Expression Of Extinction Memory Research Articles

Thought suppression inhibits the generalization of fear extinction

A challenge for translating fear extinction research into clinical treatments for stress and anxiety disorders is that extinction learning tends not to generalize beyond the treatment context. This may be because the hippocampus limits the expression of extinction memories. Consequently, downregulating the hippocampus may help to promote the generalization of extinction learning. One nonpharmacological strategy to downregulate hippocampal activity in humans is motivated forgetting, in which a participant deliberately attempts to suppress the encoding and/or retrieval of episodic memories. Here, we evaluated whether this strategy could facilitate extinction generalization by augmenting extinction training with thought suppression. Participants were threat conditioned using two conditioned stimulus (CS) categories paired with an electrical shock. Subsequently, during extinction training, one CS category was accompanied by thought suppression. Participants were tested for extinction generalization 24h later with conceptual variations of the extinguished stimuli. Contrary to our prediction, we found that extinction training paired with thought suppression resulted in enhanced shock expectancy (i.e., worse generalization) relative to standard extinction. We conclude that thought suppression during memory encoding likely acts as an inhibitory cue that blocks the acquisition of extinction memories, and therefore may not be a viable tactic to promote extinction generalization in the treatment of anxiety disorders.

Heat shock disrupts expression of excitatory and extinction memories in planaria: Interaction with amount of exposure

In planarians, as seen in rodents, natural reinforcers (sucrose) and drugs of abuse support Conditioned Place Preference (CPP), which is a form of Pavlovian learning to examine the rewarding effects of natural reinforcers and drugs of abuse. Using this preparation, we have previously observed acquisition, extinction and reinstatement of sucrose CPP. In the present experiments, we used planaria to investigate the amnestic effects of Heat Shock (HS, a known stressor in planaria) following different amounts of CPP extinction sessions. Experiment 1 showed that planarians developed a CPP response to a sucrose-paired surface. Heat shock, when given in conjunction with exposure to the sucrose-paired surface, produced amnesia as assessed by a subsequent sucrose reinstatement test. We interpreted that the amnesic effect of HS was due to HS affecting the dominant excitatory memory at the time of HS exposure. Thus, we hypothesized that after extensive extinction training (10 exposures), HS would lead to recovery from extinction (when the new inhibitory memory is dominant at the time of HS exposure). Experiment 2 explored this possibility and showed that given HS following 10 extinction sessions had no amnestic effect on the excitatory CPP response. In Experiment 3, we hypothesized that 16 extinction sessions would produce a stronger (and hence dominant) extinction inhibitory trace, which then would be vulnerable to HS. We observed that HS impaired the expression of the extinction memory following 16 exposures. These results reveal different effects of HS on CPP memories depending on the amount of extinction, and are fully consistent with the literature using rodents and humans. In addition, they suggest that planaria is a promising pre-clinical model to assess fundamental memory processes.

Fear extinction memory is negatively associated with REM sleep in insomnia disorder.

Formation and maintenance of fear-extinction memories are disrupted in post-traumatic stress disorder (PTSD) and anxiety disorders. Sleep contributes to emotional memory consolidation and emotion regulation. Insomnia disorder (ID) is characterized by persistent sleep disturbance as well as rapid eye movement (REM) sleep abnormalities and often precedes or develops in parallel with PTSD and anxiety disorders. Here, we explore the impact of chronic poor sleep and sleep immediately following fear conditioning and extinction learning on preservation of extinction memories. Twenty-four ID age- and sex-matched to 24 healthy, good sleeper controls (GS) completed up to 2 weeks of habitual sleep monitoring with daily sleep-wake diaries and actigraphy, and then participated in a two-session fear conditioning, extinction learning and extinction recall procedure. Fear Conditioning and Extinction Learning occurred during session 1, followed by Extinction Recall approximately 24 hours later. Skin-conductance responses (SCR) and shock expectancies were recorded throughout all experimental phases to evaluate associative learning and memory. Overnight sleep between sessions 1 and 2 was recorded using ambulatory polysomnography. ID showed greater physiological reactivity during Fear Conditioning. REM sleep physiology was associated with poorer extinction memory in ID but better extinction memory in GS. REM sleep physiology may differentially support emotional memory retention and expression in ID and GS. In the former, REM may enhance retention of fear memories, while in the later, REM may enhance the expression of extinction memories.

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.

Acute stress impairs the retrieval of extinction memory in humans

Extinction training is a form of inhibitory learning that allows an organism to associate a previously aversive cue with a new, safe outcome. Extinction does not erase a fear association, but instead creates a competing association that may or may not be retrieved when a cue is subsequently encountered. Characterizing the conditions under which extinction learning is expressed is important to enhancing the treatment of anxiety disorders that rely on extinction-based exposure therapy as a primary treatment technique. The ventromedial prefrontal cortex, which plays a critical role in the expression of extinction memory, has been shown to be functionally impaired after stress exposure. Further, recent work in rodents has demonstrated that exposure to stress leads to deficits in extinction retrieval, although this has yet to be tested in humans. To explore how stress might influence extinction retrieval in humans, participants underwent a differential aversive learning paradigm, in which one image was probabilistically paired with an aversive shock while the other image denoted safety. Extinction training directly followed, at which point reinforcement was omitted. A day later, participants returned to the lab and either completed an acute stress manipulation (i.e., cold pressor), or a control task, before undergoing an extinction retrieval test. Skin conductance responses and salivary cortisol concentrations were measured throughout each session as indices of fear arousal and neuroendocrine stress response, respectively. The efficacy of our stress induction was established by observing significant increases in cortisol for the stress condition only. We examined extinction retrieval by comparing conditioned responses during the last trial of extinction (day 1) with that of the first trial of re-extinction (day 2). Groups did not differ on initial fear acquisition or extinction, however, a day later participants in the stress group (n=27) demonstrated significantly lower extinction retrieval (i.e., greater fear recovery) than those in the control group (n=25). Our results suggest that acute stress impairs the retrieval of extinction learning and offers insight into why treatment strategies used in the clinic may be challenging to recruit in daily life where stress is pervasive.

Neuronal circuits of fear extinction

Fear extinction is a form of inhibitory learning that allows for the adaptive control of conditioned fear responses. Although fear extinction is an active learning process that eventually leads to the formation of a consolidated extinction memory, it is a fragile behavioural state. Fear responses can recover spontaneously or subsequent to environmental influences, such as context changes or stress. Understanding the neuronal substrates of fear extinction is of tremendous clinical relevance, as extinction is the cornerstone of psychological therapy of several anxiety disorders and because the relapse of maladaptative fear and anxiety is a major clinical problem. Recent research has begun to shed light on the molecular and cellular processes underlying fear extinction. In particular, the acquisition, consolidation and expression of extinction memories are thought to be mediated by highly specific neuronal circuits embedded in a large-scale brain network including the amygdala, prefrontal cortex, hippocampus and brain stem. Moreover, recent findings indicate that the neuronal circuitry of extinction is developmentally regulated. Here, we review emerging concepts of the neuronal circuitry of fear extinction, and highlight novel findings suggesting that the fragile phenomenon of extinction can be converted into a permanent erasure of fear memories. Finally, we discuss how research on genetic animal models of impaired extinction can further our understanding of the molecular and genetic bases of human anxiety disorders.

Fear Conditioning and Extinction Differentially Modify the Intrinsic Excitability of Infralimbic Neurons

Extinction of conditioned fear is an active learning process involving inhibition of fear expression. It has been proposed that fear extinction potentiates neurons in the infralimbic (IL) prefrontal cortex, but the cellular mechanisms underlying this potentiation remain unknown. It is also not known whether this potentiation occurs locally in IL neurons as opposed to IL afferents. To determine whether extinction enhances the intrinsic excitability of IL pyramidal neurons in layers II/III and V, we performed whole-cell patch-clamp recordings in slices from naive, conditioned, or conditioned-extinguished rats. We observed that conditioning depressed IL excitability compared with slices from naive animals, as evidenced by a decreased number of spikes evoked by injected current and an increase in the slow afterhyperpolarizing potential (sAHP). Extinction reversed these conditioning-induced effects. Furthermore, IL neurons from extinguished rats showed increased burst spiking compared with naive rats, which was correlated with extinction recall. These changes were specific to IL prefrontal cortex and were not observed in prelimbic prefrontal cortex. Together, these findings suggest that IL intrinsic excitability is reduced to allow for expression of conditioning memory and enhanced for expression of extinction memory through the modulation of Ca(2+)-gated K(+) channels underlying the sAHP. Inappropriate modulation of these intrinsic mechanisms may underlie anxiety disorders, characterized by exaggerated fear and deficient extinction.

Fear extinction in rats: Implications for human brain imaging and anxiety disorders

Fear extinction is the decrease in conditioned fear responses that normally occurs when a conditioned stimulus (CS) is repeatedly presented in the absence of the aversive unconditioned stimulus (US). Extinction does not erase the initial CS–US association, but is thought to form a new memory. After extinction training, extinction memory competes with conditioning memory for control of fear expression. Deficits in fear extinction are thought to contribute to post-traumatic stress disorder (PTSD). Herein, we review studies performed in rats showing that the medial prefrontal cortex plays a critical role in the retention and expression of extinction memory. We also review human studies indicating that prefrontal areas homologous to those critical for extinction in rats are structurally and functionally deficient in patients with PTSD. We then discuss how findings from rat studies may allow us to: (1) develop new fear extinction paradigms in humans, (2) make specific predictions as to the location of extinction-related areas in humans, and (3) improve current extinction-based behavioral therapies for anxiety disorders.