured, is the increase of of memory; with those of Bermudez-Rattoni s group that the the time spent freezing in unreinforced sessions carried out later. Most accounts consider that extinction begins in the first un- Significance reinforced retrieval session because of labilization of the memory (3, 14, 15), or by the mismatch between what the animals expect Blockade of the retrieval of contextual fear conditioning by and what really happens at the time of retrieval (19), or both. intrahippocampal muscimol administration does not impede However, it is always possible that, alternatively, the CS itself in extinction of the task measured up to 1 wk later, its eventual the absence of a CR may trigger memory labilization (3) and spontaneous recovery at 14 d, or its inhibition by two different make it susceptible both to extinction (13) and to its counterpart, protein synthesis inhibitors given into the hippocampus. These reconsolidation (14, 20). results show that extinction and retrieval are separate processes Bermudez-Rattoni and his group showed that the performance and strongly suggest that extinction is triggered or gated by the of unreinforced retrieval is not necessary to trigger reconsolidation conditioned stimulus even in the absence of retrieval. of conditioned taste aversion (5, 21) or of object recognition Author contributions: J.d.C.M., C.R.G.F., and I.I. designed research; J.d.C.M., C.R.G.F., B.S., learning (6, 16). The methodology used by this group is very and F.F. performed research; J.d.C.M., C.R.G.F., B.S., and I.I. analyzed data; and J.d.C.M., straightforward: it consists of the pharmacological blockade of C.R.G.F., and I.I. wrote the paper. retrieval with microinfusions of ciano-nitro-quinoxaline-dione, The authors declare no conflict of interest. an antagonist of AMPA receptors (16, 21), or of the GABAA 1To whom correspondence may be addressed. Email: [email protected] or receptor agonist muscimol (Mus) (5) given into the basolateral [email protected]. E230–E233 | PNAS | Published online December 30, 2014 www.pnas.org/cgi/doi/10.1073/pnas.1423465112 Downloaded by guest on September 29, 2021 PNAS PLUS Fig. 1. Effect of Mus given into the hippocampus before or after the extinction training session. Animals were subjected to a CFC task. After 24 h they received intra-CA1 infusion of Veh or Mus (0.01 μg per side) 10 min before (A) or immediately after (B) the Ext Tr of CFC, and then were subjected to a 3-min Ext Test 24 hours later. (A) The retrieval of CFC was blocked by Mus, expressed as a decrease of freezing behavior during the Ext Tr compared with the Veh group, but does not prevent the extinction learning. (B) Animals that received Mus immediately after the Ext Tr expressed the same freezing behavior in the Ext Test as the Veh group. The figure shows the percentage of time spent freezing in the first 2 min of the CFC session, in the first 3 min and last 3 min of the Ext Tr, and in the Ext Test. Data are expressed as mean ± SEM (n = 10–12 animals per group). ***P < 0.001 vs. Veh group in the first 3 min of the Ext Tr, Newman–Keuls test after one-way ANOVA. (Upper) Schematic representation of the behavioral protocol used. same drug given into other brain nuclei blocks retrieval of con- Discussion ditioned taste aversion (6); with those of Rosa et al. (25) on the Here we have demonstrated that the infusion of Mus into the blockade of retrieval of fear memory with Mus infused into the CA1 region of the hippocampus before the extinction training nucleus of the tractus solitaries; and with those of Quirk and his COGNITIVE SCIENCES session blocks the retrieval of CFC, as it does with that of other PSYCHOLOGICAL AND group infusing Mus into the basolateral amygdala or into the tasks, depending on where it is given (5, 6, 24, 25). Additionally, infra-limbic prefrontal cortex for the expression of fear extinc- we showed here that the infusion of Mus intra-CA1 after the tion (26). The results, when put together, suggest a multicenter extinction training session of CFC does not disrupt the consoli- GABAA modulation of retrieval reminiscent of the multicenter dation of extinction, which in relation to the participation of GABAA modulation of consolidation suggested 20 years ago by GABA-mediated transmission might take place predominantly Brioni (27). GABA is the main inhibitory neurotransmitter in the elsewhere (ventromedial prefrontal cortex, basolateral amyg- brain, and its effect on GABAA receptors is mimicked by Mus. dala; see refs. 12, 23, and 28). The intra-CA1 infusion of Ani or Rapa after the extinction training session blocks CFC extinction, Effect of Mus Given into the Hippocampus Before the Extinction as previously shown, indicating that this form of learning requires Training Session When the Retention Test Takes Place 7 or 14 d both ribosomal and mTOR (mammalian target of rapamycin)- Later.
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