Traumatic Memories In Posttraumatic Stress Disorder Research Articles

Ketamine treatment upon memory retrieval reduces fear memory in marmoset monkeys

Emotionally arousing experiences are retained very well as seen in posttraumatic stress disorder (PTSD). Various lines of evidence indicate that reactivation of these memories renders them labile which offers a potential time-window for intervention. We tested in non-human primates whether ketamine, administered during fear memory reactivation, affected passive (inhibitory) avoidance learning. For the consolidation of contextual emotional memory, the unescapable foot-shock paradigm in a passive avoidance task with two compartments (dark vs illuminated) was used. After entering the dark compartment, marmoset monkeys received four random foot-shocks (1 mA, 4 s) within 15-min. This stressful exposure increased the saliva cortisol and heart rate and impaired REM-sleep (p<0.05). One week later the monkeys were re-exposed to the stressful situation for the reconsolidation of the fearful experience. During the re-exposure the monkeys were treated with ketamine (0.5 mg/kg) or saline. In week 3, the monkeys were placed in the experimental setting to test their memory for the fearful experience. In contrast to the vehicle-treated monkeys, who avoided the dark compartment, the ketamine-treated monkeys entered the dark compartment that was previously associated with the fearful experience (p<0.05). Post-mortem analysis of the hippocampus showed that ketamine-treated animals exhibited less doublecortin positive neurons and BrdU-labeled cells in the dentate gyrus. This study reveals that a single low dose of ketamine, administered upon fear retrieval in monkeys, reduce contextual fear memory and attenuate neurogenesis in the hippocampus. These are important findings for considering ketamine as a potential candidate to target traumatic memories in PTSD.

Epinephrine May Contribute to the Persistence of Traumatic Memories in a Post-traumatic Stress Disorder Animal Model.

The importance of catecholamines in post-traumatic stress disorder (PTSD) still needs to be explored. We aimed to evaluate epinephrine’s (EPI) causal role and molecular mechanism for the persistence of PTSD traumatic memories. Wild-type (WT) and EPI-deficient mice (phenylethanolamine-N-methyltransferase-knockout mice, Pnmt-KO) were induced with PTSD and behavioral tests were performed. Some Pnmt-KO mice were administered with EPI or vehicle. Catecholamines were quantified by HPLC-ED. Nr4a1, Nr4a2, and Nr4a3 mRNA expression were evaluated by real-time PCR in hippocampus samples. It was observed an increase in EPI and freezing behavior, and a decrease in open arm entries in the elevated plus-maze test and time spent in the light in the light–dark test in WT mice in the PTSD-induction group compared to control. After induction of PTSD, Pnmt-KO mice showed a decrease in freezing, as well as an increase in open arm entries and transitions between compartments compared to WT. After PTSD induction, Pnmt-KO mice administered with EPI showed an increase in freezing compared with the vehicle. On day 0 of PTSD induction, it was observed an increase in mRNA expression of Nr4a2 and Nr4a3 genes in the hippocampus of WT mice compared to control, contrary to Pnmt-KO mice. In conclusion, our data suggest that EPI may be involved in the persistence of traumatic memories in PTSD, possibly through enhancement of the expression of Nr4a2 and Nr4a3 genes in the hippocampus. Peripheral administration of EPI restored contextual traumatic memories in Pnmt-KO mice, which suggests a causal role for EPI. The persistence of contextual traumatic memories may contribute to anxiety-like behavior and resistance of traumatic memory extinction in this PTSD mice model.

Hypothesis: The Psychedelic Ayahuasca Heals Traumatic Memories via a Sigma 1 Receptor-Mediated Epigenetic-Mnemonic Process.

Ayahuasca ingestion modulates brain activity, neurotransmission, gene expression and epigenetic regulation. N,N-Dimethyltryptamine (DMT, one of the alkaloids in Ayahuasca) activates sigma 1 receptor (SIGMAR1) and others. SIGMAR1 is a multi-faceted stress-responsive receptor which promotes cell survival, neuroprotection, neuroplasticity, and neuroimmunomodulation. Simultaneously, monoamine oxidase inhibitors (MAOIs) also present in Ayahuasca prevent the degradation of DMT. One peculiarity of SIGMAR1 activation and MAOI activity is the reversal of mnemonic deficits in pre-clinical models. Since traumatic memories in post-traumatic stress disorder (PTSD) are often characterised by “repression” and PTSD patients ingesting Ayahuasca report the retrieval of such memories, it cannot be excluded that DMT-mediated SIGMAR1 activation and the concomitant MAOIs effects during Ayahuasca ingestion might mediate such “anti-amnesic” process. Here I hypothesise that Ayahuasca, via hyperactivation of trauma and emotional memory-related centres, and via its concomitant SIGMAR1- and MAOIs- induced anti-amnesic effects, facilitates the retrieval of traumatic memories, in turn making them labile (destabilised). As Ayahuasca alkaloids enhance synaptic plasticity, increase neurogenesis and boost dopaminergic neurotransmission, and those processes are involved in memory reconsolidation and fear extinction, the fear response triggered by the memory can be reprogramed and/or extinguished. Subsequently, the memory is stored with this updated significance. To date, it is unclear if new memories replace, co-exist with or bypass old ones. Although the mechanisms involved in memory are still debated, they seem to require the involvement of cellular and molecular events, such as reorganisation of homo and heteroreceptor complexes at the synapse, synaptic plasticity, and epigenetic re-modulation of gene expression. Since SIGMAR1 mobilises synaptic receptor, boosts synaptic plasticity and modulates epigenetic processes, such effects might be involved in the reported healing of traumatic memories in PTSD patients. If this theory proves to be true, Ayahuasca could come to represent the only standing pharmacological treatment which targets traumatic memories in PTSD. Lastly, since SIGMAR1 activation triggers both epigenetic and immunomodulatory programmes, the mechanism here presented could help understanding and treating other conditions in which the cellular memory is dysregulated, such as cancer, diabetes, autoimmune and neurodegenerative pathologies and substance addiction.

Pharmacological blockade of memory reconsolidation in posttraumatic stress disorder: Three negative psychophysiological studies

Posttraumatic stress disorder (PTSD) may involve over-consolidated emotional memories of the traumatic event. Reactivation (RP) can return a memory to an unstable state, from which it must be restabilized (reconsolidated) if it is to persist. Pharmacological agents administered while the memory is unstable have been shown to impair reconsolidation. The N-methyl-d-aspartate (NMDA) partial agonist d-cycloserine (DCS) may promote memory destabilization. In the three studies reported here, we investigated whether the β-adrenergic blocker propranolol or the glucocorticoid (GR) antagonist mifepristone, given at the time of traumatic memory reactivation, could reduce PTSD symptoms and physiological responding during subsequent traumatic imagery. Individuals with PTSD were randomized as follows: Study One: propranolol with memory reactivation (n=10) or without reactivation (n=8); Study Two: reactivation mifepristone (n=13), non-reactivation (NRP) mifepristone (n=15), or double placebo (PL) (n=15); Study Three: reactivation mifepristone plus d-cycloserine (n=16), or two placebos (n=15). Subjects underwent memory retrieval by describing their traumatic event. A week later they engaged in script-driven traumatic mental imagery, while heart rate (HR), skin conductance (SC), and facial electromyogram (EMG) responses were measured. There were no significant group differences in physiological responsivity or change in PTSD symptoms in any of the studies. These results do not support successful blockade of reconsolidation of traumatic memories in PTSD.

Noradrenergic enhancement of reconsolidation in the amygdala impairs extinction of conditioned fear in rats-a possible mechanism for the persistence of traumatic memories in PTSD

Posttraumatic stress disorder (PTSD) is associated with enhanced noradrenergic activity. Animal and human studies demonstrate that noradrenergic stimulation augments consolidation of fear learning. Retrieval of well-established memories by presenting a learned fear cue triggers reconsolidation processes during which memories may be updated, weakened, or strengthened. We previously reported that noradrenergic blockade in the rat amygdala impairs reconsolidation of fear memories. Here we investigated the effects of noradrenergic enhancement on reconsolidation of learned fear. Using auditory fear conditioning in rats, we tested the effects of postretrieval intraamygdala infusion of the β-adrenergic receptor agonist isoproterenol or the antagonist propranolol on conditioned fear in the amygdala. A single intraamygdala infusion of isoproterenol following a retrieval of a well-consolidated memory enhanced fear memory elicited by the learned fear stimulus and impaired extinction of this memory 48 hr later. Intraamygdala infusion of the β-adrenergic receptor antagonist propranolol following a consecutive retrieval trial blocked the enhancing effects of isoproterenol on fear memory. Postretrieval β-adrenergic stimulation in the amygdala enhances reconsolidation of fear memories, making them resistant to extinction. Noradrenergic augmentation during retrieval of fear memories may thus contribute to persistence and severity of traumatic memories. Reconsolidation may be a useful tool in understanding the pathology of PTSD and may thus help in developing new and in modifying existing treatments of traumatic memories.

Will Reconsolidation Blockade Offer a Novel Treatment for Posttraumatic Stress Disorder?

OPINION article Front. Behav. Neurosci., 04 March 2011Sec. Learning and Memory https://doi.org/10.3389/fnbeh.2011.00011

‘Comparisons of traumatic and positive memories in people with and without PTSD profile’

AbstractAccording to most post‐traumatic stress disorder (PTSD) theories, memory mechanisms are involved in its development and maintenance. However, the specific memory characteristics responsible for this disorder are still not well known. In the present study, 210 participants having reported at least one traumatic experience were assigned to a PTSD or to a non‐PTSD symptom profile group. Both groups rated their memories for their most traumatic and intense positive life events. We observed that the traumatic memories of PTSD profile participants were more clear, detailed and judged as significant compared with those of the non‐PTSD profile group. However, participants in the first group acknowledged having more difficulties putting their traumatic memories into words and controlling these remembrances. These differences were absent in their positive memories. Additionally, clear relationships emerged between memory ratings and PTSD symptoms measures. Results are discussed according to fragmentation and superiority views of traumatic memories in PTSD. Copyright © 2006 John Wiley &amp; Sons, Ltd.