One's sex,sleep, and posttraumatic stress disorder

Women are approximately twice as likely as men to develop posttraumatic stress disorder (PTSD) after trauma exposure. Mechanisms underlying this difference are not well understood. Although sleep is recognized to have a critical role in PTSD and physical and psychological health more generally, research into the role of sleep in PTSD sex differences has been only recent. In this article, we review both animal and human studies relevant to sex differences in sleep and PTSD with an emphasis on the roles of sex hormones. Sleep impairment including insomnia, trauma-related nightmares, and rapid-eye-movement (REM) sleep fragmentation has been observed in individuals with chronic and developing PTSD, suggesting that sleep impairment is a characteristic of PTSD and a risk factor for its development. Preliminary findings suggested sex specific patterns of sleep alterations in developing and established PTSD. Sleep maintenance impairment in the aftermath of trauma was observed in women who subsequently developed PTSD, and greater REM sleep fragmentation soon after trauma was associated with developing PTSD in both sexes. In chronic PTSD, reduced deep sleep has been found only in men, and impaired sleep initiation and maintenance with PTSD have been found in both sexes. A limited number of studies with small samples have shown that sex hormones and their fluctuations over the menstrual cycle influenced sleep as well as fear extinction, a process hypothesized to be critical to the pathogenesis of PTSD. To further elucidate the possible relationship between the sex specific patterns of PTSD-related sleep alterations and the sexually dimorphic risk for PTSD, future studies with larger samples should comprehensively examine effects of sex hormones and the menstrual cycle on sleep responses to trauma and the risk/resilience for PTSD utilizing various methodologies including fear conditioning and extinction paradigms and animal models.     

Contribution of Hippocampal 5-HT<Subscript>3</Subscript> Receptors in Hippocampal Autophagy and Extinction of Conditioned Fear Responses after a Single Prolonged Stress Exposure in Rats

One of the hypotheses about the pathogenesis of posttraumatic stress disorder (PTSD) is the dysfunction of serotonin (5-HT) neurotransmission. While certain 5-HT receptor subtypes are likely critical for the symptoms of PTSD, few studies have examined the role of 5-HT₃ receptor in the development of PTSD, even though 5-HT₃ receptor is critical for contextual fear extinction and anxiety-like behavior. Therefore, we hypothesized that stimulation of 5-HT₃ receptor in the dorsal hippocampus (DH) could prevent hippocampal autophagy and the development of PTSD-like behavior in animals. To this end, we infused SR57227, selective 5-HT₃ agonist, into the DH after a single prolonged stress (SPS) treatment in rats. Three weeks later, we evaluated the effects of this pharmacological treatment on anxiety-related behaviors and extinction of contextual fear memory. We also accessed hippocampal autophagy and the expression of 5-HT_3A subunit, Beclin-1, LC3-I, and LC3-II in the DH. We found that SPS treatment did not alter anxiety-related behaviors but prolonged the extinction of contextual fear memory, and such a behavioral phenomenon was correlated with increased hippocampal autophagy, decreased 5-HT_3A expression, and increased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. Furthermore, intraDH infusions of SR57227 dose-dependently promoted the extinction of contextual fear memory, prevented hippocampal autophagy, and decreased expression of Beclin-1 and LC3-II/LC3-I ratio in the DH. These results indicated that 5-HT₃ receptor in the hippocampus may play a critical role in the pathogenesis of hippocampal autophagy, and is likely involved in the pathophysiology of PTSD.     

Fear extinction and BDNF: translating animal models of PTSD to the clinic

Brain-derived neurotrophic factor (BDNF) is the most studied neurotrophin involved in synaptic plasticity processes that are required for long-term learning and memory. Specifically, BDNF gene expression and activation of its high-affinity tropomyosin-related kinase B (TrkB) receptor are necessary in the amygdala, hippocampus and prefrontal cortex for the formation of emotional memories, including fear memories. Among the psychiatric disorders with altered fear processing, there is post-traumatic stress disorder (PTSD) which is characterized by an inability to extinguish fear memories. Since BDNF appears to enhance extinction of fear, targeting impaired extinction in anxiety disorders such as PTSD via BDNF signalling may be an important and novel way to enhance treatment efficacy. The aim of this review is to provide a translational point of view that stems from findings in the BDNF regulation of synaptic plasticity and fear extinction. In addition, there are different systems that seem to alter fear extinction through BDNF modulation like the endocannabinoid system and the hypothalamic-pituitary adrenal axis. Recent work also finds that the pituitary adenylate cyclase-activating polypeptide and PAC1 receptor, which are upstream of BDNF activation, may be implicated in PTSD. Especially interesting are data that exogenous fear extinction enhancers such as antidepressants, histone deacetylases inhibitors and D-cycloserine, a partial N-methyl d-aspartate agonist, may act through or in concert with the BDNF-TrkB system. Finally, we review studies where recombinant BDNF and a putative TrkB agonist, 7,8-dihydroxyflavone, may enhance extinction of fear. These approaches may lead to novel agents that improve extinction in animal models and eventually humans.     

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.     

How engram mediates learning,extinction, and relapse

Fear learning ensures survival through an expression of certain behavior as a conditioned fear response. Fear memory is processed and stored in a fear memory circuit, including the amygdala, hippocampus, and prefrontal cortex. A gradual decrease in conditioned fear response can be induced by fear extinction, which is mediated through the weakening of the original fear memory traces and the newly formed inhibition of those traces. Fear memory can also recover after extinction, which shows flexible control of the fear memory state. Here, we demonstrate how fear engram, which is a physical substrate of fear memory, changes during fear extinction and relapse by reviewing recent studies regarding engram.     

条件化恐惧记忆消退的神经振荡机制

恐惧作为个体应对内外界危险因素形成的自我保护机制的一部分,在生物体的生存中发挥着重要作用.但过度的恐惧不仅对个体生存无益,反而易引发创伤后应激障碍、焦虑等精神疾病,严重影响个体生活质量.临床上通常采用基于行为学研究结果的暴露疗法对恐惧相关疾病进行治疗,然而在患者处于治疗环境之外的时候,上述症状经常会复发.因此,解析恐惧记忆相关神经环路内信息处理的神经机制,对于理解这些疾病的发生发展,寻求切实有效的治疗方案至关重要.大量研究表明与恐惧记忆消退相关的脑区主要涉及杏仁核、内侧前额叶和海马.在恐惧消退的过程中,这3个脑区表现出特定的神经振荡模式,而且这些活动也具有同步性,构成了恐惧记忆成功消退的神经基础.未来可利用基于神经神经振荡的无创性脑刺激手段干预恐惧记忆消退的神经环路,以促进恐惧记忆的消退并避免复发,为恐惧相关障碍的临床治疗提供重要的科学依据.     

Murine GRPR and stathmin control in opposite directions both cued fear extinction and neural activities of the amygdala and prefrontal cortex

Extinction is an integral part of normal healthy fear responses, while it is compromised in several fear-related mental conditions in humans, such as post-traumatic stress disorder (PTSD). Although much research has recently been focused on fear extinction, its molecular and cellular underpinnings are still unclear. The development of animal models for extinction will greatly enhance our approaches to studying its neural circuits and the mechanisms involved. Here, we describe two gene-knockout mouse lines, one with impaired and another with enhanced extinction of learned fear. These mutant mice are based on fear memory-related genes, stathmin and gastrin-releasing peptide receptor (GRPR). Remarkably, both mutant lines showed changes in fear extinction to the cue but not to the context. We performed indirect imaging of neuronal activity on the second day of cued extinction, using immediate-early gene c-Fos. GRPR knockout mice extinguished slower (impaired extinction) than wildtype mice, which was accompanied by an increase in c-Fos activity in the basolateral amygdala and a decrease in the prefrontal cortex. By contrast, stathmin knockout mice extinguished faster (enhanced extinction) and showed a decrease in c-Fos activity in the basolateral amygdala and an increase in the prefrontal cortex. At the same time, c-Fos activity in the dentate gyrus was increased in both mutant lines. These experiments provide genetic evidence that the balance between neuronal activities of the amygdala and prefrontal cortex defines an impairment or facilitation of extinction to the cue while the hippocampus is involved in the context-specificity of extinction.     

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 parametric analysis of factors affecting acquisition and extinction of contextual fear in C57BL/6 and DBA/2 mice

Behavioral analyses of genetically modified and inbred strains of mice have revealed neural systems and molecules that are involved in memory formation. Many of these studies have examined memories that form in contextual fear conditioning, in which an organism learns that a particular context signals the occurrence of a footshock. During fear extinction, nonreinforced exposure to the context results in the loss of the conditioned fear response. The study of extinction has been instrumental for behavioral and molecular theories of memory. However, many of the transgenic, knockout, and inbred strains of mice that have been widely studied in memory have behavioral deficits in contextual fear conditioning, which makes the study of extinction in these mice particularly challenging. Here we explore several strategies for studying extinction in C57BL/6 and DBA/2 mice, two strains known to differ in contextual fear conditioning. First, we attempt to equate performance prior to extinction through several extensive conditioning protocols. Second, we examine extinction in subsets of mice matched for initial levels of context conditioning. Third, we examine within-strain effects of variables known to affect extinction. Differences between the strains persisted across extensive conditioning and extinction protocols, but both strains were sensitive to session duration and context manipulations during extinction. We describe the implications of our results for behavioral and neurobiological approaches to extinction, and we examine the general challenges in studying extinction in subjects that differ in learning or performance prior to extinction.     

Genetic disruptions of Drosophila Pavlovian learning leave extinction learning intact

Individuals who experience traumatic events may develop persistent posttraumatic stress disorder. Patients with this disorder are commonly treated with exposure therapy, which has had limited long‐term success. In experimental neurobiology, fear extinction is a model for exposure therapy. In this behavioral paradigm, animals are repeatedly exposed in a safe environment to the fearful stimulus, which leads to greatly reduced fear. Studying animal models of extinction already has lead to better therapeutic strategies and development of new candidate drugs. Lack of a powerful genetic model of extinction, however, has limited progress in identifying underlying molecular and genetic factors. In this study, we established a robust behavioral paradigm to study the short‐term effect (acquisition) of extinction in Drosophila melanogaster. We focused on the extinction of olfactory aversive 1‐day memory with a task that has been the main workhorse for genetics of memory in flies. Using this paradigm, we show that extinction can inhibit each of two genetically distinct forms of consolidated memory. We then used a series of single‐gene mutants with known impact on associative learning to examine the effects on extinction. We find that extinction is intact in each of these mutants, suggesting that extinction learning relies on different molecular mechanisms than does Pavlovian learning.     

Angiotensin type 1a receptors on corticotropin‐releasing factor neurons contribute to the expression of conditioned fear1

Although generally associated with cardiovascular regulation, angiotensin II receptor type 1a (AT_1aR) blockade in mouse models and humans has also been associated with enhanced fear extinction and decreased post‐traumatic stress disorder (PTSD) symptom severity, respectively. The mechanisms mediating these effects remain unknown, but may involve alterations in the activities of corticotropin‐releasing factor (CRF)‐expressing cells, which are known to be involved in fear regulation. To test the hypothesis that AT_1aR signaling in CRFergic neurons is involved in conditioned fear expression, we generated and characterized a conditional knockout mouse strain with a deletion of the AT_1aR gene from its CRF‐releasing cells (CRF‐AT_1aR^(?/?)). These mice exhibit normal baseline heart rate, blood pressure, anxiety and locomotion, and freeze at normal levels during acquisition of auditory fear conditioning. However, CRF‐AT_1aR^(?/?) mice exhibit less freezing than wild‐type mice during tests of conditioned fear expression—an effect that may be caused by a decrease in the consolidation of fear memory. These results suggest that central AT_1aR activity in CRF‐expressing cells plays a role in the expression of conditioned fear, and identify CRFergic cells as a population on which AT₁R antagonists may act to modulate fear extinction.     

令人烦恼的记忆

记载着挫折、恐惧、绝望等负性情绪的负性记忆,具有难以遗忘、令人烦恼的特点,与一些脑重大疾病,如创伤后应激综合征、抑郁症等存在密切关系。研究表明NMDA受体依赖性长时程增强在记忆的获取、储存等过程中起着关键作用。电休克和NMDA受体拮抗剂氯胺酮已知可导致短暂性遗忘,应用于治疗创伤后应激综合征、抑郁症具有起效快、疗效好的显著特点,提示这类脑疾病可能与负性记忆的遗忘特点有关。最近报道,遗忘具有独立的分子机理,在记忆和遗忘机理的共同作用下,既可能发生"记不住"如老年痴呆症、也可能出现"忘不了"如创伤后应激综合征和抑郁症等。深入研究遗忘的细胞分子机理,无疑有助于我们认识、预防和治疗相关脑重大疾病。     

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.     

Blockade of amygdala metabotropic glutamate receptor subtype 1 impairs fear extinction

The metabotropic glutamate receptor subtype 1 (mGluR1) is thought to be crucial for several forms of memory, but its role in memory extinction has not been determined. Here, we examined a role of mGluR1 in the extinction of conditioned fear using microinjection of an mGluR1 antagonist, CPCCOEt, into the lateral amygdala (LA), a critical structure for fear conditioning and extinction. Intra-LA injection of 3 microg CPCCOEt impaired extinction that was initiated 48 h after the conditioning, but not that initiated 2h after the conditioning, indicating that the effectiveness of CPCCOEt depends upon the length of time since fear conditioning. The CPCCOEt injection failed to alter an mGluR1-like receptor (mGluR5)-dependent acquisition of fear memory, further supporting the specificity of the injected CPCCOEt on mGluR1. Together, our results suggest that amygdala mGluR1 plays a critical role in the extinction of learned fear, but not in the acquisition of fear memory.     

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.     

ApoE isoform‐dependent deficits in extinction of contextual fear conditioning

The three major human apoE isoforms (apoE2, apoE3 and apoE4) are encoded by distinct alleles (?2, ?3 and ?4). Compared with ?3, ?4 is associated with increased risk to develop Alzheimer's disease (AD), cognitive impairments in Parkinson's disease (PD), and other conditions. In contrast, a recent study indicated an increased susceptibility to the recurring and re‐experiencing symptom cluster of Post‐Traumatic Stress Disorder (PTSD), as well as related memory impairments, in patients carrying at least one ?2 allele. Contextual fear conditioning and extinction are used in human and animal models to study this symptom cluster. In this study, acquisition (day 1, training), consolidation (day 2, first day of re‐exposure) and extinction (days 2–5) of conditioned contextual fear in human apoE2, apoE3 and apoE4 targeted replacement and C57BL/6J wild‐type (WT) mice was investigated. Male and female apoE2 showed acquisition and retrieval of conditioned fear, but failed to exhibit extinction. In contrast, WT, apoE3 and apoE4 mice showed extinction. While apoE2 mice exhibited lower freezing in response to the context on day 2 than apoE3 and apoE4 mice, this cannot explain their extinction deficit as WT mice exhibited similar freezing levels as apoE2 mice on day 2 but still exhibited extinction. Elevating freezing through extended training preserved extinction in controls, but failed to ameliorate extinction deficits in apoE2 animals. These data along with clinical data showing an association of apoE2 with susceptibility to specific symptom clusters in PTSD supports an important role for apoE isoform in the extinction of conditioned fear.     

Enhanced extinction of aversive memories by high-frequency stimulation of the rat infralimbic cortex

Electrical stimulation of the rodent medial prefrontal cortex (mPFC), including the infralimbic cortex (IL), immediately prior to or during fear extinction training facilitates extinction memory. Here we examined the effects of high-frequency stimulation (HFS) of the rat IL either prior to conditioning or following retrieval of the conditioned memory, on extinction of Pavlovian fear and conditioned taste aversion (CTA). IL-HFS applied immediately after fear memory retrieval, but not three hours after retrieval or prior to conditioning, subsequently reduced freezing during fear extinction. Similarly, IL-HFS given immediately, but not three hours after, retrieval of a CTA memory reduced aversion during extinction. These data indicate that HFS of the IL may be an effective method for reducing both learned fear and learned aversion.     

A NMDA Receptor Antagonist,MK-801 Impairs Consolidating Extinction of Auditory Conditioned Fear Responses in a Pavlovian Model

Background

In auditory fear conditioning, repeated presentation of the tone in the absence of shock leads to extinction of the acquired fear responses. The glutamate N-methyl-D-aspartate receptor (NMDAR) is thought to be involved in the extinction of the conditioned fear responses, but its detailed role in initiating and consolidating or maintaining the fear extinction memory is unclear. Here we investigated this issue by using a NMDAR antagonist, MK-801.

Methods/Main Findings

The effects of immediate (beginning at 10 min after the conditioning) and delayed (beginning at 24 h after conditioning) extinctions were first compared with the finding that delayed extinction caused a better and long-lasting (still significant on the 20^th day after extinction) depression on the conditioned fear responses. In a second experiment, MK-801 was intraperitoneally (i.p.) injected at 40 min before, 4 h or 12 h after the delayed extinction, corresponding to critical time points for initiating, consolidating or maintaining the fear extinction memory. i.p. injection of MK-801 at either 40 min before or 4 h after delayed extinction resulted in an impairment of initiating and consolidating fear extinction memory, which caused a long lasting increased freezing score that was still significant on the 7th day after extinction, compared with extinction group. However, MK-801 administered at 12 h after the delayed extinction, when robust consolidation has been occurred and stabilized, did not affect the established extinction memory. Furthermore, the changed freezing behaviors was not due to an alteration in general anxiety levels, since MK-801 treatment had no effect on the percentage of open-arm time or open-arm entries in an Elevated Plus Maze (EPM) task.

Conclusions/Significance

Our data suggested that the activation of NMDARs plays important role in initiation and consolidation but not maintenance of fear extinction memory. Together with the fact that NMDA receptor is very important for memory, our data added experimental evidence to the concept that the extinction of conditioned fear responses is a procedure of initiating and consolidating new memory other than simply “erasing” the fear memory.     

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.