Extinction Context Research Articles

Rol de Estímulos Asociados a las Claves de Extinción en la Recuperación de Respuesta

En 2 experimentos se investigo el rol de las claves de extincion (CE), y estimulos asociados a estas, en la readquisicion de la tolerancia condicionada al etanol. La ataxia causada por el etanol fue medida en 80 ratas, utilizando planos de deslizamiento en un procedimiento de 5 fases. El primer experimento (que utilizo 4 contextos y 40 ratas) mostro que la presentacion del contexto de extincion por si solo disminuyo la efectividad de la CE para reducir la readquisicion de respuesta. El segundo experimento (hecho en un solo contexto, con 40 ratas y con la diferencia de que se usaron 2 estimulos que fueron pareados para algunos sujetos o explicitamente no pareados para otros) mostro que una clave secundaria puede reducir la readquisicion, independientemente de si fue pareada con la CE o no. Los resultados de analisis de varianza mixtos y factoriales sugieren que la CE afectaria la recuperacion de la respuesta a traves de una asociacion con el contexto de extincion; sin embargo, una clave de segundo orden, asociada a la CE, no lograria activar dicha asociacion.

Un/natural death and extinction

AbstractThis article examines the question of death in the larger context of extinction, more specifically in the context of the sixth extinction, the human‐caused mass die‐off of species we are currently experiencing. The point is made that while both death and extinction are a natural part of evolutionary life on earth, there are critical aspects of both that are distinctly “unnatural”—even sinful, and should be combatted and resisted.

Prefrontal projections to the thalamic nucleus reuniens mediate fear extinction

The thalamic nucleus reuniens (RE) receives dense projections from the medial prefrontal cortex (mPFC), interconnects the mPFC and hippocampus, and may serve a pivotal role in regulating emotional learning and memory. Here we show that the RE and its mPFC afferents are critical for the extinction of Pavlovian fear memories in rats. Pharmacological inactivation of the RE during extinction learning or retrieval increases freezing to an extinguished conditioned stimulus (CS); renewal of fear outside the extinction context was unaffected. Suppression of fear in the extinction context is associated with an increase in c-fos expression and spike firing in RE neurons to the extinguished CS. The role for the RE in suppressing extinguished fear requires the mPFC, insofar as pharmacogenetically silencing mPFC to RE projections impairs the expression of extinction memory. These results reveal that mPFC-RE circuits inhibit the expression of fear, a function that is essential for adaptive emotional regulation.

Poor between-session recall of extinction learning and hippocampal activation and connectivity in children.

In healthy adults, successful between-session recall of extinction learning depends on the hippocampus and ventromedial prefrontal cortex (vmPFC), especially when tested in the extinction context. Poor extinction recall and dysfunction within hippocampal-vmPFC circuitry are associated with fear-based disorders (e.g., anxiety, posttraumatic stress disorder). Despite the early age of onset of virtually all fear-based disorders and the protracted development of the hippocampus and vmPFC across the first two decades of life, little is known about extinction recall and the underlying neural correlates in children. Here, we tested extinction recall in 43 pre-adolescent children (ages 6-11 yrs) by coupling functional magnetic resonance imaging and virtual reality with a novel interpersonal threat-related two-day (ABBA) fear-extinction paradigm. Conditioned fear responding was assessed at behavioral, subjective, physiological, and neural levels. Although children demonstrated intact within-session extinction, there was poor between-session recall of extinction learning (retention index: 13.56%), evidenced by elevations in skin conductance, avoidant behavioral responses, and subjective ratings. Elevations in conditioning fear responding were accompanied by activation in the hippocampus and insula, and increased connectivity of the hippocampus with the insula and dorsal anterior cingulate cortex - regions implicated in the return of fear in adult studies. Children who kept more distance from the extinguished cue during extinction subsequently demonstrated heightened hippocampal-cingulate coupling during recall, suggesting that avoidant behavior interferes with extinction retention. Poor extinction recall in children may have implications for developmental vulnerability to fear-based disorders, and for the application of therapeutic strategies that rely on principles of extinction (e.g., exposure therapy) to pediatric samples.

Secondary extinction reduces reinstatement of threat expectancy and conditioned skin conductance responses in human fear conditioning

Background and objectivesSecondary extinction refers to the phenomenon that extinction of one conditioned stimulus (CS) results in the reduction of conditioned responses for other CSs conditioned with the same unconditioned stimulus (US). Previous research with rats has demonstrated that secondary extinction can interfere with the return of conditioned fear after a reinstatement manipulation. Here we investigated this phenomenon in two pre-registered studies in humans. MethodIn both experiments, distinct CSs were paired with an electrical stimulation. Next, conditioned reactions to both CSs were extinguished and thereafter reinstated through the administration of three unsignaled electrical stimulations. Crucially, before participants continued with the reinstatement test, half of the participants received secondary extinction trials whereas the other half did not receive these trials. ResultsOur results indicate that secondary extinction reduced reinstatement of threat expectancies and skin conductance responses, but the effect on skin conductance was only found in the second experiment. LimitationsThe studies were conducted in a laboratory setting with healthy students. Additional research will be required to determine the feasibility of applying secondary extinction in a (sub)clinical context. ConclusionsTo our knowledge, this is the first demonstration of secondary extinction and its effect on reinstatement of conditioned fear in humans. We relate our findings to the earlier research with rats and discuss their relevance for exposure therapy.

Renewal of extinguished operant behavior following changes in social context.

Renewal is the reoccurrence of previously extinguished behavior following a change in the context in which extinction was conducted. Despite an extensive body of research examining renewal, little is known about the role of social stimuli in renewal. The present experiments provided a novel examination of renewal of operant behavior by changing social stimuli across phases in an ABA renewal preparation. In both experiments, social stimuli were arranged by placing another rat in a second compartment of a divided operant chamber. In Experiment 1, the presence of another rat defined the extinction context, whereas an empty second compartment defined the baseline and testing contexts. We reversed these contextual manipulations in Experiment 2 such that the presence of another rat defined the baseline and testing contexts and the second compartment was empty during extinction. Renewal of lever pressing occurred when the other rat was removed from the chamber in Experiment 1 and when the other rat was returned to the chamber in Experiment 2. Thus, social stimuli may function as contextual stimuli, and changes in social contexts may produce renewal of previously extinguished behavior.

Evidencia de renovación instrumental ABC previamente eliminada con los procedimientos de extinción y omisión

One experiment used a free operant procedure with rats to evaluate renewal of a response previously eliminated by using omission training or by using an extinction treatment. All rats were trained to press a lever for food in context A. Then, the operant responses were eliminated in a second context. In this phase, half of the subjects received an omission training (i. e., delivery of food for withholding responding), while the other half received an extinction procedure. Finally, a within-subject ABC renewal test was conducted. The results demonstrated that all rats showed higher levels of responding when they were tested outside extinction context, regardless the procedure used during the elimination phase.

D-Cycloserine facilitates fear extinction in adolescent rats and differentially affects medial and lateral prefrontal cortex activation

Adolescent humans and rodents are impaired in extinguishing learned fear relative to younger and older groups. This impairment could be due to differences in recruitment of medial prefrontal cortex (PFC), orbitofrontal cortex (OFC), or amygdala during extinction. For example, unlike juveniles and adults, adolescent rats do not express extinction-induced increases in phosphorylated mitogen activated protein kinase (pMAPK), a marker of synaptic plasticity, in the medial PFC. The NMDA receptor partial agonist d-cycloserine (DCS) improves extinction retention in adolescent rats. We investigated whether DCS affected recruitment of the PFC and amygdala during extinction by measuring pMAPK-immunoreactive (IR) neurons. Adolescent rats were trained to fear a conditioned stimulus in one context followed by extinction in a second context or equivalent context exposure only (i.e., no extinction). DCS (15 mg/kg, s.c.) or saline was administered systemically immediately after extinction training or context exposure. DCS enhanced extinction learning and this was associated with increased activation of the MAPK signaling pathway in the OFC after extinction training and increased activation in the medial PFC and amygdala at extinction retention. These findings suggest that DCS improves extinction learning in adolescents because it augments OFC contributions to extinction learning, enabling better medial prefrontal contributions to extinction retention.

The effects of extinction-aroused attention on context conditioning.

Two experiments assessed the effects of extinguishing a conditioned cue on subsequent context conditioning. Each experiment used a different video-game method where sensors predicted attacking spaceships and participants responded to the sensor in a way that prepared them for the upcoming attack. In Experiment 1 extinction of a cue which signaled a spaceship-attack outcome facilitated subsequent learning when the attack occurred unsignaled. In Experiment 2 extinction of a cue facilitated subsequent learning, regardless of whether the spaceship outcome was the same or different as used in the earlier training. In neither experiment did the extinction context become inhibitory. Results are discussed in terms of current associative theories of attention and conditioning.

Tyrosine receptor kinase B receptor activation reverses the impairing effects of acute nicotine on contextual fear extinction.

Anxiety and stress disorders have been linked to deficits in fear extinction. Our laboratory and others have demonstrated that acute nicotine impairs contextual fear extinction, suggesting that nicotine exposure may have negative effects on anxiety and stress disorder symptomatology. However, the neurobiological mechanisms underlying the acute nicotine-induced impairment of contextual fear extinction are unknown. Therefore, based on the previous studies showing that brain-derived neurotrophic factor is central for fear extinction learning and acute nicotine dysregulates brain-derived neurotrophic factor signaling, we hypothesized that the nicotine-induced impairment of contextual fear extinction may involve changes in tyrosine receptor kinase B signaling. To test this hypothesis, we systemically, intraperitoneally, injected C57BL/6J mice sub-threshold doses (2.5 and 4.0 mg/kg) of 7,8-dihydroxyflavone, a small-molecule tyrosine receptor kinase B agonist that fully mimics the effects of brain-derived neurotrophic factor, or vehicle an hour before each contextual fear extinction session. Mice also received injections, intraperitoneally, of acute nicotine (0.18 mg/kg) or saline 2-4 min before extinction sessions. While the animals that received only 7,8-dihydroxyflavone did not show any changes in contextual fear extinction, 4.0 mg/kg of 7,8-dihydroxyflavone ameliorated the extinction deficits in mice administered acute nicotine. Overall, these results suggest that acute nicotine-induced impairment of context extinction may be related to a disrupted brain-derived neurotrophic factor signaling.

Cortisol increases the return of fear by strengthening amygdala signaling in men

Relapses represent a major limitation to the long-term remission of pathological fear and anxiety. Stress modulates the acquisition and expression of fear memories and appears to promote fear recovery in patients with anxiety disorders. However, the neural correlates underlying stress hormone effects on the return of fear in humans remain unexplored. Likewise, little is known about the interactions between sex and stress hormones on return of fear phenomena. In this functional magnetic resonance imaging study, 32 men and 32 women were exposed to a fear renewal paradigm with fear acquisition in context A and extinction in context B. On the following day, participants received either cortisol or placebo 40 min before return of fear was tested in both contexts in a renewal and reinstatement test. Cortisol increased differential conditioned skin conductance responses in the extinction context B following reinstatement in men but not in women. On the neural level, this effect was characterized by enhanced fear-related activation in the right amygdala in men, while an activation decrement in this region was observed after cortisol treatment in women. Our results revealed that cortisol promotes the return of fear in men by strengthening a key node of the fear network – the amygdala. We thereby provide novel insights into a sex-specific mechanism mediating stress-induced fear recovery which may translate into different relapse risks and treatment strategies for men and women.

Opposite Effects of Basolateral Amygdala Inactivation on Context-Induced Relapse to Cocaine Seeking after Extinction versus Punishment.

Studies using the renewal procedure showed that basolateral amygdala (BLA) inactivation inhibits context-induced relapse to cocaine-seeking after extinction. Here, we determined whether BLA inactivation would also inhibit context-induced relapse after drug-reinforced responding is suppressed by punishment, an animal model of human relapse after self-imposed abstinence due to adverse consequences of drug use. We also determined the effect of central amygdala (CeA) inactivation on context-induced relapse.We trained rats to self-administer cocaine for 12 d (6 h/d) in Context A and then exposed them to either extinction or punishment training for 8 d in Context B. During punishment, 50% of cocaine-reinforced lever-presses produced an aversive footshock of increasing intensity (0.1-0.5 or 0.7 mA). We then tested the rats for relapse to cocaine seeking in the absence of cocaine or shock in Contexts A and B after BLA or CeA injections of vehicle or GABA agonists (muscimol-baclofen). We then retrained the rats for cocaine self-administration in Context A, repunished or re-extinguished lever pressing in Context B, and retested for relapse after BLA or CeA inactivation.BLA or CeA inactivation decreased context-induced relapse in Context A after extinction in Context B. BLA, but not CeA, inactivation increased context-induced relapse in Context A after punishment in Context B. BLA or CeA inactivation provoked relapse in Context B after punishment but not extinction. Results demonstrate that amygdala's role in relapse depends on the method used to achieve abstinence and highlights the importance of studying relapse under abstinence conditions that more closely mimic the human condition.SIGNIFICANCE STATEMENT Relapse to drug use during abstinence is often provoked by re-exposure to the drug self-administration environment or context. Studies using the established extinction-reinstatement rodent model of drug relapse have shown that inactivation of the basolateral amygdala inhibits context-induced drug relapse after extinction of the drug-reinforced responding. Here, we determined whether basolateral amygdala inactivation would also inhibit relapse after drug-reinforced responding is suppressed by punishment, a model of human relapse after self-imposed abstinence. Unexpectedly, we found that basolateral amygdala inactivation had opposite effects on relapse provoked by re-exposure to the drug self-administration environment after extinction versus punishment. Our results demonstrate that depending on the historical conditions that lead to abstinence, amygdala activity can either promote or inhibit relapse.

Greater reinforcement rate during training increases spontaneous recovery.

Spontaneous recovery occurs when a previously reinforced and recently extinguished response reemerges over the course of time, often at the beginning of a new session of extinction. Spontaneous recovery could underlie instances of treatment relapse that threaten otherwise effective behavioral interventions for problem behavior. In two experiments, we arranged multiple schedules with pigeons and a human child to assess the effects of different training reinforcer rates on spontaneous recovery. In both experiments, responding was both more resistant to extinction and more likely to relapse following training with greater reinforcement rates upon returning to extinction after time off from extinction testing. A quantitative model based on behavioral momentum theory accounted well for the data, which suggests reexposure to the extinction context following time off during extinction resulted in (1) the failure of extinction learning to generalize, and (2) greater generalization of original learning during training. The present model attempts to quantify theories attributing spontaneous recovery to changes in temporal context.

Running wheel exercise reduces renewal of extinguished instrumental behavior and alters medial prefrontal cortex neurons in adolescent, but not adult, rats.

Physical exercise in rodents has repeatedly been shown to trigger positive effects on brain function, including increased neurotrophic factors and improved learning and memory. However, most of this work has focused on the adult hippocampus and hippocampal-dependent behavior. Here we examined the effect of running wheel exercise in adult and adolescent male rats on ABA renewal of extinguished instrumental conditioning, in which acquisition occurs in Context A, extinction in Context B, and renewal testing occurs back in Context A. In the first experiment, rats were given unlocked (exercise) or locked (no exercise) running wheel access in their home cages beginning at postnatal Day 30 (adolescent) or postnatal Day 56 (adult). Rats underwent lever-press acquisition in Context A and extinction in Context B. ABA renewal testing took place 2 weeks after the start of running wheel exposure. Nonexercising adolescent rats showed greater ABA renewal than nonexercising adult rats and exercise reduced ABA renewal in adolescents but not adults. ABA renewal depends on medial prefrontal cortex function. In a second experiment, we compared adolescent and adult apical dendrite branch length, branch number, and spine density of medial prefrontal cortex pyramidal neurons after 2 weeks of unlocked or locked running wheel access. The results revealed a higher density of dendritic spines and a lower dendritic branch length in adolescent exercisers than adolescent nonexercisers. Adult exercisers and nonexercisers did not differ. Collectively, these experiments suggest that exercise may have particularly strong effects on adolescent medial prefrontal cortex function and structure. (PsycINFO Database Record

Effects of extended extinction and multiple extinction contexts on ABA renewal

The return of fear following exposure therapy suggests that extinction does not result in a permanent unlearning of the association between a conditional stimulus (CS) and an unconditional stimulus (US). One proposed mechanism of return of fear is ABA renewal in which a CS is paired with a US in context A, presented alone in context B, and followed by test trials in context A. The current study examined the effects of extended extinction and multiple extinction contexts on ABA renewal in 121 first year psychology students. Using a fear conditioning procedure, renewal of shock expectancy during test was observed when extinction was presented for 12 extinction trials in a single context. In addition, renewal was attenuated when extinction was extended to 36 extinction trials or conducted in multiple contexts with 12 extinction trials. Combining extended extinction with multiple contexts resulted in the greatest attenuation of renewal. The results suggest that prolonged exposure treatment in multiple contexts may enhance the cross-contextual generalizability of extinction learning and reduce the likelihood of renewal of fear.

Inactivation of the Prelimbic Cortex Impairs the Context-Induced Reinstatement of Ethanol Seeking.

Evidence indicates that drug relapse in humans is often provoked by exposure to the self-administered drug-associated context. An animal model called “ABA renewal procedure” has been used to study the context-induced relapse to drug seeking. Here, we reported a new and feasible training procedure for the ABA renewal method to explore the role of the prelimbic cortex in context-induced relapse to ethanol seeking. By using a saccharin fading technique, we trained rats to self-administer ethanol (10%). The drug delivery was paired with a discrete tone-light cue. Lever pressing was subsequently extinguished in a non-drug-associated context in the presence of the discrete cue. Rats were subsequently tested for reinstatement in contexts A or B, under extinction conditions. Ethanol-associated context induced the reinstatement of ethanol seeking and increased the expression of Fos in the prelimbic cortex. The rate of neural activation in the prelimbic cortex was 3.4% in the extinction context B and 7.7% in the drug-associated context A, as evidenced by double-labeling of Fos and the neuron-specific protein NeuN. The reversible inactivation of the neural activity in the prelimbic cortex with gamma-Aminobutyric acid (GABA) receptor agonists (muscimol + baclofen) attenuated the context-induced reinstatement of ethanol self-administration. These results demonstrated that the neuronal activation of the prelimbic cortex is involved in the context-induced reinstatement of ethanol seeking.

Neural Underpinnings of Cortisol Effects on Fear Extinction.

Extinction of conditioned fear embodies a crucial mechanism incorporated in exposure therapy. Clinical studies demonstrated that application of the stress hormone cortisol before exposure sessions facilitates exposure success, but the underlying neural correlates remain unknown. Context- and stimulus-dependent cortisol effects on extinction learning will be characterized in this study and tested in the extinction and in a new context. Forty healthy men participated in a 3-day fear conditioning experiment with fear acquisition in context A (day 1), extinction training in context B (day 2), and recall in context B and a new context C one week later (day 3). Hydrocortisone (30 mg) or placebo was given before extinction training. Blood-oxygen-level-dependent responses and skin conductance responses (SCRs) served as dependent measures. At the beginning of extinction training, cortisol reduced conditioned SCRs, diminished activation of the amygdala-hippocampal complex, and enhanced functional connectivity of the anterior parahippocampal gyrus with the ventromedial prefrontal cortex (vmPFC). After one week, the cortisol group showed increased hippocampal activation and connectivity to the vmPFC toward an extinguished stimulus and reduced insula activation toward a nonextinguished stimulus in the extinction context. However, this inhibitory cortisol effect did not extend to the new context. Taken together, cortisol reduced fear recall at the beginning of extinction and facilitated the consolidation of the extinction memory as evidenced by an inhibitory activation pattern one week later. The stress hormone exerted a critical impact on the amygdala-hippocampus-vmPFC network underlying fear and extinction memories. However, cortisol did not attenuate the context dependency of extinction.

D-Cycloserine facilitates extinction learning and enhances extinction-related brain activation

Extinction learning is modulated by N-methyl d-aspartate receptors (NMDAR) particularly in prefrontal and hippocampal brain regions. The use of of NMDA agonists in exposure therapy of anxiety disorders has been investigated in various patient groups. Behavioral results showed beneficial effects of pre-learning administration of the partial NMDAR agonist d-Cycloserine (DCS) on therapy success. However, the impact of DCS upon non-fear-related contextual extinction, and associated recruitment of extinction-relevant brain regions is as yet unknown. In the present fMRI study, healthy human participants performed a context-related associative learning and extinction task. A single dose of DCS, administered prior to extinction learning, enhanced extinction learning performance in an identical context, and increased activation in prefrontal, temporal as well as hippocampal/insular regions, compared to placebo controls. In contrast, DCS did not affect extinction learning in a novel context, nor the renewal effect, which describes the recovery of an extinguished response if the context of extinction differs from the context of recall. Our findings demonstrate a specific involvement of prefrontal and hippocampal NMDAR in the modification of established stimulus-outcome associations in identical contexts and thus their role in behavioral flexibility, underlining their potential for enhancing AAA extinction learning.

The effects of ethanol on diverse components of choice in the rat: reward discrimination, preference and relative valuation.

Alcohol consumption impairs judgment and choice. How alcohol alters these crucial processes is primarily unknown. Choice can be fractionated into different components including reward discrimination, preference and relative valuation that can function together or in isolation depending upon diverse factors including choice context. We examined the diverse components and contextual effects by analyzing the effects of alcohol drinking on choice behavior in a task with a reduced level of temporal and spatial constraints. Rats were trained to drink 10% ethanol during 6weeks of behavior testing using a combined sucrose-fade and two-bottle free-choice procedure. Two different sucrose pellet outcomes (e.g., constant vs. variable) were presented each week to examine the impact of voluntary drinking on reward-based decision-making. Behavioral contexts of single option, free choice and extinction were examined for each outcome set. Comparisons were made between alcohol and control groups and within the alcohol group over time to inspect choice profiles. Between-group results showed alcohol drinking animals expressed altered place preference and modified sucrose reward approach latencies. The within-group profile showed that alcohol drinking animals can express adequate reward discrimination, preference and incentive contrast during free choice. All of these components were significantly reduced during the context of extinction. Control animals were also impacted by extinction but not as severely. The findings point to a need for a greater focus on the context and the diverse components of choice when examining external and internal factors influencing decision-making during alcohol or other substance of abuse exposure.

Renewed behavior produced by context change and its implications for treatment maintenance: A review.

Behavioral treatment gains established in one setting do not always maintain in other settings. The present review examines the relevance of basic and translational research to understanding failures to maintain treatment gains across settings. Specifically, studies of the renewal effect examine how transitioning away from a treatment setting could evoke a return of undesirable behavior, rather than newly trained appropriate behavior. Studies of renewal typically arrange three phases, with a response trained and reinforced under a particular set of contextual stimuli in the first phase. Next, that response is extinguished, often under a different set of contextual stimuli. Finally, that response returns despite extinction remaining in effect upon returning to the original training context or transitioning to a novel context. Thus, removing the extinction context is sufficient to produce a recurrence of the response. The findings suggest treatment effects can become specific to the context in which the treatment was delivered. This literature offers promising methods for systematically assessing the factors contributing to treatment maintenance and improving generalization of treatment gains across contexts. Therefore, the present review suggests basic and translational research on renewal provides an empirical literature to bring greater conceptual systematization to understanding generalization and maintenance of behavioral treatment.