ABA Renewal Research Articles

Clinical translation of the ABA renewal model of treatment relapse

ABSTRACTAn 18-year-old male’s attention-maintained problem behavior was treated with an alternative (ALT) variable-interval, variable-time (VI VT) schedule arrangement with two therapists each delivering attention at different rates in a multiple schedule of reinforcement. Despite the differing rates of VI VT attention, the procedures resulted in similar rates of problem behavior in the last three treatment sessions reducing problem behavior by an average of 45%. Following treatment, the two therapists conducted separate extinction sessions, initially in a different context until problem behavior extinguished and then returning to the original treatment context (i.e., the ABA renewal test). Extinction took 4.4 times longer in the renewal test for the therapist who implemented the high-rate VI VT treatment compared with the therapist who implemented the low-rate VI VT treatment. Although these results are preliminary, the implications for clinicians is that treatment designs that use low-rate treatment may be more effective than high-rate treatment in preventing relapse.

Counterconditioned fear responses exhibit greater renewal than extinguished fear responses.

This series of experiments used rats to compare counterconditioning and extinction of conditioned fear responses (freezing) with respect to the effects of a context shift. In each experiment, a stimulus was paired with shock in context A, extinguished or counterconditioned through pairings with sucrose in context B, and then tested for renewal outside of context B. Counterconditioned fear responses exhibited greater ABA renewal than extinguished fear responses. This result was observed using a between-subjects design (Experiment 1) and a within-subject design in which counterconditioned and extinguished stimuli were equated in all respects other than their signaling of sucrose (Experiment 2). Counterconditioned fear responses also exhibited greater ABC renewal than extinguished fear responses (Experiment 3). This result was observed using a within-subject design in which context C was identical to context B in terms of its associative history, and when counterconditioned and extinguished CSs were tested in compounds matched for their association with both shock and sucrose (Experiment 4). These results are consistent with models which hold that context regulates expression of associations formed in counterconditioning and extinction, and allow the level of regulation to be greater following counterconditioning than extinction, as noted in previous studies.

Extinction in multiple contexts: Effects on the rate of extinction and the strength of response recovery.

In two human predictive-learning experiments, we investigated the effects of extinction in multiple contexts on the rate of extinction and the strength of response recovery. In each experiment, participants initially received acquisition training with a target cue in one context, followed by extinction either in a different context (extinction in a single context) or in three different contexts (extinction in multiple contexts). The results of both experiments showed that conducting extinction in multiple contexts led to higher levels of responding during extinction than did extinction in a single context. Additionally, Experiment 2 showed that extinction in multiple contexts prevented ABC renewal but had no detectable impact on ABA renewal. Our results are discussed within the framework of contemporary learning theories of contextual control and extinction.

Orexin/hypocretin neuron activation is correlated with alcohol seeking and preference in a topographically specific manner.

Orexin (ORX) (also known as hypocretin) neurons are located exclusively in the posterior hypothalamus, and are involved in a wide range of behaviours, including motivation for drugs of abuse such as alcohol. Hypothalamic subregions contain functionally distinct populations of ORX neurons that may play different roles in regulating drug-motivated and alcohol-motivated behaviours. To investigate the role of ORX neurons in ethanol (EtOH) seeking, we measured Fos activation of ORX neurons in rats following three different measures of EtOH seeking and preference: (i) context-induced reinstatement, or ABA renewal; (ii) cue-induced reinstatement of extinguished responding for EtOH; and (iii) a home cage task in which preference for EtOH (vs. water) was measured in the absence of either reinforcer. We found significant activation of ORX neurons in multiple subregions across all three behavioural tests. Notably, ORX neuron activation in the lateral hypothalamus correlated with the degree of seeking in context reinstatement and the degree of preference in home cage preference testing. In addition, Fos activation in ORX neurons in the dorsomedial hypothalamic and perifornical areas was correlated with context and home cage seeking/preference, respectively. Surprisingly, we found no relationship between the degree of cue-induced reinstatement and ORX neuron activation in any region, despite robust activation overall during reinstatement. These results demonstrate a strong relationship between ORX neuron activation and EtOH seeking/preference, but one that is differentially expressed across ORX field subregions, depending on reinstatement modality.

Medial prefrontal cortex involvement in the expression of extinction and ABA renewal of instrumental behavior for a food reinforcer

Instrumental renewal, the return of extinguished instrumental responding after removal from the extinction context, is an important model of behavioral relapse that is poorly understood at the neural level. In two experiments, we examined the role of the dorsomedial prefrontal cortex (dmPFC) and the ventromedial prefrontal cortex (vmPFC) in extinction and ABA renewal of instrumental responding for a sucrose reinforcer. Previous work, exclusively using drug reinforcers, has suggested that the roles of the dmPFC and vmPFC in expression of extinction and ABA renewal may depend at least in part on the type of drug reinforcer used. The current experiments used a food reinforcer because the behavioral mechanisms underlying the extinction and renewal of instrumental responding are especially well worked out in this paradigm. After instrumental conditioning in context A and extinction in context B, we inactivated dmPFC, vmPFC, or a more ventral medial prefrontal cortex region by infusing baclofen/muscimol (B/M) just prior to testing in both contexts. In rats with inactivated dmPFC, ABA renewal was still present (i.e., responding increased when returned to context A); however responding was lower (less renewal) than controls. Inactivation of vmPFC increased responding in context B (the extinction context) and decreased responding in context A, indicating no renewal in these animals. There was no effect of B/M infusion on rats with cannula placements ventral to the vmPFC. Fluorophore-conjugated muscimol was infused in a subset of rats following test to visualize infusion spread. Imaging suggested that the infusion spread was minimal and mainly constrained to the targeted area. Together, these experiments suggest that there is a region of medial prefrontal cortex encompassing both dmPFC and vmPFC that is important for ABA renewal of extinguished instrumental responding for a food reinforcer. In addition, vmPFC, but not dmPFC, is important for expression of extinction of responding for a food reinforcer. The role of the medial prefrontal cortex in renewal in the original conditioning context may depend in part on control over excitatory context-response or context-(response-outcome) relations that might be learned in acquisition. The role of the vmPFC in expression of extinction may depend on its control over inhibitory context-response or context-(response-outcome) relations that are learned in extinction.

Contextual Change After Fear Acquisition Affects Conditioned Responding and the Time Course of Extinction Learning-Implications for Renewal Research.

Context plays a central role in retrieving (fear) memories. Accordingly, context manipulations are inherent to most return of fear (ROF) paradigms (in particular renewal), involving contextual changes after fear extinction. Context changes are, however, also often embedded during earlier stages of ROF experiments such as context changes between fear acquisition and extinction (e.g., in ABC and ABA renewal). Previous studies using these paradigms have however focused exclusively on the context switch after extinction (i.e., renewal). Thus, the possibility of a general effect of context switch on conditioned responding that may not be conditional to preceding extinction learning remains unstudied. Hence, the current study investigated the impact of a context switch between fear acquisition and extinction on immediate conditioned responding and on the time-course of extinction learning by using a multimodal approach. A group that underwent contextual change after fear conditioning (AB; n = 36) was compared with a group without a contextual change from acquisition to extinction (AA; n = 149), while measuring physiological (skin conductance and fear potentiated startle) measures and subjective fear ratings. Contextual change between fear acquisition and extinction had a pronounced effect on both immediate conditioned responding and on the time course of extinction learning in skin conductance responses and subjective fear ratings. This may have important implications for the mechanisms underlying and the interpretation of the renewal effect (i.e., contextual switch after extinction). Consequently, future studies should incorporate designs and statistical tests that disentangle general effects of contextual change from genuine ROF effects.

The recurrence of negatively reinforced responding of humans.

The recurrence of negatively reinforced responding of humans was studied in three experiments. In each experiment during Baseline, key-pressing produced 3-s timeouts from a requirement to exert finger pressure on a force cell according to variable- or fixed-ratio schedules of reinforcement. In Experiment 1, resurgence was studied by arranging a differential-reinforcement-of-other-behavior schedule in the second phase, and extinction in the Test phase. In Experiment 2, ABA renewal was studied by extinguishing responding in the second phase in a different context and, in the Test phase, by presenting the Baseline-phase context when extinction still was in effect. In Experiment 3, reinstatement was studied by arranging extinction in the second phase, followed by the delivery of response-independent timeouts in the Test phase. Resurgence and renewal occurred consistently for each participant in Experiments 1 and 2, respectively. In Experiment 3, reinstatement was observed less consistently in four participants. The results of these experiments replicate and extend to negatively reinforced responding previous findings of the resurgence and renewal of positively reinforced responding obtained mainly with nonhuman animals.

A dissociation between recognition and reactivation: The renewal effect at 3 months of age.

Extinction allows organisms to adapt to an ever-changing environment. Despite its theoretical and applied significance, extinction has never been systematically studied with human infants. Using the operant mobile task, we examined whether 3-month-olds would exhibit evidence of original learning following extinction. In a recognition paradigm, infants exhibited renewal when tested in the acquisition context (ABA renewal) or a neutral context (ABC and AAB renewal) 1 day following extinction (Experiment 1a) and spontaneous recovery 3 days following extinction (Experiment 1b). In Experiments 2a-2b, we used a reminder paradigm to examine whether the extinguished response could be reinstated after the operant response had been forgotten. We failed, however, to find reinstatement of extinguished responding after spontaneous forgetting, regardless of the reminder and test contexts. We attributed this retention failure to competing responses at test. Although extinguished responding is recovered during infancy, this effect is elusive after the response has been forgotten.

The DA antagonist tiapride impairs context-related extinction learning in a novel context without affecting renewal

Renewal describes the recovery of an extinguished response if recall is tested in a context different from the extinction context. Behavioral studies demonstrated that attention to relevant context strengthens renewal. Neurotransmitters mediating attention and learning such as the dopaminergic (DA) system presumably modulate extinction learning and renewal. However, the role of DA for non-fear-based extinction learning and renewal in humans has not yet been investigated. This fMRI study investigated effects of DA-antagonism upon context-related extinction in a predictive learning task in which extinction occurred either in a novel (ABA) or an unchanged (AAA) context. The tiapride-treated group (TIA) showed significantly impaired ABA extinction learning and a significant within-group difference between ABA and AAA extinction, compared to placebo (PLAC). Groups did not differ in their level of ABA renewal. In ABA extinction, TIA showed reduced activation in dlPFC and OFC, hippocampus, and temporal regions. Across groups, activation in PFC and hippocampus correlated negatively with ABA extinction errors. Results suggest that in context-related extinction learning DA in PFC and hippocampus is involved in readjusting the cue-outcome relationship in the presence of a novel context. However, relating context to the appropriate association during recall does not appear to rely exclusively on DA signaling.

Renewal of conditioned responding to food cues in rats: Sex differences and relevance of estradiol

Cues associated with food can stimulate food anticipation, procurement, and consumption, independently of hunger. These and other behaviors driven by learned cues are persistent and can reappear after extinction, because the original learned associations continue to exist. Renewal, or reinstatement, of extinguished conditioned behavior may explain the inability to change maladaptive eating habits driven by food cues, similar to the mechanisms of drug use relapse. Here, we investigated sex differences in context-induced renewal of responding to food cues, and the role of estradiol in females in a Pavlovian conditioning preparation. We compared adult male and female rats because there is evidence for sex differences in learning and memory and in the control of feeding. Context-induced renewal involves conditioning and extinction in different contexts and the renewal of conditioned behavior is induced by return to the conditioning context (“ABA renewal”; experimental groups). Control groups remain in the same context during conditioning, extinction, and test. In Experiment 1, male and female rats were trained to associate a tone with food pellets during acquisition, and after extinction with tone only presentations, were tested for renewal of responding to the tone. Learning was assessed through the expression of the conditioned response, which included approach and activity directed at food receptacle (food cup behavior). Males and females learned the acquisition and extinction of tone–food associations similarly, but there were sex differences during renewal of the conditioned responses to the food cue. Males showed robust renewal of responding, while renewal in intact females was inconsistent. Males in the experimental group had significantly higher food cup behavior compared to males in the control group, while females in both groups showed similar levels of food cup behavior during the tone. In Experiment 2, we examined a potential role of estradiol in renewal, by comparing intact females with ovariectomized females with, and without, estradiol replacement. Rats in all groups acquired and extinguished tone–food associations similarly. During the test for renewal, the ovariectomized rats with estradiol replacement in the experimental group showed renewal of responding, evidenced by significantly higher food cup behavior compared to the control group. Intact and ovariectomized rats in the experimental groups had similar rates of food cup behavior as their corresponding control groups. These results provide novel evidence for sex differences and relevance of estradiol in renewal of responding to food cues and more broadly in contextual processing and appetitive associative learning, potentially relevant to maladaptive eating habits and eating disorders.

Generalization versus contextualization in automatic evaluation revisited: A meta-analysis of successful and failed replications.

To account for disparate findings in the literature on automatic evaluation, Gawronski, Rydell, Vervliet, and De Houwer (2010) proposed a representational theory that specifies the contextual conditions under which automatic evaluations reflect initially acquired attitudinal information or subsequently acquired counterattitudinal information. The theory predicts that automatic evaluations should reflect the valence of expectancy-violating counterattitudinal information only in the context in which this information had been learned. In contrast, automatic evaluations should reflect the valence of initial attitudinal information in any other context, be it the context in which the initial attitudinal information had been acquired (ABA renewal) or a novel context in which the target object had not been encountered before (ABC renewal). The current article presents a meta-analysis of all published and unpublished studies from the authors' research groups regardless of whether they produced the predicted pattern of results. Results revealed average effect sizes of d = 0.249 for ABA renewal (30 studies, N = 3,142) and d = 0.174 for ABC renewal (27 studies, N = 2,930), both of which were significantly different from zero. Effect sizes were moderated by attention to context during learning, order of positive and negative information, context-valence contingencies during learning, and sample country. Although some of the obtained moderator effects are consistent with the representational theory, others require theoretical refinements and future research to gain deeper insights into the mechanisms underlying contextual renewal.

Stimulus generalization and operant context renewal

Context renewal is the relapse of an extinguished response due to changing the stimulus context following extinction. Reinforcing operant responding in Context A and extinguishing in Context B results in relapse when either returning to Context A (ABA renewal) or introducing a novel Context C (ABC renewal). ABA renewal typically is greater than ABC renewal. The present study assessed whether renewal might be conceptualized through excitatory and inhibitory generalization gradients inferred from studies of stimulus generalization. We arranged one keylight-color alternation frequency for pigeons to signal reinforcement in Phase 1 and a different alternation frequency to signal extinction in Phase 2. During a subsequent test in extinction, we presented a range of keylight-alternation frequencies and found renewal to be a function of keylight-alternation frequency. Specifically, Phase-3 responding increased as keylight-alternation frequency differed from that arranged during extinction in Phase 2. Moreover, we observed a shift in the function beyond the originally reinforced keylight-alternation frequency arranged in training (i.e., peak shift). We discuss the relevance of these findings for conceptualizing stimulus-control processes governing generalization gradients for understanding the processes underlying context renewal.

A critical role of nucleus accumbens dopamine D1-family receptors in renewal of alcohol seeking after punishment-imposed abstinence.

In humans, places or contexts previously associated with alcohol use often provoke relapse during abstinence. This phenomenon is modeled in laboratory animals using the ABA renewal procedure, in which extinction training in context (B) suppresses alcohol seeking, and renewal of this seeking occurs when the animal returns to the original training context (A). However, extinction training does not adequately capture the motivation for abstinence in human alcoholics who typically self-initiate abstinence in response to the negative consequences of excessive use. We recently developed a procedure to study renewal in laboratory rats after abstinence imposed by negative consequences (footshock punishment). The mechanisms of renewal of punished alcohol seeking are largely unknown. Here, we used the D1-family receptor antagonist SCH 23390 to examine the role of nucleus accumbens (NAc) shell and core dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We trained alcohol-preferring "P rats" to self-administer 20% alcohol in Context A and subsequently suppressed alcohol taking via response-contingent footshock punishment in Context B. We tested the effects of systemic, NAc shell, or NAc core injections of SCH 23390 on renewal of alcohol seeking after punishment-imposed abstinence. We found that both systemic and NAc shell and core injections of SCH 23390 decreased renewal of punished alcohol seeking. Our results demonstrate a critical role of NAc dopamine in renewal of alcohol seeking after punishment-imposed abstinence. We discuss these results in reference to the brain mechanisms of renewal of alcohol seeking after extinction versus punishment.

Basic and translational evaluation of renewal of operant responding.

Treatment relapse, defined as the reemergence of problem behavior after treatment, is a serious difficulty faced by clinicians. Failures of treatment integrity (i.e., failure to implement interventions as intended) are often invoked to explain the reemergence of problem behavior. Basic studies suggest that the prevailing stimulus context might also contribute. We conducted 2 experiments in which reinforcement for a target response was followed by 2 phases of extinction with different or identical stimulus contexts relative to baseline (ABA renewal). In Experiment 1, pigeons served as subjects using procedures typical of those used in basic behavioral research. Experiment 2 was designed as a translational replication of Experiment 1, and children who had been diagnosed with autism served as participants. Returning to the previously reinforced stimulus context in both species produced a clear and immediate increase of extinguished responding. These findings are consistent with previous studies that have suggested that both reinforcement contingencies and stimulus context influence the reemergence of extinguished behavior.

Blocking NMDA-receptors in the pigeon's "prefrontal" caudal nidopallium impairs appetitive extinction learning in a sign-tracking paradigm.

Extinction learning provides the ability to flexibly adapt to new contingencies by learning to inhibit previously acquired associations in a context-dependent manner. The neural networks underlying extinction learning were mostly studied in rodents using fear extinction paradigms. To uncover invariant properties of the neural basis of extinction learning, we employ pigeons as a model system. Since the prefrontal cortex (PFC) of mammals is a key structure for extinction learning, we assessed the role of N-methyl-D-aspartate receptors (NMDARs) in the nidopallium caudolaterale (NCL), the avian functional equivalent of mammalian PFC. Since NMDARs in PFC have been shown to be relevant for extinction learning, we locally antagonized NMDARs through 2-Amino-5-phosphonovalerianacid (APV) during extinction learning in a within-subject sign-tracking ABA-renewal paradigm. APV-injection slowed down extinction learning and in addition also caused a disinhibition of responding to a continuously reinforced control stimulus. In subsequent retrieval sessions, spontaneous recovery was increased while ABA renewal was unaffected. The effect of APV resembles that observed in studies of fear extinction with rodents, suggesting common neural substrates of extinction under both appetitive and aversive conditions and highlighting the similarity of mammalian PFC and the avian caudal nidopallium despite 300 million years of independent evolution.

Super-resurgence: ABA renewal increases resurgence

Previously extinguished operant responding recurs under both resurgence and renewal procedures, but the effects of combining these procedures on recurrence has not been studied. Because renewal and resurgence are known to independently produce response recurrence, we examined whether greater resurgence would occur if the resurgence procedure was combined with an ABA renewal procedure, relative to a resurgence procedure without contextual changes. Three pigeons were exposed to a concurrent resurgence procedure in which key colors served as contextual stimuli. In the Training phase, reinforcement for pecking two keys was scheduled on concurrent variable-interval (VI) 120-s VI 120-s schedules, each correlated with different key colors. In the Alternative Reinforcement phase, reinforcement occurred when neither key was pecked for 20-s (a differential-reinforcement-of-other-behavior [DRO] 20-s schedule). During this phase, one of the key colors was changed (ABA key), while the other key color remained as in the Training phase (AAA key). In the third phase, reinforcement was not provided and the color of the ABA key was changed back to the color in effect during the Training phase while the same color remained in effect on the other key. Greater resurgence occurred on the ABA renewal key with each pigeon, demonstrating that a superimposed ABA renewal procedure increases resurgence.

Effects of vivo morpholino knockdown of lateral hypothalamus orexin/hypocretin on renewal of alcohol seeking.

Two experiments used vivo morpholinos to assess the role of orexin/hypocretin in ABA renewal of extinguished alcohol seeking. Rats were trained to respond for alcoholic beer in a distinctive context, A, and then extinguished in a second distinctive context, B. When rats were tested in the extinction context, ABB, responding was low but when they were tested in the training context, ABA, responding was significantly higher. Microinjection of an orexin/hypocretin antisense vivo morpholino into LH significantly reduced orexin/hypocretin protein expression but had no effect on the ABA renewal of alcohol seeking (Experiment 1). Microinjection of a higher dose of the antisense vivo morpholino into LH also significantly reduced orexin/hypocretin protein expression but this was not selective and yielded significant reduction in melanin -concentrating hormone (MCH) protein expression. This non-selective knockdown did significantly reduce ABA renewal as well as reduce the reacquisition of alcohol seeking. Taken together, these findings show an important role for LH in the ABA renewal of alcohol seeking but that orexin/hypocretin is not necessary for this renewal.

Effects of baseline reinforcement rate on operant ABA and ABC renewal

Renewal is a relapse phenomenon that occurs when the contextual stimuli present during extinction change, and consequently, an extinguished response increases in rate. Two experiments assessed extinction and renewal of key-pecking in pigeons in a two-component multiple schedule wherein baseline reinforcer rates were delivered at relatively rich or lean rates. In Experiment 1, an ABA design was used in which baseline stimuli were steady key lights (Context A). Food was then removed during extinction, and simultaneously, the context was changed by flashing the key lights (Context B). Following extinction, steady key lights were reintroduced, but food remained unavailable. Key-pecking was more resistant to extinction and recovered to a greater degree in the rich relative to the lean component. In Experiment 2, we introduced novel stimuli following extinction (ABC renewal) rather than reintroducing baseline stimuli. Similar to Experiment 1, in Experiment 2 resistance to change and renewal remained greater in the component associated with higher reinforcer rates during baseline. These findings provide additional support for the context-specificity of operant extinction, and support the prediction of behavioral momentum theory that stimuli associated with higher rates of reinforcement engender greater persistence and relapse than those associated with lower rates of reinforcement.

Intertrial intervals and contextual conditioning in appetitive pavlovian learning: Effects over the ABA renewal paradigm

Three experiments using rats in an appetitive conditioning procedure analyzed the effect of short and long (50s vs. 1440s) intertrial intervals (ITI) over the acquisition of conditioned stimulus (CS), context (Ctxt), and unconditioned stimulus (US) associations, as well as the effect on the extinction and renewal of the conditioned response to the CS. Experiment 1 revealed more contextual conditioned responses in groups trained with the short ITIs, however the renewal effect was not observed during test phase with either ITI condition. When subjects were pre-exposed to the contexts before the acquisition phase (Experiment 2) renewal of the conditioned response (CR) was only observed in long ITI group. However, when the acquisition context was extinguished (Experiment 3) the renewal effect observed in the Experiment 2 was weakened. In all three experiments subjects showed a similar number of responses to the tone predicting food, however they showed a clear contextual conditioning effect only for the groups trained with short ITIs. It is noteworthy that the acquisition context showed high levels of the CR in the renewal test only for groups trained with short ITIs (Experiment 2) but these responses were absent if additional contextual extinction was imposed before such test (Experiment 3). In general, all groups showed similar acquisition curves for the CS but only Short groups had an increase in the CR during the pre-CS. Also, context conditioning does not interfere with the conditioning of the CS and context pre-exposure prior to acquisition is essential in order to observe the renewal effect when long ITIs are used.

ABA renewal involves enhancements in both GluA2-lacking AMPA receptor activity and GluA1 phosphorylation in the lateral amygdala.

Fear renewal, the context-specific relapse of fear following fear extinction, is a leading animal model of post-traumatic stress disorders (PTSD) and fear-related disorders. Although fear extinction can diminish fear responses, this effect is restricted to the context where the extinction is carried out, and the extinguished fear strongly relapses when assessed in the original acquisition context (ABA renewal) or in a context distinct from the conditioning and extinction contexts (ABC renewal). We have previously identified Ser831 phosphorylation of GluA1 subunit in the lateral amygdala (LA) as a key molecular mechanism for ABC renewal. However, molecular mechanisms underlying ABA renewal remain to be elucidated. Here, we found that both the excitatory synaptic efficacy and GluA2-lacking AMPAR activity at thalamic input synapses onto the LA (T-LA synapses) were enhanced upon ABA renewal. GluA2-lacking AMPAR activity was also increased during low-threshold potentiation, a potential cellular substrate of renewal, at T-LA synapses. The microinjection of 1-naphtylacetyl-spermine (NASPM), a selective blocker of GluA2-lacking AMPARs, into the LA attenuated ABA renewal, suggesting a critical role of GluA2-lacking AMPARs in ABA renewal. We also found that Ser831 phosphorylation of GluA1 in the LA was increased upon ABA renewal. We developed a short peptide mimicking the Ser831-containing C-tail region of GluA1, which can be phosphorylated upon renewal (GluA1S); thus, the phosphorylated GluA1S may compete with Ser831-phosphorylated GluA1. This GluA1S peptide blocked the low-threshold potentiation when dialyzed into a recorded neuron. The microinjection of a cell-permeable form of GluA1S peptide into the LA attenuated ABA renewal. In support of the GluA1S experiments, a GluA1D peptide (in which the serine at 831 is replaced with a phosphomimetic amino acid, aspartate) attenuated ABA renewal when microinjected into the LA. These findings suggest that enhancements in both the GluA2-lacking AMPAR activity and GluA1 phosphorylation at Ser831 are required for ABA renewal.