Relationship between Fear Conditionability and Aversive Memories: Evidence from a Novel Conditioned-Intrusion Paradigm

Intrusive memories – a hallmark symptom of posttraumatic stress disorder (PTSD) – are often triggered by stimuli possessing similarity with cues that predicted or accompanied the traumatic event. According to learning theories, intrusive memories can be seen as a conditioned response to trauma reminders. However, direct laboratory evidence for the link between fear conditionability and intrusive memories is missing. Furthermore, fear conditioning studies have predominantly relied on standardized aversive stimuli (e.g. electric stimulation) that bear little resemblance to typical traumatic events. To investigate the general relationship between fear conditionability and aversive memories, we tested 66 mentally healthy females in a novel conditioned-intrusion paradigm designed to model real-life traumatic experiences. The paradigm included a differential fear conditioning procedure with neutral sounds as conditioned stimuli and short violent film clips as unconditioned stimuli. Subsequent aversive memories were assessed through a memory triggering task (within 30 minutes, in the laboratory) and ambulatory assessment (involuntary aversive memories in the 2 days following the experiment). Skin conductance responses and subjective ratings demonstrated successful differential conditioning indicating that naturalistic aversive film stimuli can be used in a fear conditioning experiment. Furthermore, aversive memories were elicited in response to the conditioned stimuli during the memory triggering task and also occurred in the 2 days following the experiment. Importantly, participants who displayed higher conditionability showed more aversive memories during the memory triggering task and during ambulatory assessment. This suggests that fear conditioning constitutes an important source of persistent aversive memories. Implications for PTSD and its treatment are discussed.     

Can Playing the Computer Game “Tetris” Reduce the Build-Up of Flashbacks for Trauma? A Proposal from Cognitive Science

Background

Flashbacks are the hallmark symptom of Posttraumatic Stress Disorder (PTSD). Although we have successful treatments for full-blown PTSD, early interventions are lacking. We propose the utility of developing a ‘cognitive vaccine’ to prevent PTSD flashback development following exposure to trauma. Our theory is based on two key findings: 1) Cognitive science suggests that the brain has selective resources with limited capacity; 2) The neurobiology of memory suggests a 6-hr window to disrupt memory consolidation. The rationale for a ‘cognitive vaccine’ approach is as follows: Trauma flashbacks are sensory-perceptual, visuospatial mental images. Visuospatial cognitive tasks selectively compete for resources required to generate mental images. Thus, a visuospatial computer game (e.g. “Tetris”) will interfere with flashbacks. Visuospatial tasks post-trauma, performed within the time window for memory consolidation, will reduce subsequent flashbacks. We predicted that playing “Tetris” half an hour after viewing trauma would reduce flashback frequency over 1-week.

Methodology/Principal Findings

The Trauma Film paradigm was used as a well-established experimental analog for Post-traumatic Stress. All participants viewed a traumatic film consisting of scenes of real injury and death followed by a 30-min structured break. Participants were then randomly allocated to either a no-task or visuospatial (“Tetris”) condition which they undertook for 10-min. Flashbacks were monitored for 1-week. Results indicated that compared to the no-task condition, the “Tetris” condition produced a significant reduction in flashback frequency over 1-week. Convergent results were found on a clinical measure of PTSD symptomatology at 1-week. Recognition memory between groups did not differ significantly.

Conclusions/Significance

Playing “Tetris” after viewing traumatic material reduces unwanted, involuntary memory flashbacks to that traumatic film, leaving deliberate memory recall of the event intact. Pathological aspects of human memory in the aftermath of trauma may be malleable using non-invasive, cognitive interventions. This has implications for a novel avenue of preventative treatment development, much-needed as a crisis intervention for the aftermath of traumatic events.     

Unconditioned Stimulus Revaluation to Promote Conditioned Fear Extinction in the Memory Reconsolidation Window

The retrieval-extinction paradigm, which disrupts the reconsolidation of fear memories in humans, is a non-invasive technique that can be used to prevent the return of fear in humans. In the present study, unconditioned stimulus revaluation was applied in the retrieval-extinction paradigm to investigate its promotion of conditioned fear extinction in the memory reconsolidation window after participants acquired conditioned fear. This experiment comprised three stages (acquisition, unconditioned stimulus revaluation, retrieval-extinction) and three methods for indexing fear (unconditioned stimulus expectancy, skin conductance response, conditioned stimulus pleasure rating). After the acquisition phase, we decreased the intensity of the unconditioned stimulus in one group (devaluation) and maintained constant for the other group (control). The results indicated that both groups exhibited similar levels of unconditioned stimulus expectancy, but the devaluation group had significantly smaller skin conductance responses and exhibited a growth in conditioned stimulus + pleasure. Thus, our findings indicate unconditioned stimulus revaluation effectively promoted the extinction of conditioned fear within the memory reconsolidation window.     

Updating fearful memories with extinction training during reconsolidation: a human study using auditory aversive stimuli

Learning to fear danger in the environment is essential to survival, but dysregulation of the fear system is at the core of many anxiety disorders. As a consequence, a great interest has emerged in developing strategies for suppressing fear memories in maladaptive cases. Recent research has focused in the process of reconsolidation where memories become labile after being retrieved. In a behavioral manipulation, Schiller et al., (2010) reported that extinction training, administrated during memory reconsolidation, could erase fear responses. The implications of this study are crucial for the possible treatment of anxiety disorders without the administration of drugs. However, attempts to replicate this effect by other groups have been so far unsuccessful. We sought out to reproduce Schiller et al., (2010) findings in a different fear conditioning paradigm based on auditory aversive stimuli instead of electric shock. Following a within-subject design, participants were conditioned to two different sounds and skin conductance response (SCR) was recorded as a measure of fear. Our results demonstrated that only the conditioned stimulus that was reminded 10 minutes before extinction training did not reinstate a fear response after a reminder trial consisting of the presentation of the unconditioned stimuli. For the first time, we replicated Schiller et al., (2010) behavioral manipulation and extended it to an auditory fear conditioning paradigm.     

非侵入性脑刺激应用于创伤后应激障碍和物质滥用障碍的记忆干预

记忆是进行思维、想象等高级心理活动的基础，是累积经验、促进个体生存的重要功能。然而，创伤后应激障碍和物质滥用障碍具有某种非适应性记忆过强的特征，不利于个体生存。因此，以病理性改变的记忆为靶点，通过削弱或更新非适应性记忆，可以达到缓解症状甚至治愈的目的。记忆并非是对经验的刻板记录，而是对经验不断更新整合的过程，因此记忆有被干预的可能。记忆的再次激活可能会诱发记忆消退和再巩固，这为记忆相关精神疾病的干预提供了思路和启发。非侵入性脑刺激（noninvasive brain stimulation,NIBS）技术作为一种时间、空间分辨率较高的无创神经调控技术，近年来开始被结合运用到记忆干预研究中。不同刺激参数的NIBS （如频率、极性，以及受刺激区域的初始神经激活状态）应用于特定大脑皮质区域，可以调节神经可塑性，增强或降低靶点脑区的兴奋性，从而削弱或增强行为表现，实现记忆消退增强或在再巩固时间窗内干预记忆。本文首先介绍了记忆相关的脑功能基础研究与局部脑区干预方案的理论联系，继而回顾了近年来NIBS与记忆干预相结合应用于创伤或物质滥用相关障碍的临床干预研究，为精神疾病临床诊疗提供理论依据和启发。     

Xenon Impairs Reconsolidation of Fear Memories in a Rat Model of Post-Traumatic Stress Disorder (PTSD)

Xenon (Xe) is a noble gas that has been developed for use in people as an inhalational anesthestic and a diagnostic imaging agent. Xe inhibits glutamatergic N-methyl-D-aspartate (NMDA) receptors involved in learning and memory and can affect synaptic plasticity in the amygdala and hippocampus, two brain areas known to play a role in fear conditioning models of post-traumatic stress disorder (PTSD). Because glutamate receptors also have been shown to play a role in fear memory reconsolidation – a state in which recalled memories become susceptible to modification – we examined whether Xe administered after fear memory reactivation could affect subsequent expression of fear-like behavior (freezing) in rats. Male Sprague-Dawley rats were trained for contextual and cued fear conditioning and the effects of inhaled Xe (25%, 1 hr) on fear memory reconsolidation were tested using conditioned freezing measured days or weeks after reactivation/Xe administration. Xe administration immediately after fear memory reactivation significantly reduced conditioned freezing when tested 48 h, 96 h or 18 d after reactivation/Xe administration. Xe did not affect freezing when treatment was delayed until 2 h after reactivation or when administered in the absence of fear memory reactivation. These data suggest that Xe substantially and persistently inhibits memory reconsolidation in a reactivation and time-dependent manner, that it could be used as a new research tool to characterize reconsolidation and other memory processes, and that it could be developed to treat people with PTSD and other disorders related to emotional memory.     

A Novel Form of Memory for Auditory Fear Conditioning at a Low-Intensity Unconditioned Stimulus

Fear is one of the most potent emotional experiences and is an adaptive component of response to potentially threatening stimuli. On the other hand, too much or inappropriate fear accounts for many common psychiatric problems. Cumulative evidence suggests that the amygdala plays a central role in the acquisition, storage and expression of fear memory. Here, we developed an inducible striatal neuron ablation system in transgenic mice. The ablation of striatal neurons in the adult brain hardly affected the auditory fear learning under the standard condition in agreement with previous studies. When conditioned with a low-intensity unconditioned stimulus, however, the formation of long-term fear memory but not short-tem memory was impaired in striatal neuron-ablated mice. Consistently, the ablation of striatal neurons 24 h after conditioning with the low-intensity unconditioned stimulus, when the long-term fear memory was formed, diminished the retention of the long-term memory. Our results reveal a novel form of the auditory fear memory depending on striatal neurons at the low-intensity unconditioned stimulus.     

Reversible plasticity of fear memory-encoding amygdala synaptic circuits even after fear memory consolidation

It is generally believed that after memory consolidation, memory-encoding synaptic circuits are persistently modified and become less plastic. This, however, may hinder the remaining capacity of information storage in a given neural circuit. Here we consider the hypothesis that memory-encoding synaptic circuits still retain reversible plasticity even after memory consolidation. To test this, we employed a protocol of auditory fear conditioning which recruited the vast majority of the thalamic input synaptic circuit to the lateral amygdala (T-LA synaptic circuit; a storage site for fear memory) with fear conditioning-induced synaptic plasticity. Subsequently the fear memory-encoding synaptic circuits were challenged with fear extinction and re-conditioning to determine whether these circuits exhibit reversible plasticity. We found that fear memory-encoding T-LA synaptic circuit exhibited dynamic efficacy changes in tight correlation with fear memory strength even after fear memory consolidation. Initial conditioning or re-conditioning brought T-LA synaptic circuit near the ceiling of their modification range (occluding LTP and enhancing depotentiation in brain slices prepared from conditioned or re-conditioned rats), while extinction reversed this change (reinstating LTP and occluding depotentiation in brain slices prepared from extinguished rats). Consistently, fear conditioning-induced synaptic potentiation at T-LA synapses was functionally reversed by extinction and reinstated by subsequent re-conditioning. These results suggest reversible plasticity of fear memory-encoding circuits even after fear memory consolidation. This reversible plasticity of memory-encoding synapses may be involved in updating the contents of original memory even after memory consolidation.     

Insights into the encoding of memories through the circuitry of fear

Associative learning induces physical changes to a network of cells, known as the memory engram. Fear is widely used as a model to understand the circuit motifs that underpin associative memories. Recent advances suggest that the distinct circuitry engaged by different conditioned stimuli (e.g. tone vs. context) can provide insights into what information is being encoded in the fear engram. Moreover, as the fear memory matures, the circuitry engaged indicates how information is remodelled after learning and hints at potential mechanisms for consolidation. Finally, we propose that the consolidation of fear memories involves plasticity of engram cells through coordinated activity between brain regions, and the inherent characteristics of the circuitry may mediate this process.     

Trace Fear Conditioning in Mice

In this experiment we present a technique to measure learning and memory. In the trace fear conditioning protocol presented here there are five pairings between a neutral stimulus and an unconditioned stimulus. There is a 20 sec trace period that separates each conditioning trial. On the following day freezing is measured during presentation of the conditioned stimulus (CS) and trace period. On the third day there is an 8 min test to measure contextual memory. The representative results are from mice that were presented with the aversive unconditioned stimulus (shock) compared to mice that received the tone presentations without the unconditioned stimulus. Trace fear conditioning has been successfully used to detect subtle learning and memory deficits and enhancements in mice that are not found with other fear conditioning methods. This type of fear conditioning is believed to be dependent upon connections between the medial prefrontal cortex and the hippocampus. One current controversy is whether this method is believed to be amygdala-independent. Therefore, other fear conditioning testing is needed to examine amygdala-dependent learning and memory effects, such as through the delay fear conditioning.     

Expression of freezing and fear‐potentiated startle during sustained fear in mice

Fear‐potentiated acoustic startle paradigms have been used to investigate phasic and sustained components of conditioned fear in rats and humans. This study describes a novel training protocol to assess phasic and sustained fear in freely behaving C57BL/6J mice, using freezing and/or fear‐potentiated startle as measures of fear, thereby, if needed, allowing in vivo application of various techniques, such as optogenetics, electrophysiology and pharmacological intervention, in freely behaving animals. An auditory Pavlovian fear conditioning paradigm, with pseudo‐randomized conditioned–unconditioned stimulus presentations at various durations, is combined with repetitive brief auditory white noise burst presentations during fear memory retrieval 24 h after fear conditioning. Major findings are that (1) a motion sensitive platform built on mechano‐electrical transducers enables measurement of startle responses in freely behaving mice, (2) absence or presence of startle stimuli during retrieval as well as unpredictability of a given threat determine phasic and sustained fear response profiles and (3) both freezing and startle responses indicate phasic and sustained components of behavioral fear, with sustained freezing reflecting unpredictability of conditioned stimulus (CS)/unconditioned stimulus (US) pairings. This paradigm and available genetically modified mouse lines will pave the way for investigation of the molecular and neural mechanisms relating to the transition from phasic to sustained fear.     

Fear Conditioning in an Abdominal Pain Model: Neural Responses during Associative Learning and Extinction in Healthy Subjects

Fear conditioning is relevant for elucidating the pathophysiology of anxiety, but may also be useful in the context of chronic pain syndromes which often overlap with anxiety. Thus far, no fear conditioning studies have employed aversive visceral stimuli from the lower gastrointestinal tract. Therefore, we implemented a fear conditioning paradigm to analyze the conditioned response to rectal pain stimuli using fMRI during associative learning, extinction and reinstatement.In N = 21 healthy humans, visual conditioned stimuli (CS⁺) were paired with painful rectal distensions as unconditioned stimuli (US), while different visual stimuli (CS⁻) were presented without US. During extinction, all CSs were presented without US, whereas during reinstatement, a single, unpaired US was presented. In region-of-interest analyses, conditioned anticipatory neural activation was assessed along with perceived CS-US contingency and CS unpleasantness.Fear conditioning resulted in significant contingency awareness and valence change, i.e., learned unpleasantness of a previously neutral stimulus. This was paralleled by anticipatory activation of the anterior cingulate cortex, the somatosensory cortex and precuneus (all during early acquisition) and the amygdala (late acquisition) in response to the CS⁺. During extinction, anticipatory activation of the dorsolateral prefrontal cortex to the CS⁻ was observed. In the reinstatement phase, a tendency for parahippocampal activation was found.Fear conditioning with rectal pain stimuli is feasible and leads to learned unpleasantness of previously neutral stimuli. Within the brain, conditioned anticipatory activations are seen in core areas of the central fear network including the amygdala and the anterior cingulate cortex. During extinction, conditioned responses quickly disappear, and learning of new predictive cue properties is paralleled by prefrontal activation. A tendency for parahippocampal activation during reinstatement could indicate a reactivation of the old memory trace. Together, these findings contribute to our understanding of aversive visceral learning and memory processes relevant to the pathophysiology of chronic abdominal pain.     

Directional Theta Coherence in Prefrontal Cortical to Amygdalo-Hippocampal Pathways Signals Fear Extinction

Theta oscillations are considered crucial mechanisms in neuronal communication across brain areas, required for consolidation and retrieval of fear memories. One form of inhibitory learning allowing adaptive control of fear memory is extinction, a deficit of which leads to maladaptive fear expression potentially leading to anxiety disorders. Behavioral responses after extinction training are thought to reflect a balance of recall from extinction memory and initial fear memory traces. Therefore, we hypothesized that the initial fear memory circuits impact behavioral fear after extinction, and more specifically, that the dynamics of theta synchrony in these pathways signal the individual fear response. Simultaneous multi-channel local field and unit recordings were obtained from the infralimbic prefrontal cortex, the hippocampal CA1 and the lateral amygdala in mice. Data revealed that the pattern of theta coherence and directionality within and across regions correlated with individual behavioral responses. Upon conditioned freezing, units were phase-locked to synchronized theta oscillations in these pathways, characterizing states of fear memory retrieval. When the conditioned stimulus evoked no fear during extinction recall, theta interactions were directional with prefrontal cortical spike firing leading hippocampal and amygdalar theta oscillations. These results indicate that the directional dynamics of theta-entrained activity across these areas guide changes in appraisal of threatening stimuli during fear memory and extinction retrieval. Given that exposure therapy involves procedures and pathways similar to those during extinction of conditioned fear, one therapeutical extension might be useful that imposes artificial theta activity to prefrontal cortical-amygdalo-hippocampal pathways that mimics the directionality signaling successful extinction recall.     

Reversing Stimulus Timing in Visual Conditioning Leads to Memories with Opposite Valence in Drosophila

Animals need to associate different environmental stimuli with each other regardless of whether they temporally overlap or not. Drosophila melanogaster displays olfactory trace conditioning, where an odor is followed by electric shock reinforcement after a temporal gap, leading to conditioned odor avoidance. Reversing the stimulus timing in olfactory conditioning results in the reversal of memory valence such that an odor that follows shock is later on approached (i.e. relief conditioning). Here, we explored the effects of stimulus timing on memory in another sensory modality, using a visual conditioning paradigm. We found that flies form visual memories of opposite valence depending on stimulus timing and can associate a visual stimulus with reinforcement despite being presented with a temporal gap. These results suggest that associative memories with non-overlapping stimuli and the effect of stimulus timing on memory valence are shared across sensory modalities.     

Total recall. Reconsolidation theory unifies cognitive psychology and neuroscience and creates new therapeutic options for memory-related disorders

New research reveals that long-term memory is not entirely stable and can be modified or potentially erased. These insights open new therapeutic possibilities for a range of memory-related diseases and disorders.There are many popular ideas about human memory serving as the repository of experiences etched into the substance of our brains until they are wiped out through death or disease. As the British writer Oscar Wilde put it, “Memory [...] is the diary that we all carry about with us.” And even if we sometimes cannot remember a particular event or person, we rarely doubt our memories. Friedrich Nietzsche, the German philosopher, placed great faith in memory, noting that, “The existence of forgetting has never been proved: we only know that some things don''t come to mind when we want them.”Despite these popular notions of infallible human memories, our understanding of how long-term memory works has changed dramatically during the past decade: it seems that our memories are not as permanent as we once thought. This has profound implications for both neuroscience and for treating a range of cognitive disorders including PTSD (post-traumatic stress disorder), drug addiction, chronic pain and even possibly Alzheimer disease....it seems that our memories are not as permanent as we once thoughtFor a long time, neurologists and psychiatrists had assumed that after an initial period of consolidation, during which memories are liable to change or be erased, memories eventually become enshrined and immune to alteration. But since 2000, this memory consolidation theory has gradually been replaced by a new one called reconsolidation, which posits that long-term memories can, at least in some circumstances, be changed. On activation or recall, the memory of an object or event enters an update process during which it can be strengthened, weakened or modified, just as short-term memories can be during the initial consolidation phase. The new reconsolidation theory has created great excitement among cognitive disorder researchers and practitioners. As many disorders are associated with some form of long-term memory malfunction or impairment, a reliable method that can reactivate and amend these memories would have great potential as a treatment; indeed a number of clinical trials to treat PTSD are currently testing this new understanding of memories.As many disorders are associated with some form of long-term memory malfunction or impairment, a reliable method that can reactivate and amend these memories would have great potential as a treatment...As happens so often in science, reconsolidation is actually an old idea that has been reincarnated. The theory first emerged in the 1960s when neurologists found that fear memories in rats could be greatly weakened if they were reactivated on recall (Misanin et al, 1968). Before then, it had been assumed that retrograde amnesia—the inability to access memories formed during or just before a traumatic event or illness—worked backwards in time to affect recently acquired memories. Retrograde amnesia also occurs in humans as a result of head injuries or, sometimes, extreme trauma. The experiments in rats, however, showed that even older memories might be vulnerable if they were in an active state of recall at the time of the trauma, but interest in the research waned because of the lack of any neurological or molecular basis for the theory. This all changed with the publication of a seminal paper in 2000 by Karim Nader at McGill University in Montreal, Canada, who demonstrated the reconsolidation of a fear memory in the lateral amygdala (Nader et al, 2000). This walnut-sized region in the medial temporal lobe of the brain has a key role in emotional memory in that it orchestrates the production of hormones or neurotransmitters such as dopamine, noradrenaline and adrenaline.Various forms of extinction training have long been applied to some disorders, notably PTSD...The work by Nader and Joseph LeDoux at New York University, USA, heralded the beginning of a unification between the previously largely distinct fields of neuroscience and cognitive psychology. Neuroscience had been driven chiefly by animal research to identify the underlying molecular, genetic and neurochemical basis of behaviour, emotion and memory. Cognitive psychology had been based almost entirely on behavioural experiments in humans. This unification process is still in its infancy, but advances in imaging techniques, particularly functional magnetic resonance imaging, promises to combine behavioural experiments in humans with observing changes in brain activity. According to Valérie Doyère, from the Centre of Neurosciences at Paris-Sud University in France, it will help resolve questions about how different regions of the brain interact during memory recall and reconsolidation. “I think the next step is to do neural imaging, as this would help detect at which step in the network the system has been modified or blocked,” Doyère, a pioneer of reconsolidation theory and collaborator of LeDoux and Nader, explained. “That is difficult to know unless you do have some way of analysing the neural network activity to try and see what you update and where.”Even without this insight, a lot of progress has been made in linking molecular events at the neuron level with the reconsolidation process—at least in animals. The starting point was the discovery by Nader and colleagues that reconsolidation in rats involved protein synthesis. They noted from other work that the initial consolidation of fear memories in rats could be inhibited by infusion of the protein synthesis inhibitor anisomycin into the amygdala, shortly after fear training. Such training typically involves traditional methods first used by the Russian physiologist Ivan Pavlov (1849–1936) in which an animal is given a so-called conditional stimulus (CS), such as a particular sound, followed shortly by an unconditional stimulus (US), such as an electric shock. The animal learns to associate the two so that exposure to the sound triggers fear: it begins with the activation of the amygdala, which is followed by a signalling cascade that leads to elevated heart and respiratory rates, with an associated increase in glucose production in preparation for the ''fight or flight'' response. The administration of anisomycin shortly after this training process blocks consolidation and prevents the animal from associating the CS signal with the US response.Similarly, Nader found that if the rats were exposed to the CS some days after the initial conditioning, to recall the association between the sound and the electric shock, anisomycin blocked reconsolidation and generated amnesia: the rats ''forgot'' the association between CS and US and had a greatly reduced fear response on exposure to the CS. Nader argued that this must mean the reconsolidation of the memory had been interrupted, because if the rats were given anisomycin after the initial training, but without exposure to the CS sound, they retained their fear conditioning. This link between memory reconsolidation and protein synthesis has also been demonstrated in other animals, including primitive invertebrates such as worms, suggesting that this is an evolutionarily conserved adaptation (Rose & Rankin, 2006).Attempts to observe this link between reconsolidation and protein synthesis in humans, however, have remained elusive. “We can''t test whether the mechanisms in humans are mediated by protein synthesis because those drugs would not be approved for human use,” Nader said. “Usually, rodent preps are used to understand the molecular mechanisms, and these seem to generalize to humans.”Indeed, Nader argues that evidence for reconsolidation in humans is now very strong in the light of recent work by LeDoux, demonstrating that the principles of fear extinction training in rats could be applied to humans to weaken the association between a CS trigger and memory of the US (Schiller et al, 2010). Human participants were shown an object and then given a mild electric shock in classical Pavlovian conditioning—the authors tested for the presence of the fear memory by measuring the change in skin electrical conductance in response to seeing the object. Once this fear memory was established, the authors reminded the participants of the object a day later to initiate the reconsolidation process, but then provided information that the same object was now ''safe''—this being called ''extinction training''. A day later, the participants were tested again to see whether the object elicited a fear response.The key point is that extinction training had to be conducted within the reconsolidation window, when the memory was temporarily unstable, to eliminate the fear response. The researchers also showed that rewriting the fear memory was specific to the CS object that was reactivated. If participants had been conditioned to associate several different objects with fear, then extinction training would only work on the specific object used during the training. Participants would continue to associate the other objects with fear, indicating that extinction training is selective.Various forms of extinction training have long been applied to some disorders, notably PTSD—an anxiety disorder that occurs in the aftermath of exposure to a traumatic experience involving death or the threat of death. The victim ingests a trauma memory that is emotionally overwhelming and cannot be resolved in the normal way, often intruding spontaneously into consciousness with a continued state of hypervigilance. The idea of extinction training is to force sufferers to actively recall memories frequently, but success has so far been mixed.The ability to stimulate memory could inspire new treatments for sufferers from memory loss...Although anisomycin cannot be given to PTSD sufferers to edit long-term memories, propranolol is an alternative. It has already been approved to treat hypertension as a so-called beta blocker that blocks the beta andrenergic receptor and diminishes the effect of stress hormones. Having been largely replaced by other drugs for treating high blood pressure, interest in propranolol was revived by its potential for treating PTSD in association with psychotherapy (Brunet et al, 2007). It also triggered research into the role of beta adrenergic receptors in PTSD, notably by Jacek Debiec and colleagues at New York University, who found that adrenergic signalling in the amygdala is involved in the memory consolidation process (Debiec et al, 2011).Drugs such as propranolol seem to suppress memory reconsolidation and thereby weaken the emotions associated with trauma memories. This is the theory, and early evidence of success has attracted significant interest in the USA, where PTSD is a particular problem given the country''s longstanding involvement in armed conflicts and the resulting large number of former soldiers suffering from the syndrome.The US Department of Defense''s standard treatment for PTSD has been cognitive behavioural therapy, in which individuals learn to identify thoughts that make them feel afraid or upset and then try to replace them with less distressing thoughts. But the potential of propanolol to replace or enhance cognitive behavioural therapy has prompted the US National Institutes of Health to conduct a phase II clinical trial, for which it is currently recruiting volunteers.The urgency of finding a more complete cure for PTSD has been increased by recent indications that the disorder not only diminishes quality of life for sufferers and their families, but also has serious long-term effects on physical as well as mental health, including premature ageing and a heightened risk of dementia. This link was confirmed by a recent retrospective study of 181,093 US war veterans aged 55 years or older, 53,155 of whom had PTSD (Yaffe et al, 2010). Kristine Yaffe (University of California, San Francisco and the San Francisco Veterans Affairs Medical Center) and her colleagues found that veterans with PTSD had a 10.6% risk of developing dementia compared with 6.6% among the general elderly population without PTSD. Although this result was statistically significant given that the study was adjusted for other factors such as demographic variation and psychiatric illnesses, it did not entirely preclude other risk factors. The causes of the higher risk of dementia were related to either the physiological stress on the brain with associated inflammation, or the systemic effect of long-term disruption to memory functioning, or probably a combination of both.The emphasis in treating PTSD and addictive disorders is on weakening aspects of long-term memory, but the emerging reconsolidation theory can equally provide clinical benefits by strengthening connections, as LeDoux pointed out. “Memory reconsolidation is not a process of weakening memory from the evolutionary point of view. It is an update mechanism. It allows memories to be changed when new information is available,” he said. “An extreme example from our work is that fear memory can be increased or decreased, depending on how you activate beta-adrenergic receptors. Block these during retrieval and you get a weakening of memory; stimulate these and you get an enhancement.” As happens so often in science, reconsolidation is actually an old idea that has been reincarnatedThe ability to stimulate memory could inspire new treatments for sufferers from memory loss, according to Doyère. “In the case of a disease like Alzheimer''s, it may be possible to reincorporate some elements and recover memory that has been lost. At least it may be possible to delay some of the symptoms,” she explained. Yet, more work is needed to expand on the emerging theory of reconsolidation, particularly in humans, because human memory recall goes beyond what happens in most animals. “Humans have the knowledge of a memory association and that may reactivate the emotional value,” Doyère commented. In other words, humans can better exploit their associated knowledge of events that they recall either wittingly or possibly in dreams, and this can affect the reconsolidation process. Moreover, there is also the role of sleep and dreaming in long-term memory recall and reconsolidation. In any case, it seems that reconsolidation as a unifying theory has both great therapeutic and scientific potential to explore human memory.     

Mapping and Deciphering Neural Codes of NMDA Receptor-Dependent Fear Memory Engrams in the Hippocampus

Mapping and decoding brain activity patterns underlying learning and memory represents both great interest and immense challenge. At present, very little is known regarding many of the very basic questions regarding the neural codes of memory: are fear memories retrieved during the freezing state or non-freezing state of the animals? How do individual memory traces give arise to a holistic, real-time associative memory engram? How are memory codes regulated by synaptic plasticity? Here, by applying high-density electrode arrays and dimensionality-reduction decoding algorithms, we investigate hippocampal CA1 activity patterns of trace fear conditioning memory code in inducible NMDA receptor knockout mice and their control littermates. Our analyses showed that the conditioned tone (CS) and unconditioned foot-shock (US) can evoke hippocampal ensemble responses in control and mutant mice. Yet, temporal formats and contents of CA1 fear memory engrams differ significantly between the genotypes. The mutant mice with disabled NMDA receptor plasticity failed to generate CS-to-US or US-to-CS associative memory traces. Moreover, the mutant CA1 region lacked memory traces for “what at when” information that predicts the timing relationship between the conditioned tone and the foot shock. The degraded associative fear memory engram is further manifested in its lack of intertwined and alternating temporal association between CS and US memory traces that are characteristic to the holistic memory recall in the wild-type animals. Therefore, our study has decoded real-time memory contents, timing relationship between CS and US, and temporal organizing patterns of fear memory engrams and demonstrated how hippocampal memory codes are regulated by NMDA receptor synaptic plasticity.     

Vagus Nerve Stimulation as a Tool to Induce Plasticity in Pathways Relevant for Extinction Learning

Extinction describes the process of attenuating behavioral responses to neutral stimuli when they no longer provide the reinforcement that has been maintaining the behavior. There is close correspondence between fear and human anxiety, and therefore studies of extinction learning might provide insight into the biological nature of anxiety-related disorders such as post-traumatic stress disorder, and they might help to develop strategies to treat them. Preclinical research aims to aid extinction learning and to induce targeted plasticity in extinction circuits to consolidate the newly formed memory. Vagus nerve stimulation (VNS) is a powerful approach that provides tight temporal and circuit-specific release of neurotransmitters, resulting in modulation of neuronal networks engaged in an ongoing task. VNS enhances memory consolidation in both rats and humans, and pairing VNS with exposure to conditioned cues enhances the consolidation of extinction learning in rats. Here, we provide a detailed protocol for the preparation of custom-made parts and the surgical procedures required for VNS in rats. Using this protocol we show how VNS can facilitate the extinction of conditioned fear responses in an auditory fear conditioning task. In addition, we provide evidence that VNS modulates synaptic plasticity in the pathway between the infralimbic (IL) medial prefrontal cortex and the basolateral complex of the amygdala (BLA), which is involved in the expression and modulation of extinction memory.     

Extinction Training During the Reconsolidation Window Prevents Recovery of Fear

Fear is maladaptive when it persists long after circumstances have become safe. It is therefore crucial to develop an approach that persistently prevents the return of fear. Pavlovian fear-conditioning paradigms are commonly employed to create a controlled, novel fear association in the laboratory. After pairing an innocuous stimulus (conditioned stimulus, CS) with an aversive outcome (unconditioned stimulus, US) we can elicit a fear response (conditioned response, or CR) by presenting just the stimulus alone^1,2 . Once fear is acquired, it can be diminished using extinction training, whereby the conditioned stimulus is repeatedly presented without the aversive outcome until fear is no longer expressed³. This inhibitory learning creates a new, safe representation for the CS, which competes for expression with the original fear memory⁴. Although extinction is effective at inhibiting fear, it is not permanent. Fear can spontaneously recover with the passage of time. Exposure to stress or returning to the context of initial learning can also cause fear to resurface^3,4.Our protocol addresses the transient nature of extinction by targeting the reconsolidation window to modify emotional memory in a more permanent manner. Ample evidence suggests that reactivating a consolidated memory returns it to a labile state, during which the memory is again susceptible to interference^5-9. This window of opportunity appears to open shortly after reactivation and close approximately 6hrs later^5,11,16, although this may vary depending on the strength and age of the memory¹⁵. By allowing new information to incorporate into the original memory trace, this memory may be updated as it reconsolidates^10,11. Studies involving non-human animals have successfully blocked the expression of fear memory by introducing pharmacological manipulations within the reconsolidation window, however, most agents used are either toxic to humans or show equivocal effects when used in human studies^12-14. Our protocol addresses these challenges by offering an effective, yet non-invasive, behavioral manipulation that is safe for humans.By prompting fear memory retrieval prior to extinction, we essentially trigger the reconsolidation process, allowing new safety information (i.e., extinction) to be incorporated while the fear memory is still susceptible to interference. A recent study employing this behavioral manipulation in rats has successfully blocked fear memory using these temporal parameters¹¹. Additional studies in humans have demonstrated that introducing new information after the retrieval of previously consolidated motor¹⁶, episodic¹⁷, or declarative¹⁸ memories leads to interference with the original memory trace¹⁴. We outline below a novel protocol used to block fear recovery in humans.     

Habituation of unconditioned fear can be attenuated by the presence of a safe stimulus: assessment using the neophobic response of the rat

Protection from extinction of conditioned fear has been demonstrated when a conditioned inhibitor of fear is presented during extinction treatment. The present study assessed if similar results could be obtained during the analogous habituation of unconditioned fear. The neophobic response typically elicited by the presentation of a novel flavor was used as a model of unconditioned fear. Consumption by rats was used to ascertain the impact of nonreinforced exposure to a novel flavor either alone, in compound with another novel flavor, or in compound with a safe flavor (i.e., a flavor previously trained as a conditioned inhibitor for illness). The presentation of the novel flavor alone in the absence of illness reduced neophobia. However, exposure to the novel flavor in compound with the safe flavor reduced habituation of neophobia. This effect was not observed when the novel flavor was exposed in compound with another novel flavor. These results suggest that removing safe stimuli from the therapeutical environment might improve the effectiveness of exposure therapy in the treatment of unconditioned fear.