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Since Freud, clinicians have understood that disturbing memories contribute to psychopathology and that new emotional experiences contribute to therapeutic change. Yet, controversy remains about what is truly essential to bring about psychotherapeutic change. Mounting evidence from empirical studies suggests that emotional arousal is a key ingredient in therapeutic change in many modalities. In addition, memory seems to play an important role but there is a lack of consensus on the role of understanding what happened in the past in bringing about therapeutic change. The core idea of this paper is that therapeutic change in a variety of modalities, including behavioral therapy, cognitive-behavioral therapy, emotion-focused therapy, and psychodynamic psychotherapy, results from the updating of prior emotional memories through a process of reconsolidation that incorporates new emotional experiences. We present an integrated memory model with three interactive components – autobiographical (event) memories, semantic structures, and emotional responses – supported by emerging evidence from cognitive neuroscience on implicit and explicit emotion, implicit and explicit memory, emotion-memory interactions, memory reconsolidation, and the relationship between autobiographical and semantic memory. We propose that the essential ingredients of therapeutic change include: (1) reactivating old memories; (2) engaging in new emotional experiences that are incorporated into these reactivated memories via the process of reconsolidation; and (3) reinforcing the integrated memory structure by practicing a new way of behaving and experiencing the world in a variety of contexts. The implications of this new, neurobiologically grounded synthesis for research, clinical practice, and teaching are discussed.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder associated with memories of traumatic experiences. Conditioned fear memory, a representative model of traumatic memories, is observed across species from lower to higher animals, including humans. Numerous studies have investigated the mechanisms of conditioned fear memory and have led to the identification of the underlying processes involved in fear memory regulation, including cellular and systems consolidation of fear conditioning, destabilization/reconsolidation and extinction after fear memory retrieval, and forgetting of fear memory. These studies suggested that mechanisms for fear memory regulation are shared by humans and other higher animals. Additionally, rodent studies have identified the mechanisms of fear memory at the molecular, cellular, and circuit levels. Findings from these studies in rodents have been applied to facilitate the development and improvement of PTSD intervention. For instance, reconsolidation and extinction of fear memories have been applied for PTSD treatment to improve prolonged exposure (PE) therapy, an effective psychotherapy for PTSD. Combination of medications weakening retrieved traumatic memory (e.g., by facilitating both destabilization and extinction) with PE therapy may contribute to improvement of PTSD. Interestingly, a recent study in mice identified forgetting of fear memory as another potential therapeutic target for PTSD. A better understanding of the mechanisms involved in fear memory processes is likely to facilitate the development of better treatments for PTSD. This review describes fear memory processes and their mechanisms and discusses the pros and cons of applying how this knowledge can be applied in the development of interventions for PTSD.

The purpose of this article is to review recent research that is relevant to three controversies concerning memory for trauma. First, we briefly review the debate about recovered memories of childhood sexual abuse, summarizing a third interpretation distinct from both the repression and false-memory accounts. Second, we address new findings related to claims that memories of trauma, especially in people with posttraumatic stress disorder, are especially fragmented and disorganized. Third, we discuss research designed to test whether eye movements in eye-movement desensitization and reprocessing therapy are effective.

Brain-derived neurotrophic factor (BDNF) is widely accepted for its involvement in resilience and antidepressant drug action, is a common genetic locus of risk for mental illnesses, and remains one of the most prominently studied molecules within psychiatry. Stress, which arguably remains the “lowest common denominator” risk factor for several mental illnesses, targets BDNF in disease-implicated brain regions and circuits. Altered stress-related responses have also been observed in animal models of BDNF deficiency in vivo, and BDNF is a common downstream intermediary for environmental factors that potentiate anxiety- and depressive-like behavior. However, BDNF’s broad functionality has manifested a heterogeneous literature; likely reflecting that BDNF plays a hitherto under-recognized multifactorial role as both a regulator and target of stress hormone signaling within the brain. The role of BDNF in vulnerability to stress and stress-related disorders, such as posttraumatic stress disorder (PTSD), is a prominent example where inconsistent effects have emerged across numerous models, labs, and disciplines. In the current review we provide a contemporary update on the neurobiology of BDNF including new data from the behavioral neuroscience and neuropsychiatry literature on fear memory consolidation and extinction, stress, and PTSD. First we present an overview of recent advances in knowledge on the role of BDNF within the fear circuitry, as well as address mounting evidence whereby stress hormones interact with endogenous BDNF-TrkB signaling to alter brain homeostasis. Glucocorticoid signaling also acutely recruits BDNF to enhance the expression of fear memory. We then include observations that the functional common BDNF Val66Met polymorphism modulates stress susceptibility as well as stress-related and stress-inducible neuropsychiatric endophenotypes in both man and mouse. We conclude by proposing a BDNF stress–sensitivity hypothesis, which posits that disruption of endogenous BDNF activity by common factors (such as the BDNF Val66Met variant) potentiates sensitivity to stress and, by extension, vulnerability to stress-inducible illnesses. Thus, BDNF may induce plasticity to deleteriously promote the encoding of fear and trauma but, conversely, also enable adaptive plasticity during extinction learning to suppress PTSD-like fear responses. Ergo regulators of BDNF availability, such as the Val66Met polymorphism, may orchestrate sensitivity to stress, trauma, and risk of stress-induced disorders such as PTSD. Given an increasing interest in personalized psychiatry and clinically complex cases, this model provides a framework from which to experimentally disentangle the causal actions of BDNF in stress responses, which likely interact to potentiate, produce, and impair treatment of, stress-related psychiatric disorders.

Recent research on changing fears has examined targeting reconsolidation. During reconsolidation, stored information is rendered labile after being retrieved. Pharmacological manipulations at this stage result in an inability to retrieve the memories at later times, suggesting that they are erased or persistently inhibited. Unfortunately, the use of these pharmacological manipulations in humans can be problematic. Here we introduce a non-invasive technique to target the reconsolidation of fear memories in humans. We provide evidence that old fear memories can be updated with non-fearful information provided during the reconsolidation window. As a consequence, fear responses are no longer expressed, an effect that lasted at least a year and was selective only to reactivated memories without affecting others. These findings demonstrate the adaptive role of reconsolidation as a window of opportunity to rewrite emotional memories, and suggest a non-invasive technique that can be used safely in humans to prevent the return of fear. An appointment with fear Reconsolidation is a natural mechanism in human memory: the reconsolidation phase allows new information available at the time of retrieval to be incorporated into an old memory. Although pharmacological blockade of reconsolidation has been used to prevent the return of fear in animal models, many of these manipulations involve compounds that are toxic to humans. Elizabeth Phelps and co-workers now report a non-invasive technique of rewriting fear memories that avoids the use of drugs. The procedure is based on an established technique in which memories of traumatic events are 'extinguished' by repeated exposure to traumatic reminders in a safe environment. This works up to a point, but memories are masked rather than eliminated and can return, for example with the passage of time or due to stress. The new advance lies in timing: if the 'safe' information is introduced during the reconsolidation window of old fear memories, the fear does not return. This work suggests that post-traumatic stress disorder and other anxiety conditions might be responsive to new types of non-invasive therapy. During reconsolidation of memories, stored information is rendered labile after being retrieved and can be manipulated. Previous studies have used pharmacological intervention to disrupt retrieved memories; here, however, a non-invasive, behavioural technique is used to target the reconsolidation of fear memories in humans. Non-fearful information provided during the reconsolidation window appears to update old fear memories, causing a lack of expression of fear responses.

In adult animals, fear conditioning induces a permanent memory that is resilient to erasure by extinction. In contrast, during early postnatal development, extinction of conditioned fear leads to memory erasure, suggesting that fear memories are actively protected in adults. We show here that this protection is conferred by extracellular matrix chondroitin sulfate proteoglycans (CSPGs) in the amygdala. The organization of CSPGs into perineuronal nets (PNNs) coincided with the developmental switch in fear memory resilience. In adults, degradation of PNNs by xnondroitinase ABC specifically rendered subsequently acquired fear memories susceptible to erasure. This result indicates that intact PNNs mediate the formation of erasure-resistant fear memories and identifies a molecular mechanism closing a postnatal critical period during which traumatic memories can be erased by extinction.

Memory is coded by patterns of neural activity in distinct circuits. Therefore, it should be possible to reverse engineer a memory by artificially creating these patterns of activity in the absence of a sensory experience. In olfactory conditioning, an odor conditioned stimulus (CS) is paired with an unconditioned stimulus (US; for example, a footshock), and the resulting CS–US association guides future behavior. Here we replaced the odor CS with optogenetic stimulation of a specific olfactory glomerulus and the US with optogenetic stimulation of distinct inputs into the ventral tegmental area that mediate either aversion or reward. In doing so, we created a fully artificial memory in mice. Similarly to a natural memory, this artificial memory depended on CS–US contingency during training, and the conditioned response was specific to the CS and reflected the US valence. Moreover, both real and implanted memories engaged overlapping brain circuits and depended on basolateral amygdala activity for expression.Pairing an odor conditioned stimulus (CS) with an unconditioned stimulus (US) induces memory formation. Vetere et al. replace the real CS and US with direct optogenetic stimulation of the brain and create a fully artificial odor memory in mice.

Dysregulation of the fear system is at the core of many psychiatric disorders. Much progress has been made in uncovering the neural basis of fear learning through studies in which associative emotional memories are formed by pairing an initially neutral stimulus (conditioned stimulus, CS; e.g., a tone) to an unconditioned stimulus (US; e.g., a shock). Despite recent advances, the question of how to persistently weaken aversive CS-US associations, or dampen traumatic memories in pathological cases, remains a major dilemma. Two paradigms (blockade of reconsolidation and extinction) have been used in the laboratory to reduce acquired fear. Unfortunately, their clinical efficacy is limited: Reconsolidation blockade typically requires potentially toxic drugs, and extinction is not permanent. Here, we describe a behavioral design in which a fear memory in rats is destabilized and reinterpreted as safe by presenting an isolated retrieval trial before an extinction session. This procedure permanently attenuates the fear memory without the use of drugs.

In this review, the authors highlight recent progress made in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to understanding, treatment, and possible prevention of fear disorders in the clinic. Post-traumatic stress disorder, panic disorder and phobia manifest in ways that are consistent with an uncontrollable state of fear. Their development involves heredity, previous sensitizing experiences, association of aversive events with previous neutral stimuli, and inability to inhibit or extinguish fear after it is chronic and disabling. We highlight recent progress in fear learning and memory, differential susceptibility to disorders of fear, and how these findings are being applied to the understanding, treatment and possible prevention of fear disorders. Promising advances are being translated from basic science to the clinic, including approaches to distinguish risk versus resilience before trauma exposure, methods to interfere with fear development during memory consolidation after a trauma, and techniques to inhibit fear reconsolidation and to enhance extinction of chronic fear. It is hoped that this new knowledge will translate to more successful, neuroscientifically informed and rationally designed approaches to disorders of fear regulation.

•Episodic memories can change when they are used to predict ongoing events.•The size of prediction error decisively shapes mnemonic outcomes.•Larger prediction errors promote distinct encoding of unexpected events.•Such encoding is driven by reinstatement of original events at mismatching input.•Findings highlight how unexpected events can enhance retention and encoding. Episodic memories are not static – they shift and reshape as our surroundings evolve. One powerful mechanism for change are prediction errors, which arise when predictions about what is going to happen next do not match the actual input. This study investigated how the size of prediction errors – arising from predictions based on episodic memories – affects recognition memory and neural memory representations. In an fMRI experiment, participants listened to a series of naturalistic dialogues. In a later session, a critical segment of the dialogue was altered to introduce a mismatch and thus evoke a prediction error. Importantly, larger prediction errors were linked to increased recognition memory for the original and mismatching targets, and better source memory for the mismatching targets. Representational similarity analysis revealed that larger prediction errors were also associated with stronger reinstatement of the original version during mismatching (unpredicted) input, which promoted memory for both the old and the new version. Additionally, larger prediction errors enhanced the long-term representational stability of the original memory. We argue that these results support the idea that stronger episodic prediction errors lead to a more distinct encoding of new information, which benefits the recognition of both old and new information. This could be achieved by a pattern completion mechanism in which old information is reinstated during mismatching new input.