Neural Correlates of Individual Variability in Fear Extinction

Current Opinion in Neurobiology, 2010

Although fear research has largely focused on the amygdala, recent findings highlight cortical control of the amygdala in the service of fear regulation. In rodent models, it is becoming well established that the infralimbic (IL) prefrontal cortex plays a key role in extinction learning, and recent findings are uncovering molecular mechanisms involved in extinction-related plasticity. Furthermore, mounting evidence implicates the prelimbic (PL) prefrontal cortex in the production of fear responses. Both IL and PL integrate inputs from the amygdala, as well as other structures to gate the expression of fear via projections to inhibitory or excitatory circuits within the amygdala. We suggest that dual control of the amygdala by separate prefrontal modules increases the flexibility of an organism's response to danger cues.

Current Biology, 2022

Highlights d MVPA of fMRI dissociates competing memories of fear and extinction in humans d Memories of fear/extinction coded in dorsal/ventral prefrontal cortex, respectively d Medial temporal lobe activity predicts locus of reinstatement in prefrontal cortex d In a PTSD group, extinction memory misallocated to dorsal region coding for fear

Frontiers in Behavioral Neuroscience

The symptoms of post-traumatic stress disorder (PTSD) include cognitive impairment related to medial prefrontal cortical dysfunction. Indeed, a deficit of cognitive flexibility, i.e., an inability to modify previously learned thoughts and behaviors based on changes in the environment, may underlie many of the other symptoms of PTSD, such as changes in mood, hyper-arousal, intrusive thoughts, exaggerated and over-generalized fear, and avoidance behavior. Cognitive-behavioral therapies target the cognitive dysfunction observed in PTSD patients, training them to recalibrate stress-related perceptions, interpretations and responses. Preclinically, the extinction of conditioned fear bears resemblance to one form of cognitive therapy, exposure therapy, whereby an individual learns, through repeated exposure to a fear-provoking stimulus in a safe environment, that the stimulus no longer signals imminent threat, and their fear response is suppressed. In this review article, we highlight recent findings from our lab using fear extinction as a preclinical model of exposure therapy in rodents exposed to chronic unpredictable stress (CUS). We specifically focus on the therapeutic effects of extinction on stress-compromised set-shifting as a measure of cognitive flexibility, and active vs. passive coping behavior as a measure of avoidance. Finally, we discuss mechanisms involving activity and plasticity in the medial prefrontal cortex (mPFC) necessary for the therapeutic effects of extinction on cognitive flexibility and active coping.

Neurobiology of Stress, 2016

Dysfunction in corticolimbic circuits that mediate the extinction of learned fear responses is thought to underlie the perseveration of fear in stress-related psychopathologies, including post-traumatic stress disorder. Chronic stress produces dendritic hypertrophy in basolateral amygdala (BLA) and dendritic hypotrophy in medial prefrontal cortex, whereas acute stress leads to hypotrophy in both BLA and prelimbic cortex. Additionally, both chronic and acute stress impair extinction retrieval. Here, we examined the effects of a single elevated platform stress on extinction learning and dendritic morphology in infralimbic cortex, a region considered to be critical for extinction. Acute stress produced resistance to extinction, as well as dendritic retraction in infralimbic cortex. Spine density on apical and basilar terminal branches was unaffected by stress. However, animals that underwent conditioning and extinction had decreased spine density on apical terminal branches. Thus, whereas dendritic morphology in infralimbic cortex appears to be particularly sensitive to stress, changes in spines may more sensitively reflect learning. Further, in stressed rats that underwent conditioning and extinction, the level of extinction learning was correlated with spine densities, in that rats with poorer extinction retrieval had more immature spines and fewer thin spines than rats with better extinction retrieval, suggesting that stress may have impaired learning-related spine plasticity. These results may have implications for understanding the role of medial prefrontal cortex in learning deficits associated with stress-related pathologies.

Understanding how learned fear can be reduced is at the heart of treatments for anxiety disorders. Tremendous progress has been made in this regard through extinction training in which an expected aversive outcome is omitted. However, current progress almost entirely rests on this single paradigm, resulting in a very specialized knowledgebase at the behavioural and neural level of analysis. Here, we used a paradigm-independent approach to show that different methods that lead to reduction in learned fear are dissociated in the cortex. We report that the infralimbic cortex has a very specific role in fear reduction that depends on the omission of aversive events but not on overexpectation. The orbitofrontal cortex, a structure generally overlooked in fear, is critical for downregulating fear when fear is inflated or overexpected, but not when an aversive event is omitted.

Front. Hum. Neurosci., 2013

Convergent evidence suggests that individuals with posttraumatic stress disorder (PTSD) exhibit exaggerated avoidance behaviors as well as abnormalities in Pavlonian fear conditioning. However, the link between the two features of this disorder is not well understood. In order to probe the brain basis of aberrant extinction learning in PTSD, we administered a multimodal classical fear conditioning/extinction paradigm that incorporated affectively relevant information from two sensory channels (visual and tactile) while participants underwent fMRI scanning. The sample consisted of fifteen OEF/OIF veterans with PTSD. In response to conditioned cues and contextual information, greater avoidance symptomatology was associated with greater activation in amygdala, hippocampus, vmPFC, dmPFC, and insula, during both fear acquisition and fear extinction. Heightened responses to previously conditioned stimuli in individuals with more severe PTSD could indicate a deficiency in safety learning, consistent with PTSD symptomatology. The close link between avoidance symptoms and fear circuit activation suggests that this symptom cluster may be a key component of fear extinction deficits in PTSD and/or may be particularly amenable to change through extinction-based therapies.

Nature Communications, 2023

Dysregulated fear reactions can result from maladaptive processing of traumarelated memories. In post-traumatic stress disorder (PTSD) and other psychiatric disorders, dysfunctional extinction learning prevents discretization of trauma-related memory engrams and generalizes fear responses. Although PTSD may be viewed as a memory-based disorder, no approved treatments target pathological fear memory processing. Hippocampal sharp wave-ripples (SWRs) and concurrent neocortical oscillations are scaffolds to consolidate contextual memory, but their role during fear processing remains poorly understood. Here, we show that closed-loop, SWR triggered neuromodulation of the medial forebrain bundle (MFB) can enhance fear extinction consolidation in male rats. The modified fear memories became resistant to induced recall (i.e., 'renewal' and 'reinstatement') and did not reemerge spontaneously. These effects were mediated by D2 receptor signaling-induced synaptic remodeling in the basolateral amygdala. Our results demonstrate that SWRtriggered closed-loop stimulation of the MFB reward system enhances extinction of fearful memories and reducing fear expression across different contexts and preventing excessive and persistent fear responses. These findings highlight the potential of neuromodulation to augment extinction learning and provide a new avenue to develop treatments for anxiety disorders. Learning unpleasant things and remembering them is advantageous for the organism for avoiding future reoccurrences. Memories that are irrelevant to survival or adaptation tend to fade away either by graceful degradation 1,2 or by another type of learning called active extinction 3,4. Extinction learning, the process of reducing the expression of learned fear responses, is essential for adaptive behavior in response to traumatic experiences. However, in some pathological scenarios, extinction learning is often impaired, leading to persistent and maladaptive fear responses 5. For example, post-traumatic stress disorder (PTSD) is a debilitating psychiatric disorder resulting from direct or indirect exposure to stressful events, threats, or life-threatening events perceived to compromise personal physical or mental safety 6-8. Symptoms include intense feelings of unprovoked fear, panic attacks, anxiety; intrusive

Learning & Memory, 2008

Fear responses can be eliminated through extinction, a procedure involving the presentation of fear-eliciting stimuli without aversive outcomes. Extinction is believed to be mediated by new inhibitory learning that acts to suppress fear expression without erasing the original memory trace. This hypothesis is supported mainly by behavioral data demonstrating that fear can recover following extinction. However, a recent report by Myers and coworkers suggests that extinction conducted immediately after fear learning may erase or prevent the consolidation of the fear memory trace. Since extinction is a major component of nearly all behavioral therapies for human fear disorders, this finding supports the notion that therapeutic intervention beginning very soon after a traumatic event will be more efficacious. Given the importance of this issue, and the controversy regarding immediate versus delayed therapeutic interventions, we examined two fear recovery phenomena in both rats and humans: spontaneous recovery (SR) and reinstatement. We found evidence for SR and reinstatement in both rats and humans even when extinction was conducted immediately after fear learning. Thus, our data do not support the hypothesis that immediate extinction erases the original memory trace, nor do they suggest that a close temporal proximity of therapeutic intervention to the traumatic event might be advantageous. ; fax (212) 995-4349. Article is online at

Journal of Neuroscience, 2009

Extinction in adult animals, including humans, appears to involve the medial prefrontal cortex (mPFC). However, the role of mPFC in extinction acrossdevelopmenthasnotyetbeenstudied.Givenseveralrecentdemonstrationsofdevelopmentaldifferencesinextinctionofconditionedfear at a behavioral level, different neural circuitries may mediate fear extinction across development. In all experiments, noise conditioned stimulus (CS) and shock unconditioned stimulus (US) were used. In experiment 1A, temporary unilateral inactivation of the mPFC during extinction training impaired long-term extinction the following day in postnatal day 24 (P24) rats but not in P17 rats. In experiment 1B, bilateral inactiva-tionofthemPFCagainfailedtodisruptlong-termextinctioninP17rats.Inexperiment2,extinctiontrainingincreasedphosphorylatedmitogenactivated protein kinase (pMAPK) in the mPFC for P24 rats but not for P17 rats, whereas rats of both ages displayed elevated pMAPK in the amygdala. Across both ages, "not trained," "reactivated," and "no extinction" control groups expressed very low numbers of pMAPKimmunoreactive (IR) neurons across both neural structures. This result indicates that the mere conditioning experience, the exposure to the CS, or the expression of CS-elicited fear in and of itself is not sufficient to explain the observed increase in pMAPK-IR neurons in the mPFC and/or the amygdala after extinction. Together, these findings show that extinction in P17 rats does not involve the mPFC, which has important theoretical and clinical implications for the treatment of anxiety disorders in humans.

Biological Psychiatry, 2009

Curie in the early 1900s holds new meaning given the current interest in extinction of conditioned fear in psychiatry. Decades of experimental psychology in both animals and humans have shown that stimuli paired with an aversive outcome such as electric shock induce conditioned fear responses, both behavioral and physiological. Learned fear responses can be extinguished by presenting the stimulus in the absence of shock. Rather than eliminate the original fear memory, extinction represents a type of "safety" learning that we now know depends on a network of structures including the amygdala, medial prefrontal cortex, and hippocampus (1). Fear extinction has obvious relevance for the etiology and treatment of anxiety disorders such as post-traumatic stress disorder, in which both fear extinction and prefrontal-hippocampal circuits are compromised. Indeed, much recent progress has been made in identifying areas in the human brain involved in extinction memory and in testing new pharmacological adjuncts for extinction-based therapies for anxiety disorders (2). However, the prefrontal-amygdala-hippocampal circuit is also implicated in mood and thought disorders, suggesting the interesting possibility that deficits in fear extinction might extend beyond anxiety disorders. In this issue of Biological Psychiatry, Holt et al. (3) test this hypothesis for schizophrenia, a thought disorder characterized by prefrontal deficits as well as fear-inducing perceptual disturbances and delusions.

European Journal of Neuroscience, 2010

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.

Behavioural Neurology, 2022

A growing body of evidence showed that environmental enrichment (EE) ameliorated footshock-induced fear behavior of posttraumatic stress disorder (PTSD). However, no research comprehensively tested the effect of EE, cue, and the combination of EE and cue in footshock-induced fear behavior of PTSD symptoms. The present study addressed this issue and examined whether the medial prefrontal cortex (mPFC, including the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), and infralimbic cortex (IL)), the nucleus accumbens (NAc), the basolateral amygdala (BLA), and the hippocampus (e.g., CA1, CA3, and dentate gyrus (DG)) regulated the amelioration of the EE, cue, or the combination of EE and cue. The results showed that EE or cue could reduce fear behavior. The combination of EE and cue revealed a stronger decrease in fear behavior. The cue stimulus may play an occasion setting or a conditioned stimulus to modulate the reduction in fear behavior induced by footshock. Regarding the reduction ...

Neurobiology of Learning and Memory, 2014

Chronic stress may impose a vulnerability to develop maladaptive fear-related behaviors after a traumatic event. Whereas previous work found that chronic stress impairs the acquisition and recall of extinguished fear, it is unknown how chronic stress impacts nonassociative fear, such as in the absence of the conditioned stimulus (CS) or in a novel context. Male rats were subjected to chronic stress (STR; wire mesh restraint 6h/d/21d) or undisturbed (CON), then tested on fear acquisition (3 tone-footshock pairings), and two extinction sessions (15 tones/session) within the same context. Then each group was tested (6 tones) in the same context (SAME) or a novel context (NOVEL), and brains were processed for functional activation using Fos immunohistochemistry. Compared to CON, STR showed facilitated fear acquisition, resistance to CS extinction on the first extinction day, and robust recovery of fear responses on the second extinction day. STR also showed robust freezing to the context alone during the first extinction day compared to CON. When tested in the same or a novel context, STR exhibited higher freezing to context than did CON, suggesting that STR-induced fear was independent of context. In support of this, STR showed increased Fos-like expression in the basolateral amygdala and CA1 region of the hippocampus in both the SAME and NOVEL contexts. Increased Fos-like expression was also observed in the central amygdala in STR-NOVEL vs. CON-NOVEL. These data demonstrate that chronic stress enhances fear learning and impairs extinction, and affects nonassociative processes as demonstrated by enhanced fear in a novel context. Post traumatic stress disorder (PTSD) is a debilitating and increasing public health problem, especially in combat-exposed populations. The lifetime prevalence of PTSD in the United States has been reported to be ~6% (Kessler, Petukhova, Sampson, Zaslavsky, & Wittchen, 2012). PTSD develops in a subset of those experiencing a traumatic event (Breslau, Davis,

Cognitive, Affective, & Behavioral Neuroscience, 2004

2008

Congruent findings from studies of fear learning in animals and humans indicate that research on the circuits mediating fear constitutes our best hope of understanding human anxiety disorders1-4. In mammals, repeated presentations of a conditioned stimulus (CS) that was previously paired to a noxious stimulus leads to the gradual disappearance of conditioned fear responses. Although much evidence suggests that this extinction process depends on plastic events in the amygdala1-7, the underlying mechanisms remain unclear. Intercalated (ITC) amygdala neurons constitute likely mediators of extinction because they receive CS information from the basolateral amygdala (BLA) 8, 9, and contribute inhibitory projections to the central nucleus (CEA)10, 11, the main output station of the amygdala for conditioned fear responses12. Thus, following extinction training, ITC cells could reduce the impact of CS-related BLA inputs to CEA via feed-forward inhibition. Here, we tested the hypothesis that...