Article

Parsons RG, Ressler KJ. Implications of memory modulation for post-traumatic stress and fear disorders. Nat Neurosci 16: 146-153

Department of Psychiatry and Behavioral Sciences, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
Nature Neuroscience (Impact Factor: 16.1). 01/2013; 16(2):146-53. DOI: 10.1038/nn.3296
Source: PubMed

ABSTRACT

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.

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    • "Collectively, these impairments induce an aberrant formation and activation of neural assemblies in the PFC, which result in the development of maladaptive cognitive maps that link perceptual information to a repertory of erroneous actions, resulting in the maladaptive behavioral response directed to goals. behavioral alterations observed in chronic stress-related psychiatric disorders can be categorized into three classes[1]: (i) exacerbated formation and implementation of maladaptive behavioral responses, a feature known as negative-cognitive bias, which manifests itself as the tendency to misinterpret perceptual stimuli as aversive or threatening[61,211], (ii) exacerbated long-term recall of maladaptive memories, as increased retention and recall of aversive memories[3,6,15], and (iii) behavioral perseverance, manifested as the inability to adaptively update behavioral responses to novel environmental conditions[8]. The second proposal states that the above-mentioned cognitive defects observed in psychiatric diseases are the result of the anomalous and maladaptive formation of cognitive maps that represent perception-action cycles in the PFC. "
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    ABSTRACT: Chronic stress-related psychiatric diseases, such as major depression, posttraumatic stress disorder, and schizophrenia, are characterized by a maladaptive organization of behavioral responses that strongly affect the well-being of patients. Current evidence suggests that a functional impairment of the prefrontal cortex (PFC) is implicated in the pathophysiology of these diseases. Therefore, chronic stress may impair PFC functions required for the adaptive orchestration of behavioral responses. In the present review, we integrate evidence obtained from cognitive neuroscience with neurophysiological research with animal models, to put forward a hypothesis that addresses stress-induced behavioral dysfunctions observed in stress-related neuropsychiatric disorders. We propose that chronic stress impairs mechanisms involved in neuronal functional connectivity in the PFC that are required for the formation of adaptive representations for the execution of adaptive behavioral responses. These considerations could be particularly relevant for understanding the pathophysiology of chronic stress-related neuropsychiatric disorders.
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    • "Specifically, fear acquisition can serve to model features of the etiology of these disorders. Correspondingly, simple phobias, social phobia, panic disorder, and PTSD are characterized primarily by dysregulated fear responses (Ehlers and Clark, 2000;Parsons and Ressler, 2013). Moreover, these disorders are characterized by deficits in fear extinction. "
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    ABSTRACT: Fear acquisition and extinction are valid models for the etiology and treatment of anxiety, trauma- and stressor-related disorders. These disorders are assumed to involve aversive learning under acute and/or chronic stress. Importantly, fear conditioning and stress share common neuronal circuits. The stress response involves multiple changes interacting in a time-dependent manner: (a) the fast first-wave stress response (with central actions of noradrenaline, dopamine, serotonin, corticotropin-releasing hormone, plus increased sympathetic tone and peripheral catecholamine release) and (b) the second-wave stress response (with peripheral release of glucocorticoids after activation of the hypothalamus-pituitary-adrenocortical axis). Control of fear during extinction is also sensitive to these stress-response mediators. In the present review, we will thus examine current animal and human data, addressing the role of stress and single stress-response mediators for successful acquisition, consolidation and recall of fear extinction. We report studies using pharmacological manipulations targeting a number of stress-related neurotransmitters and neuromodulators (monoamines, opioids, endocannabinoids, neuropeptide Y, oxytocin, glucocorticoids) and behavioral stress induction. As anxiety, trauma- and stressor-related disorders are more common in women, recent research focuses on female sex hormones and identifies a potential role for estradiol in fear extinction. We will thus summarize animal and human data on the role of estradiol and explore possible interactions with stress or stress-response mediators in extinction. This also aims at identifying time-windows of enhanced (or reduced) sensitivity for fear extinction, and thus also for successful exposure therapy.
    Full-text · Article · Jan 2016 · Frontiers in Behavioral Neuroscience
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    • "Considering the augmented Cannabis use by post-traumatic stress disorder (PTSD) patients (Kessler et al., 1995; Cornelius et al., 2010), which may present changes in endocannabinoid system functioning (Hauer et al., 2013; Neumeister et al., 2013), this conduct could represent an empirical selfmedication attempt to affect the maintenance of a dysfunctional aversive learning, which is believed to underlie this psychiatric condition (Parsons and Ressler, 2013; Trezza and Campolongo, 2013). Recent preclinical findings from our research group have supported this hypothesis, as CBD was able to mitigate aberrant and enduring fear memories by disrupting their reconsolidation process (Stern et al., 2012; Gazarini et al., in 2015). "
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    ABSTRACT: Δ(9)-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the major constituents of the Cannabis sativa plant, which is frequently consumed by subjects exposed to life-threatening situations to relief their symptomatology. It is still unknown, however, whether THC could also affect the maintenance of an aversive memory formed at that time when taken separately and/or in conjunction with CBD. The present study sought to investigate this matter at a preclinical level. We report that THC (0.3-10mg/kg, i.p.) was able to disrupt the reconsolidation of a contextual fear memory, resulting in reduced conditioned freezing expression for over 22 days. This effect was dependent on activation of cannabinoid type-1 receptors located in prelimbic subregion of the medial prefrontal cortex and on memory retrieval/reactivation. Since CBD may counteract the negative psychotropic effects induced by THC and has been shown to be a reconsolidation blocker, we then investigated and demonstrated that associating sub-effective doses of these two compounds was equally effective in attenuating fear memory maintenance in an additive fashion and in a dose ratio of 10 to 1, which contrasts with that commonly found in C. sativa recreational samples. Of note, neither THC alone nor CBD plus THC interfered with anxiety-related behaviors and locomotor activity, as assessed in the elevated plus-maze test, at a time point coinciding with that used to evaluate their effects on memory reconsolidation. Altogether, present findings suggest a potential therapeutic value of using THC and/or CBD to mitigate a dysfunctional aversive memory through reconsolidation disruption in post-traumatic stress disorder patients. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.
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