Efficacy of traumatic memory reactivation with or without propranolol in PTSD with high dissociative experiences.

Background: Post-traumatic stress disorder (PTSD) with dissociative symptoms is now a full-fledged subtype of this disorder. The dissociative subtype is associated with a greater number of psychiatric comorbidities. To date, the impact of dissociation on the efficacy of PTSD treatment remains unclear.Objective: The aim of this study was to compare the efficacy of a traumatic memory reactivation procedure with the administration of propranolol or a placebo once a week for six consecutive weeks in reducing PTSD and MDE symptoms between PTSD subjects with or without high dissociative symptoms.Method: For that, we conducted a randomized clinical trial in 66 adults diagnosed with longstanding PTSD and measured the SCID PTSD module, the PTSD Checklist (PCL-S), Beck's Depression Inventory-II (BDI-II), and the Dissociative Experiences Scale (DES).Results: Patients with and without high dissociative experience had significant improvement in their PCL-S scores over the 6 treatment sessions, and PCL-S scores continued to decline in all patients during the post-treatment period. However, there was no correlation between the presence/absence of high dissociative experiences and no specific effect of propranolol treatment. We found exactly the same results for MDE symptoms. Interestingly, patients with high dissociative experiences before treatment exhibited very significant improvement in their DES scores after the 6 treatment sessions, and patients maintained this improvement 3 months post-treatment.Conclusions: The traumatic memory reactivation procedure is an effective way to treat dissociative symptoms in patients with PTSD, and improvement of these dissociative symptoms was associated with a decrease in both PTSD and depression severity.

Traumatic memory reactivation procedure is an effective way to treat dissociative symptoms in patients with PTSD.The improvement of these dissociative symptoms was associated to a decrease of both PTSD and depression severity.Dissociative symptoms do not seem to mitigate the efficacy of traumatic memory reactivation during the treatment of PTSD.

Traumatic memory reactivation with or without propranolol for PTSD and comorbid MD symptoms: a randomised clinical trial.

Post-traumatic stress disorder (PTSD) is difficult to treat but one promising strategy is to block memory reconsolidation of the traumatic event. This study aimed to evaluate the efficacy of traumatic memory reactivation under the influence of propranolol, a noradrenergic beta-receptor blocker, in reducing PTSD symptoms as well as comorbid major depression (MD) symptoms. We conducted a double blind, placebo-controlled, randomised clinical trial in 66 adults diagnosed with longstanding PTSD. Propranolol or a placebo was administered 90 min before a brief memory reactivation session, once a week for 6 consecutive weeks. Measures included the SCID PTSD module, the PTSD Check List (PCL-S) and the Beck Depression Inventory-II (BDI-II). PTSD symptoms decreased both in the pre-reactivation propranolol group (39.28%) and the pre-reactivation placebo group (34.48 %). During the 6 treatment sessions, PCL-S and BDI-II scores decreased to similar extent in both groups and there were no treatment differences. During the 3-month follow-up period, there were no treatment effects for the mean PCL-S and BDI-II scores. However, in patients with severe PTSD symptoms (PCL-S ≥ 65) before treatment, PCL-S and BDI-II scores continued to decline 3 months after the end of treatment in the propranolol group while they increased in the placebo group. Repeated traumatic memory reactivation seemed to be effective for PTSD and comorbid MD symptoms. However, the efficacy of propranolol was not greater than that of placebo 1 week post treatment. Furthermore, in this traumatic memory reactivation, PTSD symptom severity at baseline might have influenced the post-treatment effect of propranolol.

Influence of early stress on memory reconsolidation: Implications for post-traumatic stress disorder treatment.

Post-traumatic stress disorder (PTSD) is a common consequence of exposure to a life-threatening event. Currently, pharmacological treatments are limited by high rates of relapse, and novel treatment approaches are needed. We have recently demonstrated that propranolol, a ß-adrenergic antagonist, inhibited aversive memory reconsolidation in animals. Following this, in an open-label study 70% of patients with PTSD treated with propranolol during reactivation of traumatic memory exhibited full remission. However, the reason why 30% of these patients did not respond positively to propranolol treatment is still unclear. One of the major candidates as factor of treatment resistance is the patient's early-life traumatic history. To test the role of this factor, mice with pre- or postnatal stress are being tested in fear conditioning and in a new behavioral task, the "city-like", specifically designed as a mouse model of PTSD. After reactivation of the traumatic event, mice received propranolol injection to block the noradrenergic system during memory reconsolidation. Results show that, in the "city-like" test, control mice strongly avoided the shock compartment but also the compartments containing cues associated with the electric shocks. Injection of propranolol after reactivation greatly reduced the memory of the traumatic event, but this effect was not present when mice had received pre- or postnatal stress. Moreover, propranolol produced only a very weak effect in the fear conditioning test, and never changed the corticosterone level whatever the behavioral experiment. Taken together our results suggest that our new behavioural paradigm is well adapted to PTSD study in mice, and that early stress exposure may have an impact on propranolol PTSD treatment outcome. These data are critical to understanding the effect of propranolol treatment, in order to improve the therapeutic protocol currently used in humans.

HDAC inhibition promotes both initial consolidation and reconsolidation of spatial memory in mice.

Accumulating evidence suggests a critical role for epigenetic regulations in long term memory (LTM) formation. Among them, post-translational modifications of proteins, as histone acetylation, are an important regulator of chromatin remodelling and gene transcription. While the implication of histone acetylation in memory consolidation is widely accepted, less is known about its role in memory reconsolidation i.e. during memory restabilization after its reactivation. In the present study, we investigated the role of histone acetylation during the initial consolidation and the reconsolidation of spatial memory, using a weak massed learning procedure in the Morris water maze paradigm in mice. Usually a weak learning is sufficient for short term memory (STM) formation, but insufficient to upgrade STM to LTM. We found that promoting histone acetylation through intra-hippocampal infusion of a class I selective histone deacetylase (HDAC) inhibitor immediately after a subthreshold spatial learning improved LTM but not STM retention. More importantly, inhibiting HDAC activity after the reactivation of a weak memory promoted specifically LTM reconsolidation without affecting post-reactivation STM. These findings argue in favour of an important role for histone acetylation in memory consolidation, and more particularly during the reconsolidation of spatial memory in mice.

Effects of Propranolol, a ß-noradrenergic Antagonist, on Memory Consolidation and Reconsolidation in Mice.

Memory reconsolidation impairment using the ß-noradrenergic receptor blocker propranolol is a promising novel treatment avenue for patients suffering from pathogenic memories, such as post-traumatic stress disorder (PTSD). However, in order to better inform targeted treatment development, the effects of this compound on memory need to be better characterized via translational research. We examined the effects of systemic propranolol administration in mice undergoing a wide range of behavioral tests to determine more specifically which aspects of the memory consolidation and reconsolidation are impaired by propranolol. We found that propranolol (10 mg/kg) affected memory consolidation in non-aversive tasks (object recognition and object location) but not in moderately (Morris water maze (MWM) to highly (passive avoidance, conditioned taste aversion) aversive tasks. Further, propranolol impaired memory reconsolidation in the most and in the least aversive tasks, but not in the moderately aversive task, suggesting its amnesic effect was not related to task aversion. Moreover, in aquatic object recognition and location tasks in which animals were forced to behave (contrary to the classic versions of the tasks); propranolol did not impair memory reconsolidation. Taken together our results suggest that the memory impairment observed after propranolol administration may result from a modification of the emotional valence of the memory rather than a disruption of the contextual component of the memory trace. This is relevant to the use of propranolol to block memory reconsolidation in individuals with PTSD, as such a treatment would not erase the traumatic memory but only reduce the emotional valence associated with this event.

Characterization of spatial memory reconsolidation.

Reconsolidation is necessary for the restabilization of reactivated memory traces. However, experimental parameters have been suggested as boundary conditions for this process. Here we investigated the role of a spatial memory trace's age, strength, and update on the reconsolidation process in mice. We first found that protein synthesis is necessary for reconsolidation to occur in the hippocampal CA3 region after reactivation of partially acquired and old memories but not for strongly acquired and recent memories. We also demonstrated that the update of a previously stable memory required, again, a memory reconsolidation in the hippocampal CA3. Finally, we found that the reactivation of a strongly acquired memory requires an activation of the anterior cingulate cortex as soon as 24 h after acquisition. This study demonstrates the importance of the knowledge of the task on the dynamic nature of memory reconsolidation processing.

Cortical abnormalities and non-spatial learning deficits in a mouse model of CranioFrontoNasal syndrome.

Eph receptors and their ephrin ligands play critical roles in the development of the nervous system, however, less is known about their functions in the adult brain. Here, we investigated the function of ephrinB1, an ephrinB family member that is mutated in CranioFrontoNasal Syndrome. We show that ephrinB1 deficient mice (EfnB1(Y/-)) demonstrate spared spatial learning and memory but exhibit exclusive impairment in non-spatial learning and memory tasks. We established that ephrinB1 does not control learning and memory through direct modulation of synaptic plasticity in adults, since it is not expressed in the adult brain. Rather we show that the cortex of EfnB1(Y/-) mice displayed supernumerary neurons, with a particular increase in calretinin-positive interneurons. Further, the increased neuron number in EfnB1(Y/-) mutants correlated with shorter dendritic arborization and decreased spine densities of cortical pyramidal neurons. Our findings indicate that ephrinB1 plays an important role in cortical maturation and that its loss has deleterious consequences on selective cognitive functions in the adult.

Involvement of protein degradation by the ubiquitin proteasome system in opiate addictive behaviors.

Plastic changes in the nucleus accumbens (NAcc), a structure occupying a key position in the neural circuitry related to motivation, are among the critical cellular processes responsible for drug addiction. During the last decade, it has been shown that memory formation and related neuronal plasticity may rely not only on protein synthesis but also on protein degradation by the ubiquitin proteasome system (UPS). In this study, we assess the role of protein degradation in the NAcc in opiate-related behaviors. For this purpose, we coupled behavioral experiments to intra-accumbens injections of lactacystin, an inhibitor of the UPS. We show that protein degradation in the NAcc is mandatory for a full range of animal models of opiate addiction including morphine locomotor sensitization, morphine conditioned place preference, intra-ventral tegmental area morphine self-administration and intra-venous heroin self-administration but not for discrimination learning rewarded by highly palatable food. This study provides the first evidence of a specific role of protein degradation by the UPS in addiction.

Ventral striatal plasticity and spatial memory.

Spatial memory formation is a dynamic process requiring a series of cellular and molecular steps, such as gene expression and protein translation, leading to morphological changes that have been envisaged as the structural bases for the engram. Despite the role suggested for medial temporal lobe plasticity in spatial memory, recent behavioral observations implicate specific components of the striatal complex in spatial information processing. However, the potential occurrence of neural plasticity within this structure after spatial learning has never been investigated. In this study we demonstrate that blockade of cAMP response element binding protein-induced transcription or inhibition of protein synthesis or extracellular proteolytic activity in the ventral striatum impairs long-term spatial memory. These findings demonstrate that, in the ventral striatum, similarly to what happens in the hippocampus, several key molecular events crucial for the expression of neural plasticity are required in the early stages of spatial memory formation.

Symptoms of traumatic stress in mothers of children victims of a motor vehicle accident.

BACKGROUND: Motor vehicle accidents (MVAs) are the main cause of Posttraumatic stress disorder (PTSD) in industrialized countries. This includes the frequently occurring but understudied situation of parents learning that their children were injured. However, unlike in other types of trauma survivors, little is known about the predictors of PTSD symptoms in mothers whose child has suffered an MVA. METHODS: A group of 72 mothers and 28 fathers were prospectively assessed for peritraumatic distress, peritraumatic dissociation, and PTSD symptoms 1 and 5 weeks after their child had suffered an MVA. RESULTS: Levels of peritraumatic distress and dissociation were comparable to other trauma victims, 18% of the mothers were considered to be suffering from probable PTSD. In mothers, significant positive correlations were found between PTSD symptoms and peritraumatic distress (r=.34) and dissociation (r=.37), whereas mothers' PTSD symptoms were associated with decreased peritraumatic dissociation in fathers (r=-.37). Even after controlling for covictim/witness status, peritraumatic distress was a predictor of mothers' PTSD symptoms, explaining 14% of the variance. CONCLUSIONS: Peritraumatic response and PTSD symptoms should be routinely assessed among parents whose child has experienced a traumatic event.

Pharmacological intervention of hippocampal CA3 NMDA receptors impairs acquisition and long-term memory retrieval of spatial pattern completion task.

Pattern completion is the ability to retrieve complete information on the basis of incomplete retrieval cues. Although it has been demonstrated that this cognitive capacity depends on the NMDA receptors (NMDA-Rs) of the hippocampal CA3 region, the role played by these glutamatergic receptors in the pattern completion process has not yet been specified. In the present study, we investigated the function of the CA3 NMDA-Rs during the different memory stages (acquisition, memory consolidation, and retrieval) in a spatial pattern completion task (when some visual cues were removed from the environment) in comparison to a standard spatial water maze task (when all visual cues were available in the environment). Thus, we coupled a massed training with the injection of NMDA-receptor antagonist (AP5) into the CA3 subfield of the dorsal hippocampus of C57BL/6 mice. Our results show that NMDA-Rs are not implicated in a standard situation but are crucial during both acquisition and long-term memory retrieval in pattern completion. This work provides the first evidence of a specific role of CA3 NMDA-Rs during memory process involved in the reactivation of incomplete memory trace, particularly when the amount of environmental information available is strongly limited.

Recruitment of adult-generated neurons into functional hippocampal networks contributes to updating and strengthening of spatial memory.

The dentate gyrus (DG), a hippocampal subregion, continuously produces new neurons in the adult mammalian brain that become functionally integrated into existing neural circuits. To what extent this form of plasticity contributes to memory functions remains to be elucidated. Using mapping of activity-dependent gene expression, we visualized in mice injected with the birthdating marker 5-bromo-2'-deoxyuridine the recruitment of new neurons in a set of controlled water maze procedures that engage specific spatial memory processes and require hippocampal-cortical networks. Here, we provide new evidence that adult-generated hippocampal neurons make a specific but differential contribution to the processing of remote spatial memories. First, we show that new neurons in the DG are recruited into neuronal networks that support retrieval of remote spatial memory and that their activation is situation-specific. We further reveal that once selected, new hippocampal neurons are durably incorporated into memory circuits, and also that their recruitment into hippocampal networks contributes predominantly to the updating and strengthening of a previously encoded memory. We find that initial spatial training during a critical period, when new neurons are more receptive to surrounding neuronal activity, favors their subsequent recruitment upon remote memory retrieval. We therefore hypothesize that new neurons activated during this critical period become tagged so that once mature, they are preferentially recruited into hippocampal networks underlying remote spatial memory representation when encountering a similar experience.

Protein degradation, as with protein synthesis, is required during not only long-term spatial memory consolidation but also reconsolidation.

The formation of long-term memory requires protein synthesis, particularly during initial memory consolidation. This process also seems to be dependant upon protein degradation, particularly degradation by the ubiquitin-proteasome system. The aim of this study was to investigate the temporal requirement of protein synthesis and degradation during the initial consolidation of allocentric spatial learning. As memory returns to a labile state during reactivation, we also focus on the role of protein synthesis and degradation during memory reconsolidation of this spatial learning. Male CD1 mice were submitted to massed training in the spatial version of the Morris water maze. At various time intervals after initial acquisition or after a reactivation trial taking place 24 h after acquisition, mice received an injection of either the protein synthesis inhibitor anisomycin or the protein degradation inhibitor lactacystin. This injection was performed into the hippocampal CA3 region, which is specifically implicated in the processing of spatial information. Results show that, in the CA3 hippocampal region, consolidation of an allocentric spatial learning task requires two waves of protein synthesis taking place immediately and 4 h after acquisition, whereas reconsolidation requires only the first wave. However, for protein degradation, both consolidation and reconsolidation require only one wave, taking place immediately after acquisition or reactivation, respectively. These findings suggest that protein degradation is a key step for memory reconsolidation, as for consolidation. Moreover, as protein synthesis-dependent reconsolidation occurred faster than consolidation, reconsolidation did not consist of a simple repetition of the initial consolidation.

Effects of intra-accumbens NMDA and AMPA receptor antagonists on short-term spatial learning in the Morris water maze task.

Glutamatergic transmission within the nucleus accumbens (Nac) is considered to subserve the transfer of different types of information from the cortical and limbic regions. In particular, it has been suggested that glutamatergic afferences from the hippocampus and the prefrontal cortex provide the main source of contextual information to the Nac. Accordingly, several authors have demonstrated that the blockade of glutamate receptors within the Nac impairs various spatial tasks. However, the exact role of the different classes of glutamate receptors within the Nac in short-term spatial memory is still not clear. In this study we investigated the involvement of two major classes of glutamate receptors, NMDA and AMPA receptors, within the Nac in the acquisition of spatial information, using the Morris water maze task. Focal injections of the NMDA antagonist, AP-5 (0.1 and 0.15 microg/side), and the AMPA antagonist, DNQX (0.005, 0.01 microg/side), were performed before a massed training phase, and mice were tested for retention immediately after. NMDA and AMPA receptor blockade induced no effect during training. On the contrary, injection of the two glutamatergic antagonists impaired spatial localization during the probe test. These data demonstrate an involvement of the Nac in short-term spatial learning. Moreover, they prove that within this structure the short-term processing of spatial information needs the activation of both NMDA and AMPA receptors.

Reactivation with a simple exposure to the experimental environment is sufficient to induce reconsolidation requiring protein synthesis in the hippocampal CA3 region in mice.

Our understanding of the memory reconsolidation process is at an earlier stage than that of consolidation. For example, it is unclear if, as for memory consolidation, reconsolidation of a memory trace necessitates protein synthesis. In fact, conflicting results appear in the literature and this discrepancy may be due to differences in the experimental reactivation procedure. Here, we addressed the question of whether protein synthesis in the CA3 hippocampal region is crucial in memory consolidation and reconsolidation of allocentric knowledge after reactivation in different experimental conditions in the Morris water maze. We showed (1) that an injection of the protein synthesis inhibitor anisomycin in the CA3 region during consolidation or after a single reactivation trial disrupted performance and (2) that protein synthesis is required even after a simple contextual reactivation without any learning trial and independently of the presence of the reinforcement. This work demonstrates that a simple exposure to the spatial environment is sufficient to reactivate the memory trace, to make it labile, and that reconsolidation of this trace requires de novo protein synthesis.

CREB antisense oligodeoxynucleotide administration into the dorsal hippocampal CA3 region impairs long- but not short-term spatial memory in mice.

The transcription factor cAMP response-element binding protein (CREB) has a pivotal role in hippocampal synaptic plasticity and hippocampus-dependent long-term memory. We recently demonstrated that the dorsal hippocampal CA3 region is involved in memory consolidation of spatial information tested on a Morris water maze in mice. To test whether activation of CREB in the CA3 region is required for memory consolidation of spatial information, bilaterally cannulated mice were infused 18 h before the beginning of the behavioral training with antisense or control sense CREB oligodeoxynucleotides (ODNs) or buffer. Mice were then subjected to massed training in a spatial version of the water maze and tested for retention 0 or 24 h after the last training session. We showed that CREB antisense ODN-infusion in the CA3 region impaired long-term memory when tested 24 h later but had no effect on spatial acquisition or short-term memory tested immediately after behavioral training. These findings provide evidence that the regionally restricted activation of CREB in the dorsal hippocampal CA3 region is critical for the long-term memory consolidation phase of spatial learning but not for short-term memory.

Post-training intrahippocampal injection of synthetic poly-alpha-2,8-sialic acid-neural cell adhesion molecule mimetic peptide improves spatial long-term performance in mice.

Several data have shown that the neural cell adhesion molecule (NCAM) is necessary for long-term memory formation and might play a role in the structural reorganization of synapses. The NCAM, encoded by a single gene, is represented by several isoforms that differ with regard to their content of alpha-2,8-linked sialic acid residues (PSA) on their extracellular domain. The carbohydrate PSA is known to promote plasticity, and PSA-NCAM isoforms remain expressed in the CA3 region of the adult hippocampus. In the present study, we investigated the effect on spatial memory consolidation of a PSA gain of function by injecting a PSA mimetic peptide (termed pr2) into the dorsal hippocampus. Mice were subjected to massed training in the spatial version of the water maze. Five hours after the last training session, experimental mice received an injection of pr2, whereas control mice received PBS or reverse peptide injections in the hippocampal CA3 region. Memory retention was tested at different time intervals: 24 h, 1 wk, and 4 wk. The results showed that the post-training infusion of pr2 peptide significantly increases spatial performance whenever it was assessed after the training phase. By contrast, administration of the control reverse peptide did not affect retention performance. These findings provide evidence that (1) PSA-NCAM is involved in memory consolidation processes in the CA3 hippocampal region, and (2) PSA mimetic peptides can facilitate the formation of long-term spatial memory when injected during the memory consolidation phase.

Co-activation of glutamate and dopamine receptors within the nucleus accumbens is required for spatial memory consolidation in mice.

RATIONALE: The nucleus accumbens receives glutamatergic and dopaminergic inputs converging onto common dendrites. Recent behavioral data demonstrated that intra-accumbens administrations of either glutamate or dopamine (DA) antagonist impair spatial memory consolidation. Thus, also based on the biochemical and molecular findings demonstrating interactions among the different receptors subtypes for glutamate and dopamine, it is conceivable that memory consolidation within this structure might be modulated by glutamate-dopamine receptor interactions. OBJECTIVES: The purpose of this study was to examine the effects of intra-accumbens co-administrations of glutamate and DA antagonists on the consolidation of spatial information. METHODS: On day 1, CD1 male mice were placed in an open field containing five different objects and immediately after three sessions of habituation the animals were injected intra-accumbens with either vehicle or low doses of the N-methyl-D: -aspartate (NMDA; AP-5 50 ng/side), the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; DNQX 5 ng/side), the D1 (SCH23390 12.5 ng/side) and the D2 (sulpiride 25 ng/side) antagonists that were ineffective alone in disrupting object displacement. Separate groups were then focally injected with a combination of one of the glutamate antagonists with one of the dopamine antagonists. Twenty-four hours later, the ability of mice to discriminate object displacement was assessed. RESULTS: Controls and mice injected with ineffective doses of the NMDA, the AMPA, the D1 or the D2 antagonists were always able to react to the object displacement. On the contrary, the groups administered with the different combinations (AP-5 and SCH23390, AP-5 and sulpiride, DNQX and SCH23390, DNQX and sulpiride) of glutamate and dopamine antagonists did not discriminate the spatial change. CONCLUSIONS: These results demonstrate that glutamate-dopamine receptor interactions within the accumbens are essential for the consolidation process of spatial information.

Hippocampal CA3-region is crucial for acquisition and memory consolidation in Morris water maze task in mice.

This experiment investigated the involvement of the dorsal hippocampal CA3-region in the different phases of learning and memory in spatial and non-spatial tasks. To do so, we temporarily inactivated the CA3-subfield by a focal injection of diethyldithiocarbamate (DDC) which chelates most of the heavy metals present in this region. The effects of temporary inactivation of the CA3-region were examined in an associative task, the Morris water maze (MWM). To study the different phase of memory we used a new behavioural massed-procedure founded on four massed training sessions in the spatial and the non-spatial (cue) version of this task. In the spatial version, we showed that a bilateral injection of DDC into the CA3-region impairs the acquisition but not the recall of spatial information. The main result of this study is that the same injection performed immediately after the training session also perturbed memory consolidation. In the cue version of the MWM, we found no difference between the DDC-injected mice and their controls in acquisition or memory consolidation of non-spatial information. These results suggest that the hippocampal CA3-region is essential for spatial memory processes and specifically in memory consolidation of spatial information.