Retrieval and the Extinction of Memory

1. Memory is assessed by measuring retrieval which is often elicited by the solely presentation of the conditioned stimulus (CS). However, as known since Pavlov, presentation of the CS alone generates extinction.2. One-trial avoidance (IA) is a much used conditioned fear paradigm in which the CS is the safe part of a training apparatus, the unconditioned stimulus (US) is a footshock and the conditioned response (CR) is to stay in the safe area. Retrieval of the memory for the step-down version of this task is measured in the absence of the US, as latency to step-down from the safe area (i.e., a platform).3. Extinction of the IA response is installed at the moment of the first non-reinforced test session, as clearly shown by the fact that many drugs, including PKA, ERK and protein synthesis inhibitors as well as NMDA receptor antagonists, hinder extinction when infused into the hippocampus or the basolateral amygdala at the moment of the first test session but not later.4. Some, but not all the molecular systems required for extinction are also activated by retrieval, further endorsing the hypothesis that although retrieval is necessary for the generation of extinction this last process constitutes a new learning secondary to the non-reinforced expression of the original trace.     

Rats more readily acquire a time-of-day go no-go discrimination than a time-of-day choice discrimination

Male Sprague-Dawley rats were used to compare six time-place training procedures that differed with respect to housing or training conditions. All procedures involved training food-deprived rats to enter one choice arm of a T-maze during a morning test session and to enter the other choice arm during an afternoon session to obtain Cocoa Puffs(R). The task proved to be difficult. Only 39 of 49 rats attained a criterion of nine correct choices on ten consecutive trials within a total of 120 trials. Making one choice arm distinct, limiting consecutive same correct choices to two, giving one session during the light and one during the dark portion of the light cycle, extinguishing perseveration of the same choice responses, and housing the rats with a natural light cycle all failed to significantly decrease the errors or trials to a 90% correct choice criterion. In contrast, all responding rats (n=7) showed significantly better than chance performance within 48 trials when the task was a go no-go discrimination based on time of day. Learning to make a response during a session when a choice to either choice arm is reinforced and to withhold responding during a session when a choice to neither choice arm is reinforced was relatively easy for the rats to acquire. Continued high level performance after the light cycle was eliminated, a random feeding schedule was initiated, and other time-related cues were masked suggests that the rats used internal cues or an internal clock to make the correct go or no-go response. It was concluded that rats are prepared to use time of day as an occasion-setting stimulus, but have difficulty using time of day as a signal for a specific response.     

Isolated effects of number of acquisition trials on extinction of rat conditioned approach behavior

Four conditioned approach experiments with rats assessed for effects of number of acquisition trials on extinction of conditioned responding, when number of acquisition sessions and total acquisition time were held constant. In Experiment 1, 32 trials per acquisition session led to more extinction responding than did 1 or 2 trials per session but less than did 4 trials per session. In Experiment 2, 2 trials per acquisition session led to more spontaneous recovery than did 32 trials per session. These latter findings are reminiscent of the overtraining extinction effect (OEE). Experiment 3 attempted to reduce the OEE with a preconditioning phase of partial reinforcement. Experiment 4 attempted to reduce the beneficial within-subject effects of increasing the number of acquisition trials on extinction observed by Gottlieb and Rescorla (2010) by extinguishing stimuli in different sessions. Overall, results suggest a procedural asymmetry: between-subject, increasing the number of trials between any pair of trials does not lead to greater persistence of responding during extinction; within-subject, it does. Results are discussed from an associative perspective, with a focus on explanations involving either frustration or comparator mechanisms, and from an information processing perspective, with a focus on Rate Estimation Theory.     

Intertrial interval as a contextual stimulus

Four experiments with rats investigated whether the time between appetitive conditioning trials can serve as a discriminative cue for responding during the next conditional stimulus (CS). In Experiment 1, rats that received extinction trials with a 4-min intertrial interval (ITI) showed spontaneous recovery after a retention interval of 16 min, whereas rats that received extinction with a 16-min ITI did not. Experiments 2 and 3 investigated more explicit discriminations between the 4- and 16-min ITIs. When a 16-min ITI signaled that the CS would be reinforced and a 4-min ITI signaled that it would not, the ITIs modulated responding to the CS. But when the 4-min ITI signaled reinforcement and the 16-min ITI did not, there was less evidence of modulation by the ITIs. This asymmetry was due at least partly to a difficulty in performance rather than learning. Experiment 4 investigated similar discriminations with 1- and 4-min ITIs. Here the results took a different form: time in the reinforced ITI elicited responding directly, but did not modulate responding to the CS. ITI can function as a contextual cue, and the results suggest new similarities between the processes behind interval timing and associative learning.     

Inhibition of Spontaneous Recovery of Fear by mGluR5 after Prolonged Extinction Training

Fear behavior is vital for survival and involves learning contingent associations of non-threatening cues with aversive stimuli. In contrast, excessive levels of fear can be maladaptive and lead to anxiety disorders. Generally, extensive sessions of extinction training correlates with reduced spontaneous recovery. The molecular mechanisms underlying the long-term inhibition of fear recovery following repeated extinction training are not fully understood. Here we show that in rats, prolonged extinction training causes greater reduction in both fear-potentiated startle and spontaneous recovery. This effect was specifically blocked by metabotropic glutamate receptor 5 (mGluR5), but not by mGluR1 antagonists and by a protein synthesis inhibitor. Similar inhibition of memory recovery following prolonged extinction training was also observed in mice. In agreement with the instrumental role of mGluR5 in the prolonged inhibition of fear recovery, we found that FMR1−/− mice which exhibit enhanced mGluR5-mediated signaling exhibit lower spontaneous recovery of fear after extinction training than wild-type littermates. At the molecular level, we discovered that prolonged extinction training reversed the fear conditioning-induced increase in surface expression of GluR1, AMPA/NMDA ratio, postsynaptic density-95 (PSD-95) and synapse-associated protein-97 (SAP97). Accordingly, delivery of Tat-GluR2_3Y, a synthetic peptide that blocks AMPA receptor endocytosis, inhibited prolonged extinction training-induced inhibition of fear recovery. Together, our results demonstrate that prolonged extinction training results in the mGluR5-dependent long-term inhibition of fear recovery. This effect may involve the degradation of original memory and may explain the beneficial effects of prolonged exposure therapy for the treatment of phobias.     

Spatial associative memory: a possible species difference in rats and pigeons

Previous research has shown that pigeons can remember which of four spatially distinct responses was last reinforced, for at least 72 h. The present study sought to replicate this finding using rats. Rats were tested in an operant chamber containing four spatially distinct levers. In each session one lever was randomly selected to provide reinforcement for 15 min. This reinforced period was preceded by a non-reinforced period that was 30 s long, on average. During the non-reinforced period the amount the rat pressed on the previously reinforced lever was compared to responding on the other three levers, and was taken as a measure of memory. Sessions were separated either by 17 min, 24 or 72 h. Unlike pigeons, rats responded at chance levels following each of these retention intervals. This finding adds to previous research suggesting differences in cognitive processes in rats and pigeons.     

Dynamics of acetylcholinesterase activity in the brain during elaboration and stabilization of defensive conditioned reflexes

Electro-defensive condtioned reflexes (CR) to light were elaborated in rats in Y-maze in one experimental session and their training was continued during subsequent 20 sessions. Immediately after CR elaboration or the 20th session of its training, AChE activity in the motor and visual cortex and the hippocampus decreased, increasing again in 24 hours. Animals used as active control which received non-paired photic and electric stimuli, exhibited opposite changes of AChE activity.     

Neural-network simulations of two context-dependence phenomena

This paper describes simulations of two context-dependence phenomena in Pavlovian conditioning, using a neural-network model that draws on knowledge from neuroscience and makes no distinction between operant and respondent learning mechanisms. One phenomenon is context specificity or the context-shift effect, the decrease of conditioned responding (CR) when the conditioned stimulus (CS) is tested in a context different from the one in which it had been paired with the unconditioned stimulus (US). The other effect is renewal, the recovery of CR in the training context after extinction in another context. For specificity (simulation 1), two neural networks were first given 200 CS-US pairings in a context. Then, the CS was tested either in the training context or a new context. Output activations in the new context were substantially lower. For renewal (simulation 2), two networks were first given 200 CS-US pairings in a context, then 100 extinction trials in either the same context or a new one, and then tested back in the training context. Output activations during the test phase were substantially higher after extinction in a new context. The results are interpreted in terms of the dynamics of activations and weights.     

Dissociable anterograde amnesic effects of retrosplenial cortex and hippocampal lesions on spontaneous object recognition memory in rats

The amnesic effects of excitotoxic lesions of the rat retrosplenial cortex (RS) and hippocampus (HPC) in the spontaneous object recognition (SOR) performance were investigated. The SOR test consisted of the sample-exposure session(s) and a test session. First, to test retrograde amnesia, rats received four sample-exposure sessions within a day at 4 weeks and 1 day before the surgery, respectively. In the test sessions conducted 1 week after the surgery, both lesion groups showed a temporally ungraded retrograde amnesia. Second, to test anterograde amnesia, 1- and 4-week retention intervals were inserted between the four sample-exposure sessions and the test session. The RS-lesioned rats showed a retention interval-dependent impairment in the test sessions, while the HPC-lesioned rats showed an impairment regardless of the retention interval. Finally, to test short-term recognition memory, 5- or 30-min delay was interposed between the single sample-exposure session and the test session. Both lesion groups performed normally irrespective of the delay length. These results suggest that both the RS and HPC are important for long-term object recognition memory, but these areas have different roles in it. ? 2012 Wiley Periodicals, Inc.     

Early-session increases in responding during extinction

After training under a variable-interval 60-s schedule of reinforcement, four rats were exposed to 30-min extinction tests, which occurred either at the start or at the end of the session (each session being 50-min long). Response rate in extinction decreased when the extinction test occurred at the end of the session, but first increased and then decreased when the extinction test occurred at the start of the session. Consistent with other recent results, this finding suggests that some variable, other than reinforcement, contributes to early-session increases in responding.     

The role of contextual conditioning in the effect of reinforcer devaluation on instrumental performance by rats

Different groups of rats received different amounts of training to lever press for a food reinforcer before an aversion was conditioned to the food. This devaluation of the reinforcer reduced responding in both subsequent extinction and reinforced tests of responding to a degree that was independent of the amount of instrumental training. Moreover, interpolating context extinction between aversion conditioning and the extinction test reduced the magnitude of the devaluation effect, thereby indicating that Pavlovian contextual conditioning may play a role in the instrumental devaluation effect.     

尾壳核内注射脑啡肽和bestatin对大鼠操作式条件...

Female Wistar rats were trained in a Skinner-box, 30 trials per day in a dark room to establish operant defence conditioning. Training started with a light (15 s), then combined with footshock for further 8 s. When the rats learned to press the key to avoid footshock within 15 s, conditioned response was considered established. After the rats reached a conditioning rate (CR) above 80% for 5 days, cannulae were implanted into caudate-putamen. Two to three days later, Met-enkephalin (MEK) or bestatin (an aminopeptidase inhibitor) was injected bilaterally into caudate-putamen. 30 min, 2 h, 24 h and 48 h after injection, conditioning tests were conducted, with each session consisting of 30 trials. Control experiments were done when 0.9% NaCl (NS) was injected. After injection of NS, CR maintained above 80% in all 4 test sessions. MEK (60 ng/rat) or bestatin (10 micrograms/rat) significantly lowered the CR during the 30 min and 2 h test session. In the latter case, the latency (L) was also prolonged. However both CR and L returned to the control level in the 24 h and 48 h test sessions. Naloxone (2 mg/kg, i.p.) blocked the conditioning-depression effect of bestatin. No significant alteration was seen in locomotor activity after MEK or bestatin injection. The results suggest that enkephalin in caudate-putamen may be involved in the regulation of retrieval of conditioning. Bestatin mimics the effect of MEK on conditioning reflex probably by increasing production of endogenous enkephalin.     

The role of contextual cues in operant responding in rats

Following lever-press training on a variable-interval 60-second schedule of food presentation, groups of rats either remained in their home cages or were exposed to the operant chamber, from which lever and food had been removed, for five sessions. The lever was replaced in the chamber and rats from Group 1 (exposure to chamber) and Group 3 (home cage) were returned to the variable-interval schedule. Although response rates in test sessions were somewhat lower than at the end of training, there was no statistically significant difference in rates for either group. Rats in Group 2 (exposure to chamber) and Group 4 (home cage) received two test sessions of extinction. During the first session, Group 2 rates of lever pressing were significantly higher than Group 4 rates. These findings do not support the view that associations between contextual cues and the reinforcer serve to energize instrumental behavior (Pearce & Hall, 1979), and provide only minimal support for the view that contextual cues control responses that compete with the operant (Mills, 1980).     

Amount of training and stimulus salience affect associability changes in serial conditioning

Q. J. Exp. Psychol. 44B (1992) 17 reported that extended training with a serial compound of two conditioned stimuli, S1-->S2, resulted in losses in the rate at which S1-food associations were formed in a subsequent test phase. However, this ability of S1 to participate in new learning (its associability) could be restored by omitting S2 on some trials. Variables that affect performance in this task were examined in five Pavlovian appetitive conditioning experiments with rats. In Experiment 1, the associability of S1 decreased gradually as a function of the number of training sessions with a consistent S1-S2 relation. In Experiment 2, after extended exposure to a consistent S1-S2 relation, the associability of S1 was restored with as few as one training session in which the S1-S2 relation was made inconsistent by omitting S2 on some trials. In Experiments 3-5, test phase conditioning of S1 after inconsistent training was found to be either greater than, less than, or similar to, conditioning of S1 after consistent training, depending on the relative salience of the events used as S1 and S2. The results showed that both intrinsic and extrinsic relations among stimuli must be considered when interpreting the results of experiments in stimulus selection.     

Stimulus specificity in the acquisition and extinction of conditioned taste aversion

An experiment evaluated whether the acquisition and extinction of conditioned taste aversion in the rat is stimulus-specific by testing the degree of response transfer between sweet and salty tastes. Animals in the paired-same and paired-different groups received a presentation of a gustatory CS and a cyclophosphamide injection US. Nonconditioned control groups received unpaired CS /US presentations or the CS followed by a vehicle injection. Taste avoidance was evaluated in three nonreinforced test sessions. In the paired-same, unpaired and vehicle groups, all test sessions were conducted with the same flavor as originally used in training, whereas the paired-different group was tested with a novel flavor on the first and second sessions and with the originally trained flavor in last session. Stimulus specific acquisition was apparent in the first test session, when the animals in the group paired-same exhibited lower fluid intake than the other three groups. Evidence of specificity of extinction was apparent in the last test session, when animals in the group paired-different exhibited lower fluid intake than the other three groups. These results provide further evidence of stimulus specificity in acquisition and extinction of conditioned taste aversion, supporting the associative interpretation of these phenomena.     

Spontaneous Recovery of Fear Reverses Extinction-Induced Excitability of Infralimbic Neurons

In rodents, the infralimbic (IL) region of the medial prefrontal cortex plays a key role in the recall of fear extinction. Previously we showed that fear conditioning decreases the intrinsic excitability of IL neurons, and that fear extinction reverses the depressed excitability. In the current study, we examined the time course of the extinction-induced changes in adolescent rats. Immediately after extinction, IL neurons continued to show depressed excitability. However 4 hours after extinction, IL neurons showed an increase in evoked spikes that correlated with a reduced fast afterhyperpolarizing potential. This suggests that acquisition of fear extinction induces an increase in spike firing 4 hours later, during the consolidation of extinction. We also examined IL excitability in a group of rats that showed spontaneous recovery of fear 17 days after extinction (SR group). Similar to neurons after fear conditioning, IL neurons from the SR group showed depressed intrinsic excitability compared to neurons 4 hours after extinction, suggesting that extinction-induced enhancement in intrinsic excitability decreases with time reverting back to a depressed state. These results suggest that plasticity in IL contributes to the spontaneous recovery of fear and preventing this depression of IL excitability could prolong fear extinction.     

A comparison of explicitly unpaired treatment and extinction: recovery of sign-tracking within a context renewal design

The present experiment compared the effectiveness of explicitly unpaired treatment and extinction in preventing the recovery of sign-tracking within a context renewal design. Three groups of rats were first trained on a sign-tracking procedure in Context A where insertions of a retractable lever were paired with food. In a second phase, the sign-tracking response was eliminated. One group received standard extinction of the CS in Context B, while another group received explicitly unpaired treatment in Context B where food was presented only during inter-trial intervals (and not paired with the lever). A third group received this explicitly unpaired treatment in Context A. After the sign-tracking response was eliminated, all groups received a test session in Context A where the lever was presented alone and no food was delivered at any time. Significantly more responding occurred in the group that received explicitly unpaired treatment in Context B than in either of the other groups. This demonstrates that there are situations where explicitly unpaired treatment is less effective than extinction in preventing the reappearance of previously eliminated responding.     

Differences between simultaneous and blocked training detected by a transfer test

Secondary data analysis was used to compare responding early on a transfer test from rats previously trained simultaneously or successively on multiple temporal discriminations for the same number of trials [Guilhardi, P., Church, R.M., 2005 a. Dynamics of temporal discrimination. Learn. Behav., 33, 399-416]. Three fixed intervals (30, 60, and 120 s) were signaled by three stimuli (light, noise, and clicker). Twelve rats were trained with the three stimulus-interval pairs intermixed on each experimental session (simultaneous condition); 12 other rats were trained in successive blocks of 10 sessions on each pair (blocked condition). Then, all rats had a transfer test in which all three stimulus-interval pairs were presented intermixed on each session. Rats in the simultaneous and blocked condition responded similarly during training, but differently during early stages of the transfer test. One possibility is that rats in the blocked condition were controlled by the previous interval, not by the current stimulus. These results challenge the usual assumptions from models of timing and conditioning that both simultaneous and blocked training produce learning of the associations between stimulus and interval in a multiple interval training task.     

Resurgence of derived stimulus relations: Replication and extensions

Resurgence typically refers to the recovery of a previously reinforced response when a more recently reinforced response is extinguished. Under conditions of punishment, Wilson and Hayes (1996) observed the recovery of derived stimulus relations that never had been correlated with differential consequences. The present study systematically replicated the findings of Wilson and Hayes by observing the recovery of derived stimulus relations under extinction conditions and with an additional equivalence class. College students received arbitrary-matching-to-sample training in Phase 1 that resulted in four 4-member stimulus-equivalence classes. These derived relations were not correlated with differential consequences. In Phase 2, with the same stimuli, the students received training that resulted in four different 4-member stimulus-equivalence classes. After the emergence and reinforcement of the latter derived relations, their extinction generated the recurrence of the derived relations from Phase 1. The implications of these findings for conceptualizing resurgence are discussed.     

Modulation of long-term memory and extinction responses induced by growth hormone (GH) and growth hormone releasing hormone (GHRH) in rats

The purpose of this work is to study the participation of growth hormone (GH) and growth hormone releasing hormone (GHRH) in the modulation of long-term memory and the extinction response of a passive avoidance task in rats. However, the effect on memory vary according to the age of the animals due to plasma levels of either hormone being modified during the aging process. Male Wistar rats were divided according to age into two experimental blocks (young rats 3 months old and aged rats 24 months old at the start of the experiment) where each block received the same treatment. Each experimental block was then divided randomly into three groups where two were experimental and the other served as control. The animals were then submitted to a one-trial passive avoidance conditioning and tested for memory retention 24 hrs after as well as twice a week until the extinction response occurred. The control group received an isotonic saline solution and the other two groups received 0.8 U.I. Of GH or 4 mcg of GHRH respectively. All substances were in a 0.08 ml volume and applied 24 hrs before training as well as 24 hrs before each retention session. The results indicate that GH and GHRH modulate longterm memory as well as the extinction response and in either case the response seems to vary with age. GH and GHRH facilitates long-term memory in young rats but not in aged rats. Finally, whereas GH delays the extinction response in both groups, GHRH retards the extinction only in aged rats.