Abstract:
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.

Abstract:
One of the cardinal features of post-traumatic stress disorder (PTSD) is a paradoxical memory alteration including both emotional hypermnesia for salient trauma-related cues and amnesia for the surrounding traumatic context. Interestingly, some clinical studies have suggested that contextual amnesia would causally contribute to the PTSD-related hypermnesia insofar as decontextualized, traumatic memory is prone to be reactivated in contexts that can be very different from the original traumatic context. However, most current animal models of PTSD-related memory focus exclusively on the emotional hypermnesia, i.e., the persistence of a strong fear memory, and do not distinguish normal (adaptive) from pathological (PTSD-like) fear memory, leaving unexplored the hypothetical critical role of contextual amnesia in PTSD-related memory formation, and thus challenging the development of innovative treatments. Having developed the first animal model that precisely recapitulates the two memory components of PTSD in mice (emotional hypermnesia and contextual amnesia), we recently demonstrated that contextual amnesia, induced by optogenetic inhibition of the hippocampus (dorsal CA1), is a causal cognitive process of PTSD-like hypermnesia formation. Moreover, the hippocampus-dependent contextualization of traumatic memory, by optogenetic activation of dCA1 in traumatic condition, prevents PTSD-like hypermnesia formation. Finally, once PTSD-like memory has been formed, the re-contextualization of traumatic memory by its reactivation in the original traumatic context normalizes this pathological fear memory. Revealing the key role of contextual amnesia in PTSD-like memory, this procedure opens a therapeutic perspective based on trauma contextualization and the underlying hippocampal mechanisms.

Abstract:
Obesity is a chronic condition associated with adverse memory and emotional outcomes in humans and animal models. We have recently demonstrated that post-weaning (i.e., periadolescent) high-fat diet (HFD)-induced obesity has opposite effect on hippocampal and amygdala-dependent memory in rodents: while HFD consumption impairs spatial and relational memory, it enhances cue-dependent emotional memory. However, it is still not clear whether this bidirectional HFD effect on memory is related to bidirectional alterations of hippocampal and amygdala synaptic plasticity and if it is influenced by the duration of diet intake. In the current study, we compared in male rats the impact of 2-3 and 6-7 months of HFD intake starting at weaning, thus covering adolescence, on in vivo long-term potentiation (LTP) recorded simultaneously in the hippocampal area CA1 and the basolateral amygdala (BLA). As expected, 6-7 months of HFD intake abolished LTP in the CA1 and enhanced LTP in the BLA. However, 2-3 months of of HFD exposure enhanced LTP in both CA1 and BLA suggesting a transient compensatory mechanism in hippocampus. These results indicate that post-weaning HFD intake progressively leads to bidirectional modulation of hippocampal and amygdala synaptic plasticity, as we previously demonstrated for related memory processes, yet with a different temporal dynamic.

Abstract:
GluN2B subunits of NMDA receptors have been proposed as a target for treating age-related memory decline. They are indeed considered as crucial for hippocampal synaptic plasticity and hippocampus-dependent memory formation, which are both altered in aging. Because a synaptic enrichment in GluN2B is associated with hippocampal LTP in vitro, a similar mechanism is expected to occur during memory formation. We show instead that a reduction of GluN2B synaptic localization induced by a single-session learning in dorsal CA1 apical dendrites is predictive of efficient memorization of a temporal association. Furthermore, synaptic accumulation of GluN2B, rather than insufficient synaptic localization of these subunits, is causally involved in the age-related impairment of memory. These challenging data identify extra-synaptic redistribution of GluN2B-containing NMDAR induced by learning as a molecular signature of memory formation and indicate that modulating GluN2B synaptic localization might represent a useful therapeutic strategy in cognitive aging.

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.

Abstract:
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.

Abstract:
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 whereas 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 receptor (GR) 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.

Abstract:
Memory impairment is an early and disabling manifestation of multiple sclerosis whose anatomical and biological substrates are still poorly understood. We thus investigated whether memory impairment encountered at the early stage of the disease could be explained by a differential vulnerability of particular hippocampal subfields. By using experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, we identified that early memory impairment was associated with selective alteration of the dentate gyrus as pinpointed in vivo with diffusion-tensor-imaging (DTI). Neuromorphometric analyses and electrophysiological recordings confirmed dendritic degeneration, alteration in glutamatergic synaptic transmission and impaired long-term synaptic potentiation selectively in the dentate gyrus, but not in CA1, together with a more severe pattern of microglial activation in this subfield. Systemic injections of the microglial inhibitor minocycline prevented DTI, morphological, electrophysiological and behavioral impairments in EAE-mice. Furthermore, daily infusions of minocycline specifically within the dentate gyrus were sufficient to prevent memory impairment in EAE-mice while infusions of minocycline within CA1 were inefficient. We conclude that early memory impairment in EAE is due to a selective disruption of the dentate gyrus associated with microglia activation. These results open new pathophysiological, imaging, and therapeutic perspectives for memory impairment in multiple sclerosis.