Age-related impairment of declarative memory: linking memorization of temporal associations to GluN2B redistribution in dorsal CA1

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

False Opposing Fear Memories Are Produced as a Function of the Hippocampal Sector Where Glucocorticoid Receptors Are Activated

International audienceInjection 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. © Copyright © 2020 Kaouane, Ducourneau, Marighetto, Segal and Desmedt

Effets bénéfiques de la chrononutrition sur les altérations de mémoire associées à l’obésité chez la souris

Une alimentation trop riche en gras et en sucre (HFD) affecte non seulement le métabolisme et le système cardiovasculaire mais aussi le fonctionnement cérébral. Cela est particulièrement préoccupant chez l’adolescent qui montre souvent une alimentation déséquilibrée et chez qui le cerveau est toujours en maturation. Chez la souris, nous avons montré que la consommation d’un régime HFD durant l’adolescence affecte des processus de mémoire associés à l’hippocampe alors que le même régime consommé par un animal adulte n’entraine pas de déficits. La chrononutrition ayant prouvé ses effets bénéfiques sur le métabolisme, nous avons testé ses effets potentiels sur la mémoire chez des souris ayant consommé un régime HFD pendant l’adolescence. Nos résultats montrent que les souris soumises au régime HFD restreint dans le temps ne développe pas les déficits de mémoire observés chez les souris sous régime HFD ad libitum. Afin de comprendre les mécanismes moléculaires impliqués nous avons étudiés l’oscillation circadienne d’un ensemble de gènes exprimés dans l’hippocampe dans les différents groupes expérimentaux. Nous montrons que 49% des gènes montrant une oscillation circadienne sous régime contrôle perdent cette oscillation sous régime HFD ad libitum. Grâce à la chrononutrition 60% de ces gènes récupèrent une rythmicité circadienne. Parmi ces gènes, notre attention s’est focalisée sur le récepteur aux glucocorticoïdes (GR) dont l’implication dans la mémoire est connue. Nous confirmons une hyperactivation du GR hippocampique chez les animaux sous régime HFD ad libitum ainsi que la prévention des déficits de mémoire par blocage pharmacologique du GR

Bidirectional modulation of hippocampal and amygdala synaptic plasticity by post-weaning obesogenic diet intake in male rats: Influence of the duration of diet exposure

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

Preventing and treating PTSD-like memory by trauma contextualization

International audiencePost-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

Role of glucocorticoid signaling in obesity-induced memory alterations in mice

We have previously shown that the consumption of an obesogenic diet during the adolescence period induces memory alterations in adulthood, in particular hippocampus-dependent memory tasks. Because glucocorticoid hormones (GC) regulate memory processes and their receptors (glucocorticoid receptor=GR and mineralocorticoid receptor) are highly expressed in hippocampus, we have examined the potential role of GC in the memory alterations observed in adolescent mice fed a high fat-high sucrose diet (HFD) for 12 weeks compared to age-matched mice fed normal chow. In basal conditions, the circadian secretion of corticosterone was not different between groups after 12 weeks of either diet. However, HFD abolished the circadian oscillatory expression of the GR mRNA in hippocampus. Interestingly, this alteration of circadian gene expression is rescued if the mice under HFD have their food temporally restricted to the active phase for the last 4 weeks of HFD. Hippocampal GR protein and its phosphorylation at serine 211 and Serine 284 was then studied in basal condition and during memory consolidation. Phosphorylation of GR increased both in basal conditions and after contextual fear conditioning, especially at Serine 284 in HFD mice compared to controls. We also studied hippocampal neuronal spine dynamics in wild-type animals and in a mouse knock-in harboring mutation in the Serine 284 phosphorylation site of GR. Wild-type mice under HFD as well as the KI mouse mutant display decreased spine formation and enhanced spine elimination after contextual fear conditioning compared to their respective controls. Finally, to investigate the functional role of hippocampal GR in obesity-induced memory alterations, we infused within the dorsal hippocampus the GR antagonist RU38486 in HFD mice and controls immediately after training of an object recognition memory task, known to be impaired by HFD. Blockade of the GR specifically within hippocampus prevented the long-term memory alterations in HFD fed mice. Overall, these data point to an important role of GR signaling in the memory alterations observed in mice fed HFD during adolescence.This project is supported by Fondation Carrefour and the scientific expertise ensured by the scientific committee of Fédération de Recherche sur le Cerveau

Obesogenic diet induces circuit-specific memory deficits in mice

Obesity is associated with neurocognitive dysfunction, including memory deficits. This is particularly worrisome when obesity occurs during adolescence, a maturational period for brain structures critical for cognition. In rodent models, we recently reported that memory impairments induced by obesogenic high-fat diet (HFD) intake during the periadolescent period can be reversed by chemogenetic manipulation of the ventral hippocampus (vHPC). Here, we used an intersectional viral approach in HFD-fed male mice to chemogenetically inactivate specific vHPC efferent pathways to nucleus accumbens (NAc) or medial prefrontal cortex (mPFC) during memory tasks. We first demonstrated that HFD enhanced activation of both pathways after training and that our chemogenetic approach was effective in normalizing this activation. Inactivation of the vHPC–NAc pathway rescued HFD-induced deficits in recognition but not location memory. Conversely, inactivation of the vHPC–mPFC pathway restored location but not recognition memory impairments produced by HFD. Either pathway manipulation did not affect exploration or anxiety-like behaviour. These findings suggest that HFD intake throughout adolescence impairs different types of memory through overactivation of specific hippocampal efferent pathways and that targeting these overactive pathways has therapeutic potential

Selective dentate gyrus disruption causes memory impairment at the early stage of experimental multiple sclerosis

International audienceMemory 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 minocy-cline 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

Neurobiol Dis

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.Translational Research and Advanced Imaging LaboratoryBordeaux Region Aquitaine Initiative for Neuroscienc