RESUMEN
Memories initially formed in hippocampus gradually stabilize to cortex over weeks-to-months for long-term storage. The mechanistic details of this brain re-organization remain poorly understood. We recorded bulk neural activity in circuits that link hippocampus and cortex as mice performed a memory-guided virtual-reality task over weeks. We identified a prominent and sustained neural correlate of memory in anterior thalamus, whose inhibition substantially disrupted memory consolidation. More strikingly, gain amplification enhanced consolidation of otherwise unconsolidated memories. To gain mechanistic insights, we developed a technology for simultaneous cellular-resolution imaging of hippocampus, thalamus, and cortex throughout consolidation. We found that whereas hippocampus equally encodes multiple memories, the anteromedial thalamus preferentially encodes salient memories, and gradually increases correlations with cortex to facilitate tuning and synchronization of cortical ensembles. We thus identify a thalamo-cortical circuit that gates memory consolidation and propose a mechanism suitable for the selection and stabilization of hippocampal memories into longer-term cortical storage.
Asunto(s)
Consolidación de la Memoria , Memoria a Largo Plazo , Ratones , Animales , Memoria a Largo Plazo/fisiología , Tálamo/fisiología , Hipocampo/fisiología , Consolidación de la Memoria/fisiología , EncéfaloRESUMEN
We talk to first author Emily R. Feierman and corresponding author Erica Korb about the journey toward their paper "Histone variant H2BE enhances chromatin accessibility in neurons to promote synaptic gene expression and long-term memory" (this issue of Molecular Cell) and changes smoothing the road for women in science.
Asunto(s)
Histonas , Humanos , Histonas/metabolismo , Histonas/genética , Historia del Siglo XXI , Historia del Siglo XX , Cromatina/metabolismo , Cromatina/genética , Neuronas/metabolismo , Animales , Memoria a Largo Plazo/fisiología , FemeninoRESUMEN
Histone proteins affect gene expression through multiple mechanisms, including through exchange with histone variants. Recent findings link histone variants to neurological disorders, yet few are well studied in the brain. Most notably, widely expressed variants of H2B remain elusive. We applied recently developed antibodies, biochemical assays, and sequencing approaches to reveal broad expression of the H2B variant H2BE and defined its role in regulating chromatin structure, neuronal transcription, and mouse behavior. We find that H2BE is enriched at promoters, and a single unique amino acid allows it to dramatically enhance chromatin accessibility. Further, we show that H2BE is critical for synaptic gene expression and long-term memory. Together, these data reveal a mechanism linking histone variants to chromatin accessibility, transcriptional regulation, neuronal function, and memory. This work further identifies a widely expressed H2B variant and uncovers a single histone amino acid with profound effects on genomic structure.
Asunto(s)
Cromatina , Histonas , Memoria a Largo Plazo , Neuronas , Sinapsis , Histonas/metabolismo , Histonas/genética , Animales , Cromatina/metabolismo , Cromatina/genética , Memoria a Largo Plazo/fisiología , Neuronas/metabolismo , Ratones , Sinapsis/metabolismo , Sinapsis/genética , Regiones Promotoras Genéticas , Ratones Endogámicos C57BL , Regulación de la Expresión Génica , Transcripción Genética , Masculino , HumanosRESUMEN
A central assumption of neuroscience is that long-term memories are represented by the same brain areas that encode sensory stimuli1. Neurons in inferotemporal (IT) cortex represent the sensory percept of visual objects using a distributed axis code2-4. Whether and how the same IT neural population represents the long-term memory of visual objects remains unclear. Here we examined how familiar faces are encoded in the IT anterior medial face patch (AM), perirhinal face patch (PR) and temporal pole face patch (TP). In AM and PR we observed that the encoding axis for familiar faces is rotated relative to that for unfamiliar faces at long latency; in TP this memory-related rotation was much weaker. Contrary to previous claims, the relative response magnitude to familiar versus unfamiliar faces was not a stable indicator of familiarity in any patch5-11. The mechanism underlying the memory-related axis change is likely intrinsic to IT cortex, because inactivation of PR did not affect axis change dynamics in AM. Overall, our results suggest that memories of familiar faces are represented in AM and perirhinal cortex by a distinct long-latency code, explaining how the same cell population can encode both the percept and memory of faces.
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Reconocimiento Facial , Memoria a Largo Plazo , Reconocimiento en Psicología , Lóbulo Temporal , Animales , Cara , Reconocimiento Facial/fisiología , Macaca mulatta/fisiología , Memoria a Largo Plazo/fisiología , Neuronas/fisiología , Corteza Perirrinal/fisiología , Corteza Perirrinal/citología , Estimulación Luminosa , Reconocimiento en Psicología/fisiología , Lóbulo Temporal/anatomía & histología , Lóbulo Temporal/citología , Lóbulo Temporal/fisiología , RotaciónRESUMEN
Social communication guides decision-making, which is essential for survival. Social transmission of food preference (STFP) is an ecologically relevant memory paradigm in which an animal learns a desirable food odour from another animal in a social context, creating a long-term memory1,2. How food-preference memory is acquired, consolidated and stored is unclear. Here we show that the posteromedial nucleus of the cortical amygdala (COApm) serves as a computational centre in long-term STFP memory consolidation by integrating social and sensory olfactory inputs. Blocking synaptic signalling by the COApm-based circuit selectively abolished STFP memory consolidation without impairing memory acquisition, storage or recall. COApm-mediated STFP memory consolidation depends on synaptic inputs from the accessory olfactory bulb and on synaptic outputs to the anterior olfactory nucleus. STFP memory consolidation requires protein synthesis, suggesting a gene-expression mechanism. Deep single-cell and spatially resolved transcriptomics revealed robust but distinct gene-expression signatures induced by STFP memory formation in the COApm that are consistent with synapse restructuring. Our data thus define a neural circuit for the consolidation of a socially communicated long-term memory, thereby mechanistically distinguishing protein-synthesis-dependent memory consolidation from memory acquisition, storage or retrieval.
Asunto(s)
Amígdala del Cerebelo , Preferencias Alimentarias , Consolidación de la Memoria , Memoria a Largo Plazo , Conducta Social , Animales , Masculino , Ratones , Amígdala del Cerebelo/fisiología , Amígdala del Cerebelo/citología , Consolidación de la Memoria/fisiología , Memoria a Largo Plazo/fisiología , Ratones Endogámicos C57BL , Odorantes/análisis , Bulbo Olfatorio/fisiología , Bulbo Olfatorio/citología , Análisis de la Célula Individual , Sinapsis/metabolismo , Transcriptoma , Preferencias Alimentarias/fisiología , Preferencias Alimentarias/psicologíaRESUMEN
Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala is a centre of salience networks that underlie emotional experiences and thus has a key role in long-term fear memory formation1. Here we used spatial and single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide and BDNF signalling, MAPK and CREB activation, ubiquitination pathways, and synaptic connectivity as key components of long-term memory. Notably, upon long-term memory formation, a neuronal subpopulation defined by increased Penk and decreased Tac expression constituted the most prominent component of the memory engram of the basolateral amygdala. These transcriptional changes were observed both with single-cell RNA sequencing and with single-molecule spatial transcriptomics in intact slices, thereby providing a rich spatial map of a memory engram. The spatial data enabled us to determine that this neuronal subpopulation interacts with adjacent astrocytes, and functional experiments show that neurons require interactions with astrocytes to encode long-term memory.
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Astrocitos , Comunicación Celular , Perfilación de la Expresión Génica , Memoria a Largo Plazo , Neuronas , Astrocitos/citología , Astrocitos/metabolismo , Astrocitos/fisiología , Complejo Nuclear Basolateral/citología , Complejo Nuclear Basolateral/metabolismo , Complejo Nuclear Basolateral/fisiología , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Memoria a Largo Plazo/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Neuronas/citología , Neuronas/metabolismo , Neuronas/fisiología , Análisis de Secuencia de ARN , Imagen Individual de Molécula , Análisis de Expresión Génica de una Sola Célula , UbiquitinaciónRESUMEN
An enduring problem in neuroscience is determining whether cases of amnesia result from eradication of the memory trace (storage impairment) or if the trace is present but inaccessible (retrieval impairment). The most direct approach to resolving this question is to quantify changes in the brain mechanisms of long-term memory (BM-LTM). This approach argues that if the amnesia is due to a retrieval failure, BM-LTM should remain at levels comparable to trained, unimpaired animals. Conversely, if memories are erased, BM-LTM should be reduced to resemble untrained levels. Here we review the use of BM-LTM in a number of studies that induced amnesia by targeting memory maintenance or reconsolidation. The literature strongly suggests that such amnesia is due to storage rather than retrieval impairments. We also describe the shortcomings of the purely behavioral protocol that purports to show recovery from amnesia as a method of understanding the nature of amnesia.
Asunto(s)
Amnesia/fisiopatología , Encéfalo/fisiopatología , Disfunción Cognitiva/fisiopatología , Memoria a Largo Plazo/fisiología , Animales , Humanos , Mantenimiento , Memoria a Corto Plazo/fisiologíaRESUMEN
The abundance of distractors in the world poses a major challenge to our brain's limited processing capacity, but little is known about how selective attention modulates stimulus representations in the brain to reduce interference and support durable target memory. Here, we collected functional magnetic resonance imaging (fMRI) data in a selective attention task in which target and distractor pictures of different visual categories were simultaneously presented. Participants were asked to selectively process the target according to the effective cue, either before the encoding period (i.e., perceptual attention) or the maintenance period (i.e., reflective attention). On the next day, participants were asked to perform a memory recognition task in the scanner in which the targets, distractors, and novel items were presented in a pseudorandom order. Behavioral results showed that perceptual attention was better at enhancing target memory and reducing distractor memory than reflective attention, although the overall memory capacity (memory for both target and distractor) was comparable. Using multiple-voxel pattern analysis of the neural data, we found more robust target representation and weaker distractor representation in working memory for perceptual attention than for reflective attention. Interestingly, perceptual attention partially shifted the regions involved in maintaining the target representation from the visual cortex to the parietal cortex. Furthermore, the targets and distractors simultaneously presented in the perceptual attention condition showed reduced pattern similarity in the parietal cortex during retrieval compared to items not presented together. This neural pattern repulsion positively correlated with individuals' recognition of both targets and distractors. These results emphasize the critical role of selective attention in transforming memory representations to reduce interference and improve long-term memory performance.
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Atención , Imagen por Resonancia Magnética , Memoria a Largo Plazo , Memoria a Corto Plazo , Lóbulo Parietal , Humanos , Atención/fisiología , Lóbulo Parietal/fisiología , Masculino , Memoria a Corto Plazo/fisiología , Femenino , Memoria a Largo Plazo/fisiología , Adulto , Adulto Joven , Objetivos , Mapeo Encefálico , Estimulación Luminosa/métodos , Percepción Visual/fisiologíaRESUMEN
Orb2 the Drosophila homolog of cytoplasmic polyadenylation element binding (CPEB) protein forms prion-like oligomers. These oligomers consist of Orb2A and Orb2B isoforms and their formation is dependent on the oligomerization of the Orb2A isoform. Drosophila with a mutation diminishing Orb2A's prion-like oligomerization forms long-term memory but fails to maintain it over time. Since this prion-like oligomerization of Orb2A plays a crucial role in the maintenance of memory, here, we aim to find what regulates this oligomerization. In an immunoprecipitation-based screen, we identify interactors of Orb2A in the Hsp40 and Hsp70 families of proteins. Among these, we find an Hsp40 family protein Mrj as a regulator of the conversion of Orb2A to its prion-like form. Mrj interacts with Hsp70 proteins and acts as a chaperone by interfering with the aggregation of pathogenic Huntingtin. Unlike its mammalian homolog, we find Drosophila Mrj is neither an essential gene nor causes any gross neurodevelopmental defect. We observe a loss of Mrj results in a reduction in Orb2 oligomers. Further, Mrj knockout exhibits a deficit in long-term memory and our observations suggest Mrj is needed in mushroom body neurons for the regulation of long-term memory. Our work implicates a chaperone Mrj in mechanisms of memory regulation through controlling the oligomerization of Orb2A and its association with the translating ribosomes.
Asunto(s)
Proteínas de Drosophila , Proteínas del Choque Térmico HSP40 , Memoria a Largo Plazo , Animales , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas del Choque Térmico HSP40/metabolismo , Proteínas del Choque Térmico HSP40/genética , Proteínas HSP70 de Choque Térmico/metabolismo , Proteínas HSP70 de Choque Térmico/genética , Memoria a Largo Plazo/fisiología , Factores de Escisión y Poliadenilación de ARNm/metabolismo , Factores de Escisión y Poliadenilación de ARNm/genética , Cuerpos Pedunculados/metabolismo , Multimerización de Proteína , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismoRESUMEN
Active forgetting is an essential component of the memory management system of the brain1. Forgetting can be permanent, in which prior memory is lost completely, or transient, in which memory exists in a temporary state of impaired retrieval. Temporary blocks on memory seem to be universal, and can disrupt an individual's plans, social interactions and ability to make rapid, flexible and appropriate choices. However, the neurobiological mechanisms that cause transient forgetting are unknown. Here we identify a single dopamine neuron in Drosophila that mediates the memory suppression that results in transient forgetting. Artificially activating this neuron did not abolish the expression of long-term memory. Instead, it briefly suppressed memory retrieval, with the memory becoming accessible again over time. The dopamine neuron modulates memory retrieval by stimulating a unique dopamine receptor that is expressed in a restricted physical compartment of the axons of mushroom body neurons. This mechanism for transient forgetting is triggered by the presentation of interfering stimuli immediately before retrieval.
Asunto(s)
Dopamina/metabolismo , Neuronas Dopaminérgicas/fisiología , Drosophila melanogaster/fisiología , Recuerdo Mental/fisiología , Animales , Sistema Nervioso Central/citología , Sistema Nervioso Central/fisiología , Condicionamiento Psicológico , Dendritas/fisiología , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citología , Estimulación Eléctrica , Femenino , Memoria a Largo Plazo/fisiología , Cuerpos Pedunculados/citología , Cuerpos Pedunculados/fisiología , Odorantes , Receptores de Dopamina D1/metabolismo , Factores de TiempoRESUMEN
Insects rely on path integration (vector-based navigation) and landmark guidance to perform sophisticated navigational feats, rivaling those seen in mammals. Bees in particular exhibit complex navigation behaviors including creating optimal routes and novel shortcuts between locations, an ability historically indicative of the presence of a cognitive map. A mammalian cognitive map has been widely accepted. However, in insects, the existence of a centralized cognitive map is highly contentious. Using a controlled laboratory assay that condenses foraging behaviors to short distances in walking bumblebees, we reveal that vectors learned during path integration can be transferred to long-term memory, that multiple such vectors can be stored in parallel, and that these vectors can be recalled at a familiar location and used for homeward navigation. These findings demonstrate that bees meet the two fundamental requirements of a vector-based analog of a decentralized cognitive map: Home vectors need to be stored in long-term memory and need to be recalled from remembered locations. Thus, our data demonstrate that bees possess the foundational elements for a vector-based map. By utilizing this relatively simple strategy for spatial organization, insects may achieve high-level navigation behaviors seen in vertebrates with the limited number of neurons in their brains, circumventing the computational requirements associated with the cognitive maps of mammals.
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Encéfalo , Navegación Espacial , Animales , Abejas/fisiología , Encéfalo/fisiología , Navegación Espacial/fisiología , Memoria/fisiología , Memoria a Largo Plazo/fisiología , Cognición/fisiologíaRESUMEN
The integrated stress response (ISR), a pivotal protein homeostasis network, plays a critical role in the formation of long-term memory (LTM). The precise mechanism by which the ISR controls LTM is not well understood. Here, we report insights into how the ISR modulates the mnemonic process by using targeted deletion of the activating transcription factor 4 (ATF4), a key downstream effector of the ISR, in various neuronal and non-neuronal cell types. We found that the removal of ATF4 from forebrain excitatory neurons (but not from inhibitory neurons, cholinergic neurons, or astrocytes) enhances LTM formation. Furthermore, the deletion of ATF4 in excitatory neurons lowers the threshold for the induction of long-term potentiation, a cellular model for LTM. Transcriptomic and proteomic analyses revealed that ATF4 deletion in excitatory neurons leads to upregulation of components of oxidative phosphorylation pathways, which are critical for ATP production. Thus, we conclude that ATF4 functions as a memory repressor selectively within excitatory neurons.
Asunto(s)
Factor de Transcripción Activador 4 , Memoria a Largo Plazo , Neuronas , Animales , Ratones , Factor de Transcripción Activador 4/metabolismo , Factor de Transcripción Activador 4/genética , Astrocitos/metabolismo , Potenciación a Largo Plazo , Memoria a Largo Plazo/fisiología , Ratones Noqueados , Neuronas/metabolismo , Prosencéfalo/metabolismo , MasculinoRESUMEN
The role of gene expression during learning and in short-term memories has been studied extensively1-3, but less is known about remote memories, which can persist for a lifetime4. Here we used long-term contextual fear memory as a paradigm to probe the single-cell gene expression landscape that underlies remote memory storage in the medial prefrontal cortex. We found persistent activity-specific transcriptional alterations in diverse populations of neurons that lasted for weeks after fear learning. Out of a vast plasticity-coding space, we identified genes associated with membrane fusion that could have important roles in the maintenance of remote memory. Unexpectedly, astrocytes and microglia also acquired persistent gene expression signatures that were associated with remote memory, suggesting that they actively contribute to memory circuits. The discovery of gene expression programmes associated with remote memory engrams adds an important dimension of activity-dependent cellular states to existing brain taxonomy atlases and sheds light on the elusive mechanisms of remote memory storage.
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Regulación de la Expresión Génica , Consolidación de la Memoria , Memoria a Largo Plazo/fisiología , Transcripción Genética , Animales , Astrocitos/metabolismo , Biomarcadores/análisis , Exocitosis , Miedo/fisiología , Masculino , Ratones , Microglía/metabolismo , Neuronas/clasificación , Neuronas/citología , Neuronas/metabolismo , Corteza Prefrontal/citología , Corteza Prefrontal/fisiología , Análisis de la Célula Individual , Factores de TiempoRESUMEN
Transforming growth factor ß (TGFß) is required for long-term memory (LTM) for sensitization in Aplysia. When LTM is induced using a two-trial training protocol, TGFß inhibition only blocks LTM when administrated at the second, not the first trial. Here, we show that TGFß acts as a "repetition detector" during the induction of two-trial LTM. Secretion of the biologically inert TGFß proligand must coincide with its proteolytic activation by the Bone morphogenetic protein-1 (BMP-1/Tolloid) metalloprotease, which occurs specifically during trial two of our two-trial training paradigm. This paradigm establishes long-term synaptic facilitation (LTF), the cellular correlate of LTM. BMP-1 application paired with a single serotonin (5HT) pulse induced LTF, whereas neither a single 5HT pulse nor BMP-1 alone effectively did so. On the other hand, inhibition of endogenous BMP-1 activity blocked the induction of two-trial LTF. These results suggest a unique role for TGFß in the interaction of repeated trials: during learning, repeated stimuli engage separate steps of the TGFß cascade that together are necessary for the induction of long-lasting memories.
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Potenciación a Largo Plazo , Factor de Crecimiento Transformador beta , Animales , Potenciación a Largo Plazo/fisiología , Factor de Crecimiento Transformador beta/farmacología , Plasticidad Neuronal/fisiología , Memoria a Largo Plazo/fisiología , Aplysia/fisiologíaRESUMEN
Activation of neuronal protein synthesis upon learning is critical for the formation of long-term memory. Here, we report that learning in the contextual fear conditioning paradigm engenders a decrease in eIF2α (eukaryotic translation initiation factor 2) phosphorylation in astrocytes in the hippocampal CA1 region, which promotes protein synthesis. Genetic reduction of eIF2α phosphorylation in hippocampal astrocytes enhanced contextual and spatial memory and lowered the threshold for the induction of long-lasting plasticity by modulating synaptic transmission. Thus, learning-induced dephosphorylation of eIF2α in astrocytes bolsters hippocampal synaptic plasticity and consolidation of long-term memories.
Asunto(s)
Astrocitos , Potenciación a Largo Plazo , Potenciación a Largo Plazo/fisiología , Plasticidad Neuronal/genética , Hipocampo/fisiología , Biosíntesis de Proteínas , Región CA1 Hipocampal , Memoria a Largo Plazo/fisiologíaRESUMEN
The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.
Asunto(s)
Hipocampo , Discapacidad Intelectual , Histona Demetilasas con Dominio de Jumonji , Consolidación de la Memoria , Memoria a Largo Plazo , Animales , Hipocampo/metabolismo , Ratones , Masculino , Femenino , Discapacidad Intelectual/genética , Histona Demetilasas con Dominio de Jumonji/genética , Histona Demetilasas con Dominio de Jumonji/metabolismo , Consolidación de la Memoria/fisiología , Memoria a Largo Plazo/fisiología , Potenciación a Largo Plazo/genética , Potenciación a Largo Plazo/fisiología , Ratones Endogámicos C57BL , Proteínas de Unión al ADNRESUMEN
Adaptive behavior relies both on specific rules that vary across situations and stable long-term knowledge gained from experience. The frontoparietal control network (FPCN) is implicated in the brain's ability to balance these different influences on action. Here, we investigate how the topographical organization of the cortex supports behavioral flexibility within the FPCN. Functional properties of this network might reflect its juxtaposition between the dorsal attention network (DAN) and the default mode network (DMN), two large-scale systems implicated in top-down attention and memory-guided cognition, respectively. Our study tests whether subnetworks of FPCN are topographically proximal to the DAN and the DMN, respectively, and how these topographical differences relate to functional differences: the proximity of each subnetwork is anticipated to play a pivotal role in generating distinct cognitive modes relevant to working memory and long-term memory. We show that FPCN subsystems share multiple anatomical and functional similarities with their neighboring systems (DAN and DMN) and that this topographical architecture supports distinct interaction patterns that give rise to different patterns of functional behavior. The FPCN acts as a unified system when long-term knowledge supports behavior but becomes segregated into discrete subsystems with different patterns of interaction when long-term memory is less relevant. In this way, our study suggests that the topographical organization of the FPCN and the connections it forms with distant regions of cortex are important influences on how this system supports flexible behavior.
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Encéfalo , Red Nerviosa , Humanos , Masculino , Femenino , Adulto , Red Nerviosa/fisiología , Red Nerviosa/diagnóstico por imagen , Encéfalo/fisiología , Imagen por Resonancia Magnética , Atención/fisiología , Adulto Joven , Red en Modo Predeterminado/fisiología , Red en Modo Predeterminado/diagnóstico por imagen , Memoria a Largo Plazo/fisiología , Mapeo Encefálico/métodos , Lóbulo Parietal/fisiología , Memoria a Corto Plazo/fisiologíaRESUMEN
Chronic stress causes cognitive deficits, such as impairments in episodic-like hippocampus-dependent memory. Stress regulates an opioid-related neuropeptide named Nociceptin/Orphanin FQ (N/OFQ), the ligand of the G protein-coupled receptor NOP. Since this peptide has deleterious effects on memory, we hypothesized that the N/OFQ system could be a mediator of the negative effects of stress on memory. Chronic stress was mimicked by chronic exposure to corticosterone (CORT). The NOP receptor was either acutely blocked using selective antagonists, or knocked-down specifically in the hippocampus using genetic tools. Long-term memory was assessed in the object recognition (OR) and object location (OL) paradigms. Acute injection of NOP antagonists before learning had a negative impact on memory in naive mice whereas it restored memory performances in the chronic stress model. This rescue was associated with a normalization of neuronal cell activity in the CA3 part of the hippocampus. Chronic CORT induced an upregulation of the N/OFQ precursor in the hippocampus. Knock-down of the NOP receptor in the CA3/Dentate Gyrus region prevented memory deficits in the CORT model. These data demonstrate that blocking the N/OFQ system can be beneficial for long-term memory in a neuroendocrine model of chronic stress. We therefore suggest that NOP antagonists could be useful for the treatment of memory deficits in stress-related disorders.
Asunto(s)
Corticosterona , Modelos Animales de Enfermedad , Hipocampo , Memoria a Largo Plazo , Receptor de Nociceptina , Nociceptina , Péptidos Opioides , Receptores Opioides , Estrés Psicológico , Animales , Receptores Opioides/metabolismo , Ratones , Estrés Psicológico/metabolismo , Masculino , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Péptidos Opioides/metabolismo , Memoria a Largo Plazo/efectos de los fármacos , Memoria a Largo Plazo/fisiología , Antagonistas de Narcóticos/farmacología , Ratones Endogámicos C57BL , Cognición/efectos de los fármacos , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/tratamiento farmacológicoRESUMEN
Remote memory usually decreases over time, whereas remote drug-cue associated memory exhibits enhancement, increasing the risk of relapse during abstinence. Memory system consolidation is a prerequisite for remote memory formation, but neurobiological underpinnings of the role of consolidation in the enhancement of remote drug memory are unclear. Here, we found that remote cocaine-cue associated memory was enhanced in rats that underwent self-administration training, together with a progressive increase in the response of prelimbic cortex (PrL) CaMKII neurons to cues. System consolidation was required for the enhancement of remote cocaine memory through PrL CaMKII neurons during the early period post-training. Furthermore, dendritic spine maturation in the PrL relied on the basolateral amygdala (BLA) input during the early period of consolidation, contributing to remote memory enhancement. These findings indicate that memory consolidation drives the enhancement of remote cocaine memory through a time-dependent increase in activity and maturation of PrL CaMKII neurons receiving a sustained BLA input.