Abstract For over a century, clinicians have consistently described the paradoxical co-existence in posttraumatic stress disorder (PTSD) of sensory intrusive hypermnesia and declarative amnesia for ...the same traumatic event. Although this amnesia is considered as a critical etiological factor of the development and/or persistence of PTSD, most current animal models in basic neuroscience have focused exclusively on the hypermnesia, i.e., the persistence of a strong fear memory, neglecting the qualitative alteration of fear memory. The latest is characterized by an underrepresentation of the trauma in the context-based declarative memory system in favor of its overrepresentation in a cue-based sensory/emotional memory system. Combining psychological and neurobiological data as well as theoretical hypotheses, this review supports the idea that contextual amnesia is at the core of PTSD and its persistence and that altered hippocampal-amygdalar interaction may contribute to such pathologic memory. In a first attempt to unveil the neurobiological alterations underlying PTSD-related hypermnesia/amnesia, we describe a recent animal model mimicking in mice some critical aspects of such abnormal fear memory. Finally, this line of argument emphasizes the pressing need for a systematic comparison between normal/adaptive versus abnormal/maladaptive fear memory to identify biomarkers of PTSD while distinguishing them from general stress-related, potentially adaptive, neurobiological alterations.
Abstract
Post-traumatic stress disorder (PTSD) is characterized by emotional hypermnesia on which preclinical studies focus so far. While this hypermnesia relates to salient traumatic cues, partial ...amnesia for the traumatic context can also be observed. Here, we show in mice that contextual amnesia is causally involved in PTSD-like memory formation, and that treating the amnesia by re-exposure to all trauma-related cues cures PTSD-like hypermnesia. These findings open a therapeutic perspective based on trauma contextualization and the underlying hippocampal mechanisms.
A cardinal feature of Post-traumatic stress-related disorder (PTSD) is a paradoxical memory alteration including both intrusive emotional hypermnesia and declarative/contextual amnesia. Most ...preclinical, but also numerous clinical, studies focus almost exclusively on the emotional hypermnesia aiming at suppressing this recurrent and highly debilitating symptom either by reducing fear and anxiety or with the ethically questionable idea of a rather radical erasure of traumatic memory. Of very mixed efficacy, often associated with a resurgence of symptoms after a while, these approaches focus on PTSD-related symptom while neglecting the potential cause of this symptom: traumatic amnesia. Two of our preclinical studies have recently demonstrated that treating contextual amnesia durably prevents, and even treats, PTSD-related hypermnesia. Specifically, promoting the contextual memory of the trauma, either by a cognitivo-behavioral, optogenetic or pharmacological approach enhancing a hippocampus-dependent memory processing of the trauma normalizes the fear memory by inducing a long-lasting suppression of the erratic traumatic hypermnesia.
Posttraumatic stress disorder (PTSD) is characterized by a hypermnesia of the trauma and by a memory impairment that decreases the ability to restrict fear to the appropriate context. Infusion of ...glucocorticoids in the hippocampus after fear conditioning induces PTSD-like memory impairments and an altered pattern of neural activation in the hippocampal-amygdalar circuit. Mice become unable to identify the context as the correct predictor of the threat and show fear responses to a discrete cue not predicting the threat in normal conditions. These data demonstrate PTSD-like memory impairments in rodents and identify a potential pathophysiological mechanism of this condition.
This scientific commentary refers to ‘Silencing of amygdala circuits during sepsis prevents the development of anxiety-related behaviours’, by Bourhy et al. (https://doi.org/10.1093/brain/awab475).
A cardinal feature of post-traumatic stress disorder (PTSD) is a long-lasting paradoxical alteration of memory with hypermnesia for salient traumatic cues and amnesia for peri-traumatic contextual ...cues. So far, pharmacological therapeutic approach of this stress-related disorder is poorly developed mainly because of the lack of animal model for this paradoxical memory alteration. Using a model that precisely recapitulates the two memory components of PTSD in mice, we tested if brexpiprazole, a new antipsychotic drug with pro-cognitive effects in rodents, may persistently prevent the expression of PTSD-like memory induced by injection of corticosterone immediately after fear conditioning. Acute administration of brexpiprazole (0.3 mg/kg) 7 days' post-trauma first blocks the expression of the maladaptive fear memory for a salient but irrelevant trauma-related cue. In addition, it enhances (with superior efficacy when compared to diazepam, prazosin, and escitalopram) memory for the traumatic context, correct predictor of the threat. This beneficial effect of brexpiprazole is overall maintained 1 week after treatment. In contrast brexpiprazole fully spares normal/adaptive cued fear memory, showing that the effect of this drug is specific to an abnormal/maladaptive (PTSD-like) fear memory of a salient cue. Finally, this treatment not only promotes the switch from PTSD-like to normal fear memory, but also normalizes most of the alterations in the hippocampal-amygdalar network activation associated with PTSD-like memory, as measured by C-Fos expression. Altogether, these preclinical data indicate that brexpiprazole could represent a new pharmacological treatment of PTSD promoting the normalization of traumatic memory.
Memory impairment is one of the disabling manifestations of multiple sclerosis (MS) possibly present from the early stages of the disease and for which there is no specific treatment. Hippocampal ...synaptic dysfunction and dendritic loss, associated with microglial activation, can underlie memory deficits, yet the molecular mechanisms driving such hippocampal neurodegeneration need to be elucidated. In early-stage experimental autoimmune encephalomyelitis (EAE) female mice, we assessed the expression level of molecules involved in microglia-neuron interactions within the dentate gyrus and found overexpression of genes of the complement pathway. Compared to sham immunized mice, the central element of the complement cascade, C3, showed the strongest and 10-fold upregulation, while there was no increase of downstream factors such as the terminal component C5. The combination of in situ hybridization with immunofluorescence showed that C3 transcripts were essentially produced by activated microglia. Pharmacological inhibition of C3 activity, by daily administration of rosmarinic acid, was sufficient to prevent early dendritic loss, microglia-mediated phagocytosis of synapses in the dentate gyrus, and memory impairment in EAE mice, while morphological markers of microglial activation were still observed. In line, when EAE was induced in C3 deficient mice (C3KO), dendrites and spines of the dentate gyrus as well as memory abilities were preserved. Altogether, these data highlight the central role of microglial C3 in early hippocampal neurodegeneration and memory impairment in EAE and, therefore, pave the way toward new neuroprotective strategies in MS to prevent cognitive deficit using complement inhibitors.
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•Complement cascade, especially C3, is upregulated in EAE dentate gyrus.•Microglia is the main source of C3 production in EAE dentate gyrus.•C3 inhibition reduces microglial dependent synaptic loss in EAE dentate gyrus.•C3 inhibition preserves memory performances in EAE mice.
Injection of corticosterone (CORT) in the dorsal hippocampus (DH) can mimic post-traumatic stress disorder (PTSD)-related memory in mice: both maladaptive hypermnesia for a salient but irrelevant ...simple cue and amnesia for the traumatic context. However, accumulated evidence indicates a functional dissociation within the hippocampus such that contextual learning is primarily associated with the DH while emotional processes are more linked to the ventral hippocampus (VH). This suggests that CORT might have different effects on fear memories as a function of the hippocampal sector preferentially targeted, and the type of fear learning (contextual vs. cued) considered. We tested this hypothesis in mice using CORT infusion into the DH or VH after fear conditioning, during which a tone was either paired (predicting-tone) or unpaired (predicting-context) with the shock. We first replicate our previous results showing that intra-DH CORT infusion impairs contextual fear conditioning while inducing fear responses to the not predictive tone. Second, we show that, in contrast, intra-VH CORT infusion has opposite effects on fear memories: in the predicting-tone situation, it blocks tone fear conditioning while enhancing the fear responses to the context. In both situations, a false fear memory is formed based on an erroneous selection of the predictor of the threat. Third, these opposite effects of CORT on fear memory are both mediated by glucocorticoid receptors (GRs) activation, and reproduced by post-conditioning stress or systemic CORT injection. These findings demonstrate that false opposing fear memories can be produced depending on the hippocampal sector in which the GRs are activated.
A rising concern in autism spectrum disorder (ASD) is the heightened sensitivity to trauma, the potential consequences of which have been overlooked, particularly upon the severity of the ASD traits. ...We first demonstrate a reciprocal relationship between ASD and post-traumatic stress disorder (PTSD) and reveal that exposure to a mildly stressful event induces PTSD-like memory in four mouse models of ASD. We also establish an unanticipated consequence of stress, as the formation of PTSD-like memory leads to the aggravation of core autistic traits. Such a susceptibility to developing PTSD-like memory in ASD stems from hyperactivation of the prefrontal cortex and altered fine-tuning of parvalbumin interneuron firing. Traumatic memory can be treated by recontextualization, reducing the deleterious effects on the core symptoms of ASD in the Cntnap2 KO mouse model. This study provides a neurobiological and psychological framework for future examination of the impact of PTSD-like memory in autism.
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•This study demonstrates a reciprocal relationship between ASD and PTSD-like memory•Recontextualization constitutes a behavioral strategy to treat PTSD-related amnesia•Recontextualization rescues PTSD-like memory in ASD and aggravation of core traits•Prefrontal parvalbumin interneurons are a target to treat PTSD-like memory in ASD
Behavioral neuroscience; Molecular neuroscience; Cellular neuroscience
Many of the behavioral consequences of stress are mediated by the activation of the glucocorticoid receptor by stress-induced high levels of glucocorticoid hormones. To explore the molecular ...mechanisms of these effects, we combined in vivo and in vitro approaches. We analyzed mice carrying a brain-specific mutation (GR(NesCre)) in the glucocorticoid receptor gene (GR, also called Nr3c1) and cell lines that either express endogenous glucocorticoid receptor or carry a constitutively active form of the receptor (DeltaGR) that can be transiently induced. In the hippocampus of the wild-type corrected mice after stress, as well as in the cell lines, activation of glucocorticoid receptors greatly increased the expression and enzymatic activity of proteins in the MAPK signaling pathway and led to an increase in the levels of both Egr-1 mRNA and protein. In parallel, inhibition of the MAPK pathway within the hippocampus abolished the increase in contextual fear conditioning induced by glucocorticoids. The present results provide a molecular mechanism for the stress-related effects of glucocorticoids on fear memories.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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