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Safety learning creates associations between conditional stimuli and the absence of threat. Studies of human fear conditioning have accumulated evidence for the neural signatures of safety over various paradigms, aligning on several common brain systems. While these systems are often interpreted as underlying safety learning in a generic sense, they may instead reflect the expression of learned safety, pertaining to processes of fear inhibition, positive affect, and memory. Animal models strongly suggest these can be separable from neural circuits implicated in the conditioning process itself (or safety acquisition). While acquisition-expression distinctions are ubiquitous in behavioural science, this lens has not been applied to safety learning, which remains a novel area in the field. In this mini-review, we overview findings from prevalent safety paradigms in humans, and synthesise these with insights from animal models to propose that the neurobiology of safety learning be conceptualised along an acquisition-expression model, with the aim of stimulating richer brain-based characterisations of this important process., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

While there are a number of recommended first-line interventions for posttraumatic stress disorder (PTSD), treatment efficacy has been less than ideal. Generally, PTSD treatment models explain symptom manifestation via associative learning, treating the individual as a passive organism - acted upon - rather than self as agent. At their core, predictive coding (PC) models introduce the fundamental role of self-conceptualisation and hierarchical processing of one's sensory context in safety learning. This theoretical article outlines how predictive coding models of emotion offer a parsimonious framework to explain PTSD treatment response within a value-based decision-making framework. Our model integrates the predictive coding elements of the perceived: self, world and self-in the world and how they impact upon one or more discrete stages of value-based decision-making: (1) mental representation; (2) emotional valuation; (3) action selection and (4) outcome valuation. We discuss treatment and research implications stemming from our hypotheses., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The endocannabinoid system is known to be involved in mechanisms relevant to PTSD aetiology and maintenance, though this understanding is mostly based on animal models of the disorder. Here we review how human paradigms can successfully translate animal findings to human subjects, with the view that substantially increased insight into the effect of endocannabinoid signalling on stress responding, emotional and intrusive memories, and fear extinction can be gained using modern paradigms and methods for assessing the state of the endocannabinoid system in PTSD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Anxiety and stress-related disorders are more prevalent in women and associated with negative emotional memory consolidation as well as impaired fear extinction recall. Recent research has identified a role of gonadal steroid hormones in influencing emotional memories and fear extinction, however most individual studies have small samples and employed various protocols. A systematic review and meta-analysis were conducted on studies that examined sex hormones (estrogen, progesterone, testosterone, allopregnanolone, dehydroepiandrosterone) on four aspects of memory, namely, intentional recall (k = 13), recognition memory (k = 7), intrusive memories (k = 9), and extinction recall (k = 11). The meta-analysis on natural cycling women revealed that progesterone level was positively associated with negative recall and negative intrusive memories, and this effect on intentional recall was enhanced under stress induction. Estradiol level was positively associated with extinction recall. This study reveals an important role of progesterone and estradiol in influencing emotional memory consolidation. It highlights the need to control for these hormonal effects and examine progesterone and estradiol concurrently across all menstrual phases in future emotional memory paradigms., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The endocannabinoid system is an increasingly recognised pharmacological target for treating stress and anxiety disorders, including post-traumatic stress disorder (PTSD). Recent preclinical developments have implicated the endocannabinoid system in stress responses, emotional memories and fear extinction, all critical to PTSD aetiology. However, preclinical research in endocannabinoid biology has neglected the influential role of sex hormone differences on PTSD symptomology, which is particularly important given that PTSD is twice as common in women as in men. In this review, we compile and consider the evidence that the endocannabinoid system is influenced by ovarian hormones, with application to stress disorders such as PTSD. It is clear that therapeutic modulation of the endocannabinoid system needs to be approached with awareness of ovarian hormonal influences, and knowledge of these influences may enhance treatment outcomes for female PTSD populations., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Recent prospective studies in emergency services have identified impaired fear extinction learning and memory to be a significant predictor of Posttraumatic Stress Disorder (PTSD), complementing a wealth of cross-sectional evidence of extinction deficits associated with the disorder. Additional fields of research show specific risk factors and biomarkers of the disorder, including candidate genotypes, stress and sex hormones, cognitive factors, and sleep disturbances. Studies in mostly nonclinical populations also reveal that the aforementioned factors are involved in fear extinction learning and memory. Here, we provide a comprehensive narrative review of the literature linking PTSD to these risk factors, and linking these risk factors to impaired fear extinction. On balance, the evidence suggests that fear extinction may play a role in the relationship between risk factors and PTSD. Should this notion hold true, this review carries important implications for the improvement of exposure-based treatments, as well as strategies for the implementation of treatment., (Copyright © 2016 Elsevier Ltd. All rights reserved.)