The psychology of extinction has been studied for decades. Approximately 10 years ago, however, there began a concerted effort to understand the neural circuits of extinction of fear conditioning, in ...both animals and humans. Progress during this period has been facilitated by a high degree of coordination between rodent and human researchers examining fear extinction. Here we review the major advances and highlight new approaches to understanding and exploiting fear extinction. Research in fear extinction could serve as a model for translational research in other areas of behavioral neuroscience.
This article is part of a Special Issue “SBN 2014”.
Women are more vulnerable to stress- and fear-based disorders, such as anxiety and post-traumatic stress disorder. Despite the growing literature ...on this topic, the neural basis of these sex differences remains unclear, and the findings appear inconsistent. The neurobiological mechanisms of fear and stress in learning and memory processes have been extensively studied, and the crosstalk between these systems is beginning to explain the disproportionate incidence and differences in symptomatology and remission within these psychopathologies. In this review, we discuss the intersect between stress and fear mechanisms and their modulation by gonadal hormones and discuss the relevance of this information to sex differences in anxiety and fear-based disorders. Understanding these converging influences is imperative to the development of more effective, individualized treatments that take sex and hormones into account.
•Women are more vulnerable to anxiety and fear-related disorders than men.•Estrogen levels can modulate fear and stress responses in women and female rodents.•Stress affects the critical nodes of fear circuitry.•Interactions between sex hormones, stress, and fear should be further examined.•Treatment for anxiety and fear-based disorders should account for hormone status.
In this review, the authors propose that the fear extinction model can be used as an experimental tool to cut across symptom dimensions of multiple anxiety disorders to enhance our understanding of ...the psychopathology of these disorders and potentially facilitate the detection of biomarkers for them. The authors evaluate evidence for this proposition from studies examining the neurocircuitry underlying fear extinction in rodents, healthy humans, and clinical populations. The authors also assess the potential use of the fear extinction model to predict vulnerability for anxiety and treatment response and to improve existing treatments or develop novel ones. Finally, the authors suggest potential directions for future research that will help to further validate extinction as a biomarker for anxiety across diagnostic categories and to bridge the gap between basic neuroscience and clinical practice.
Obsessive-compulsive disorder (OCD) affects approximately 2–3% of the population and is characterized by recurrent intrusive thoughts (obsessions) and repetitive behaviors or mental acts ...(compulsions), typically performed in response to obsessions or related anxiety. In the past few decades, the prevailing models of OCD pathophysiology have focused on cortico-striatal circuitry. More recent neuroimaging evidence, however, points to critical involvement of the lateral and medial orbitofrontal cortices, the dorsal anterior cingulate cortex and amygdalo-cortical circuitry, in addition to cortico-striatal circuitry, in the pathophysiology of the disorder. In this review, we elaborate proposed features of OCD pathophysiology beyond the classic parallel cortico-striatal pathways and argue that this evidence suggests that fear extinction, in addition to behavioral inhibition, is impaired in OCD.
The learning principles that guide the acquisition and extinction of avoidance are not fully understood. We developed a novel paradigm to study the temporal dynamics of relief, a putative reinforcer ...of avoidance, and the recovery of fear and avoidance following extinction. During conditioning, the avoidance action canceled the aversive unconditional stimulus (US), without terminating the predictive conditional stimulus (CS). Relief pleasantness was rated after fixed CS offsets, when US omission occured. Avoidance was effective to one CS, but not to another, to track stimulus-specific avoidance learning. Fear was extinguished under response prevention in a separate context. Recovery tests took place 24 h later, in both contexts and with a monetary cost added to the avoidance action. We found that avoidance gradually became stimulus-specific during conditioning, but hardly recovered during delayed testing. Across all phases, initial omissions of the aversive US triggered relief that gradually declined over consecutive omissions, in line with a theoretical prediction error signal. Participants that scored low on distress tolerance, however, displayed sustained levels of relief over continuous omissions. We propose that such forms of sustained relief may produce over-reinforcement of foregoing avoidance actions and promote the development of pathological avoidance. The current paradigm represents an efficacious tool to study the temporal dynamics of relief across avoidance learning and fear extinction and to characterize relief dysregulations in relation to psychopathology.
•Relief is a putative reinforcer of avoidance behaviors, but has receveid little empirical scrutiny.•A new avoidance paradigm tracked the temporal dynamics of relief and the influence of fear extinction and recovery in healthy individuals.•Relief ratings followed a theoretical course of prediction error signaling during avoidance conditioning, extinction and re-extinction.•Skin conductance and ratings of expectancy/relief recovered during delayed testing, but avoidance was greatly reduced under a monetary cost.
Exploring the neural circuits of the extinction of conditioned fear is critical to advance our understanding of fear- and anxiety-related disorders. The field has focused on examining the role of ...various regions of the medial prefrontal cortex, insular cortex, hippocampus, and amygdala in conditioned fear and its extinction. The contribution of this ‘fear network’ to the conscious awareness of fear has recently been questioned. And as such, there is a need to examine higher/multiple cortical systems that might contribute to the conscious feeling of fear and anxiety. Herein, we studied functional connectivity patterns across the entire brain to examine the contribution of multiple networks to the acquisition of fear extinction learning and its retrieval. We conducted trial-by-trial analyses on data from 137 healthy participants who underwent a two-day fear conditioning and extinction paradigm in a functional magnetic resonance imaging (fMRI) scanner. We found that functional connectivity across a broad range of brain regions, many of which are part of the default mode, frontoparietal, and ventral attention networks, increased from early to late extinction learning only to a conditioned cue. The increased connectivity during extinction learning predicted the magnitude of extinction memory tested 24 h later. Together, these findings provide evidence supporting recent studies implicating distributed brain regions in learning, consolidation and expression of fear extinction memory in the human brain.
Learning and memory for extinction of conditioned fear is a basic mammalian mechanism for regulating negative emotion. Sleep promotes both the consolidation of memory and the regulation of emotion. ...Sleep can influence consolidation and modification of memories associated with both fear and its extinction. After brief overviews of the behavior and neural circuitry associated with fear conditioning, extinction learning, and extinction memory in the rodent and human, interactions of sleep with these processes will be examined. Animal and human studies suggest that sleep can serve to consolidate both fear and extinction memory. In humans, sleep also promotes generalization of extinction memory. Time-of-day effects on extinction learning and generalization are also seen. Rapid eye movement (REM) may be a sleep stage of particular importance for the consolidation of both fear and extinction memory as evidenced by selective REM deprivation experiments. REM sleep is accompanied by selective activation of the same limbic structures implicated in the learning and memory of fear and extinction. Preliminary evidence also suggests extinction learning can take place during slow wave sleep. Study of low-level processes such as conditioning, extinction, and habituation may allow sleep effects on emotional memory to be identified and inform study of sleep's effects on more complex, emotionally salient declarative memories. Anxiety disorders are marked by impairments of both sleep and extinction memory. Improving sleep quality may ameliorate anxiety disorders by strengthening naturally acquired extinction. Strategically timed sleep may be used to enhance treatment of anxiety by strengthening therapeutic extinction learned via exposure therapy.
Background Fear extinction is a laboratory model of fear inhibition and is the basis of exposure therapy for anxiety disorders. Emerging evidence from naturally cycling female rodents and women ...indicates that estrogens are necessary to the consolidation of fear extinction. Hormonal contraceptives (HCs) inhibit estrogen production; yet, their effects on fear extinction are unknown. Methods We used a cross-species translational approach to investigate the impact of HCs and estradiol supplementation on fear extinction in healthy women ( n =76) and female rats ( n = 140). Results Women using HCs exhibited significantly poorer extinction recall compared with naturally cycling women. The extinction impairment was also apparent in HC-treated female rats and was associated with reduced serum estradiol levels. The impairment could be rescued in HC-treated rats either by terminating HC treatment after fear learning or by systemic injection of estrogen-receptor agonists before fear extinction, all of which restored serum estradiol levels. Finally, a single administration of estradiol to naturally cycling women significantly enhanced their ability to recall extinction memories. Conclusions Together, these findings suggest that HCs may impact women’s ability to inhibit fear but that this impairment is not permanent and could potentially be alleviated with estrogen treatment.
Highlights • PTSD is triggered by well-delineated stressors, facilitating causal brain models. • Amygdala and dACC abnormalities confer vulnerability for increased fear upon stress. • Reduced ...hippocampus–vmPFC connectivity following stress may impair fear inhibition. • The functions of these brain circuits imply a temporal trajectory of PTSD symptoms.
Examining the neural circuits of fear/threat extinction advanced our mechanistic understanding of several psychiatric disorders, including anxiety disorders (AX) and posttraumatic stress disorder ...(PTSD). More is needed to understand the interplay of large-scale neural networks during fear extinction in these disorders. We used dynamic functional connectivity (FC) to study how FC might be perturbed during conditioned fear extinction in individuals with AX or PTSD. We analyzed neuroimaging data from 338 individuals that underwent a two-day fear conditioning and extinction paradigm. The sample included healthy controls (HC), trauma-exposed non-PTSD controls, and patients diagnosed with AX or PTSD. Dynamic FC during extinction learning gradually increased in the HC group but not in patient groups. The lack of FC change in patients was predominantly observed within and between the default mode, frontoparietal control, and somatomotor networks. The AX and PTSD groups showed impairments in different, yet partially overlapping connections especially involving the dorsolateral prefrontal cortex. Extinction-induced FC predicted ventromedial prefrontal cortex activation and FC during extinction memory recall only in the HC group. FC impairments during extinction learning correlated with fear- and anxiety-related clinical measures. These findings suggest that relative to controls, individuals with AX or PTSD exhibited widespread abnormal FC in higher-order cognitive and attention networks during extinction learning and failed to establish a link between neural signatures during extinction learning and memory retrieval. This failure might underlie abnormal processes related to the conscious awareness, attention allocation, and sensory processes during extinction learning and retrieval in fear- and anxiety-related disorders.
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