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

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].

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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. Animals received intra-CA1 infusions of Veh or Mus mediated protein synthesis in the hippocampus (29, 30). (0.01 μg per side) 10 min before the Ext Tr of CFC, and 7 or 14 d These findings indicate that behavioral expression during an later they were subjected to a 3-min Ext Test (23). As shown in unreinforced retrieval session is not necessary for the initiation, Fig. 2, animals treated with Mus before the Ext Tr and subjected maintenance, or spontaneous recovery of the extinction learning, to the Ext Test 7 (Fig. 2A) or 14 d (Fig. 2B) later expressed levels as was previously thought (14, 15). Instead, they suggest that the of freezing behavior similar to those of the Veh groups, in- mere perception of the CS, at least in the absence of retrieval, dicating that Mus does not affect the persistence of the extinc- could well be necessary for extinction to start or persist. Per- tion of CFC at 7 d after Ext Tr, nor its spontaneous recovery at ception of the CS (in this case, the context) would not, of course, 14 d. These results suggest that, whatever the mechanism for the be expected to be hindered by Mus given outside the sensory early persistence of extinction is, or that of its spontaneous re- pathways involved. Thus, perception of the CS seems to be far covery after 2 wk, the inhibition of retrieval caused by Mus in the more important for the triggering of extinction learning than the session in which it was given does not affect extinction persis- behavioral response to it. Unless some other subbehavioral tence or spontaneous recovery. correlate of retrieval is found, this seems to be the simplest and most parsimonious explanation for the present results and per- Effect of Anisomycin and Rapamycin Given into the Hippocampus haps also for those of Balderas et al. (6), Santoyo-Zedillo et al. After the Extinction Training Session Regardless of the Effect of (16), and García de la Torre et al. (21) on reconsolidation. Mus. Animals received intra-CA1 infusions of Veh or Mus When our results are put together with those obtained by (0.01 μg per side) 10 min before the Ext Tr of CFC and also Bermudez-Rattoni and his group in two other different tasks (5, received Veh or anisomycin (Ani; 80 μg per side) (Fig. 3A)or 6, 16, 21), it seems clear that extinction and reconsolidation must rapamycin (Rapa; 5 pg per side) (Fig. 3B) immediately after that. be considered under a new light: perhaps not as opposite be- Twenty-four hours later animals were subjected to a 3-min Ext havioral processes that can be triggered by retrieval (14) but Test (23). As shown in Fig. 3, animals treated with Veh 10 min possibly as part of a continuum or a diversity of protein synthesis- before plus Ani (Fig. 3A) or Rapa (Fig. 3B) immediately after mediated events, some of which may indeed overlap (31), and the Ext Tr expressed higher levels of freezing behavior than the that can be set into motion by the simple perception of the CS or Veh group during the Ext Test, and the same effect was seen in CSs, or some other event other than the performance or the the group of animals that received Mus 10 min before plus Ani inhibition of performance of a behavioral response. or Rapa immediately after the Ext Tr, indicating that even in the Both extinction and reconsolidation require two sets of pro- absence of retrieval, Ani and Rapa were able to impair the tein synthesis-mediated events, one ribosomal and sensitive to consolidation of the extinction of CFC. Ani, and the other presumably dendritic and sensitive to Rapa

de Carvalho Myskiw et al. PNAS | Published online December 30, 2014 | E231 Downloaded by guest on September 29, 2021 hippocampal pyramidal cells have been described by Frey and Morris (33, 34), and since then by others (35–40), as part of the process of synaptic tagging and capture believed to play a key role in the maintenance and interaction of memories (33–40). Materials and Methods Animals. Male Wistar rats (3 mo old, 300–330 g), purchased from Centro de Reprodução e Experimentação de Animais de Laboratorio of the Uni- versidade Federal do Rio Grande do Sul (our regular provider), were used. Animals were housed four to a cage with free access to food and water, under a 12-h light/dark cycle (lights on at 7:00 AM). The temperature of the animals’ room was maintained at 22–24 °C. All procedures are in accordance with the guidelines of the NIH Guide for the Care and Use of Laboratory Animals and were approved by the Bioethics Committee of the Pontifical Catholic University of Rio Grande do Sul.

Surgery. Animals were anesthetized with i.p. injections of a mixture of ketamine (75 mg/kg) and xylazine (10 mg/kg) and implanted with a 22-gauge

Fig. 2. Effect of Mus into the hippocampus before the extinction training session on the extinction retention test 7 or 14 d later. 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 the Ext Tr, and were subjected to the Ext Test 7 d (A)or14d(B) later. Mus did not affect the persistence or spontaneous recovery of the extinction of CFC. Data are expressed as mean ± SEM (n = 8–12 animals per group). **P < 0.01; ***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.

(30, 32). The two are indispensable for extinction and for reconsolidation, and they may be triggered or gated by the sheer perception of the CS or by other related behaviorally un- expressed consequences of memory reactivation. The protein synthesis events involved in memory formation occur in several posttraining waves and are essential for the consolidation of the several forms of learning in which they have been identified (2, Fig. 3. Effect of Ani and Rapa given into the hippocampus after the ex- 28, 30), and take place, as far as is known, in just one wave. They tinction training session, regardless of the effects of Mus. Animals were are also essential for the consolidation of extinction learning (29, subjected to a CFC task. After 24 h they received intra-CA1 infusion of Veh or 30). The posttraining protein synthesis processes take place in Mus (0.01 μg per side) 10 min before the Ext Tr plus Veh or Ani (A;80μg per different cell regions (the mTOR apparatus and the ribosomes), side) or Rapa (B; 5 pg per side) immediately after, and then were subjected so it might be necessary to postulate that they may relate to each to a 3-min Ext Test 24 hours later. Ani and Rapa impaired the consolidation of the extinction of CFC in both groups of animals treated with Veh or Mus other by mechanisms linked to the synapses whose plastic before the Ext Tr. Data are expressed as mean ± SEM (n = 8–12 animals per changes mediate extinction (30) and the hitherto undescribed group). ***P < 0.001 vs. Veh group in the first 3 min of the Ext Tr; ##P < 0.01, synaptic events involved in reconsolidation (20). Such trafficking ###P < 0.001 vs. Veh group in the Ext Test, Newman–Keuls test after one-way processes between synapses and protein synthesis systems in ANOVA. (Upper) Schematic representation of the behavioral protocol used.

E232 | www.pnas.org/cgi/doi/10.1073/pnas.1423465112 de Carvalho Myskiw et al. Downloaded by guest on September 29, 2021 bilateral guide cannula 1 mm above the dorsal CA1 area of the hippocampus of the foot shocks. Twenty-four hours later, animals were placed again in PNAS PLUS (anterior, −4.2 mm; lateral, ±3.0 mm; ventral, −1.8 mm) (41). Acrylic cement the same apparatus for a 3-min extinction retention test, with no foot was used to affix the cannulae to the skull. Animals were allowed 7 d to shocks (23). recover from surgery before behavioral procedures. Animals were handled once daily for 3 consecutive days, and all behavioral procedures were con- Pharmacological Treatments. For the pharmacological treatments, animals ducted between 8:00 and 11:00 AM. were gently restrained by hand, and an injection needle (30 gauge) was fit- ted tightly into the guides, extending 1 mm from the tip of the guide can- CFC Apparatus. CFC was performed in the conditioning chamber (Panlab) with nulae. The injection needle was connected to a 10-μL Hamilton microsyringe, × × aluminum walls (35 35 35 cm) and a transparent plastic front lid. The and the infusion was performed at a rate of 0.5 μL/30 s. The microinfusion floor of the chamber consists of parallel stainless-steel grid bars. The grid volume used was 1 μL per side into the dorsal CA1 area of the hippocampus. was connected to a device to deliver the foot-shock presentations. The After the injection the needle was left in place for 1 additional minute and conditioning chamber was placed inside a sound-attenuating box (Panlab) then carefully withdrawn and placed on the other side. with a ventilating fan. The chamber was cleaned with 70% ethanol before and after each use. The percentage of the time that the animals spent The drugs and the doses used were the agonist of GABAA receptors, Mus μ μ freezing in the apparatus was measured automatically by a counter con- (0.01 g per side); the inhibitor of ribosomal translation, Ani (80 g per side); nected to photocells. Freezing (no visible movement except for respiration) and the inhibitor of mTOR-mediated protein synthesis, Rapa (5 pg per side) was scored and converted into a percentage. (Sigma-Aldrich). All drugs were freshly dissolved in sterile saline 0.9%.

Extinction of CFC. For the CFC, animals were placed into the conditioning Statistical Analysis. Data are presented as means ± SEs and were analyzed chamber, and after 2 min two electrical foot shocks (0.5 mA, 2 s) were statistically by one-way ANOVA followed by Newman-Keuls Test using delivered with a 30-s interval between them. Animals were removed from Graphpad Prism software. P < 0.05 was considered statistically significant. the conditioning chamber 30 s after the last foot shock and placed back in their home cages. After 24 h, animals were placed in the same condi- ACKNOWLEDGMENTS. This work was supported by research grants from the tioning chamber for a 20-min extinction training of CFC, with the absence National Council of Research of Brazil.

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