RESUMO
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.
Assuntos
Consolidação da Memória , Memória de Longo Prazo , Camundongos , Animais , Memória de Longo Prazo/fisiologia , Tálamo/fisiologia , Hipocampo/fisiologia , Consolidação da Memória/fisiologia , EncéfaloRESUMO
Myriad experiences produce transient memory, yet, contingent on the internal state of the organism and the saliency of the experience, only some memories persist over time. How experience and internal state influence the duration of memory at the molecular level remains unknown. A self-assembled aggregated state of Drosophila Orb2A protein is required specifically for long-lasting memory. We report that in the adult fly brain the mRNA encoding Orb2A protein exists in an unspliced non-protein-coding form. The convergence of experience and internal drive transiently increases the spliced protein-coding Orb2A mRNA. A screen identified pasilla, the fly ortholog of mammalian Nova-1/2, as a mediator of Orb2A mRNA processing. A single-nucleotide substitution in the intronic region that reduces Pasilla binding and intron removal selectively impairs long-term memory. We posit that pasilla-mediated processing of unspliced Orb2A mRNA integrates experience and internal state to control Orb2A protein abundance and long-term memory formation.
Assuntos
Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Íntrons , Memória de Longo Prazo , Ribonucleoproteínas/metabolismo , Fatores de Transcrição/genética , Fatores de Poliadenilação e Clivagem de mRNA/genética , Animais , Sequência de Bases , Comportamento Animal , Encéfalo/metabolismo , Condicionamento Psicológico , Proteínas de Drosophila/química , Drosophila melanogaster/genética , Aprendizagem , Modelos Animais , Motivação , Mutação , Isoformas de Proteínas/metabolismo , Splicing de RNA , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/química , Fatores de Poliadenilação e Clivagem de mRNA/metabolismoRESUMO
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.
Assuntos
Cromatina , Histonas , Memória de Longo Prazo , Neurônios , Sinapses , Histonas/metabolismo , Histonas/genética , Animais , Cromatina/metabolismo , Cromatina/genética , Memória de Longo Prazo/fisiologia , Neurônios/metabolismo , Camundongos , Sinapses/metabolismo , Sinapses/genética , Regiões Promotoras Genéticas , Camundongos Endogâmicos C57BL , Regulação da Expressão Gênica , Transcrição Gênica , Masculino , HumanosRESUMO
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.
Assuntos
Histonas , Humanos , Histonas/metabolismo , Histonas/genética , História do Século XXI , História do Século XX , Cromatina/metabolismo , Cromatina/genética , Neurônios/metabolismo , Animais , Memória de Longo Prazo/fisiologia , FemininoRESUMO
Dopamine neurons promote learning by processing recent changes in reward values, such that reward may be maximized. However, such a flexible signal is not suitable for habitual behaviors that are sustained regardless of recent changes in reward outcome. We discovered a type of dopamine neuron in the monkey substantia nigra pars compacta (SNc) that retains past learned reward values stably. After reward values of visual objects are learned, these neurons continue to respond differentially to the objects, even when reward is not expected. Responses are strengthened by repeated learning and are evoked upon presentation of the objects long after learning is completed. These "sustain-type" dopamine neurons are confined to the caudal-lateral SNc and project to the caudate tail, which encodes long-term value memories of visual objects and guides gaze automatically to stably valued objects. This population of dopamine neurons thus selectively promotes learning and retention of habitual behavior.
Assuntos
Dopamina/metabolismo , Hábitos , Macaca mulatta/fisiologia , Memória de Longo Prazo , Neurônios/citologia , Animais , Gânglios da Base/fisiologia , Comportamento Animal , Masculino , Neurônios/fisiologia , Fenômenos Fisiológicos OcularesRESUMO
Memories are thought to be formed in response to transient experiences, in part through changes in local protein synthesis at synapses. In Drosophila, the amyloidogenic (prion-like) state of the RNA binding protein Orb2 has been implicated in long-term memory, but how conformational conversion of Orb2 promotes memory formation is unclear. Combining in vitro and in vivo studies, we find that the monomeric form of Orb2 represses translation and removes mRNA poly(A) tails, while the oligomeric form enhances translation and elongates the poly(A) tails and imparts its translational state to the monomer. The CG13928 protein, which binds only to monomeric Orb2, promotes deadenylation, whereas the putative poly(A) binding protein CG4612 promotes oligomeric Orb2-dependent translation. Our data support a model in which monomeric Orb2 keeps target mRNA in a translationally dormant state and experience-dependent conversion to the amyloidogenic state activates translation, resulting in persistent alteration of synaptic activity and stabilization of memory.
Assuntos
Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Memória de Longo Prazo , Fatores de Transcrição/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Regiões 3' não Traduzidas , Proteínas Amiloidogênicas/química , Proteínas Amiloidogênicas/metabolismo , Animais , Proteínas de Drosophila/química , Proteínas de Drosophila/genética , Camundongos , Poliadenilação , Biossíntese de Proteínas , Estrutura Terciária de Proteína , Proteínas de Ligação a RNA/metabolismo , Serina Endopeptidases/genética , Fatores de Transcrição/química , Fatores de Poliadenilação e Clivagem de mRNA/químicaRESUMO
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.
Assuntos
Reconhecimento Facial , Memória de Longo Prazo , Reconhecimento Psicológico , Lobo Temporal , Animais , Face , Reconhecimento Facial/fisiologia , Macaca mulatta/fisiologia , Memória de Longo Prazo/fisiologia , Neurônios/fisiologia , Córtex Perirrinal/fisiologia , Córtex Perirrinal/citologia , Estimulação Luminosa , Reconhecimento Psicológico/fisiologia , Lobo Temporal/anatomia & histologia , Lobo Temporal/citologia , Lobo Temporal/fisiologia , RotaçãoRESUMO
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.
Assuntos
Tonsila do Cerebelo , Preferências Alimentares , Consolidação da Memória , Memória de Longo Prazo , Comportamento Social , Animais , Masculino , Camundongos , Tonsila do Cerebelo/fisiologia , Tonsila do Cerebelo/citologia , Consolidação da Memória/fisiologia , Memória de Longo Prazo/fisiologia , Camundongos Endogâmicos C57BL , Odorantes/análise , Bulbo Olfatório/fisiologia , Bulbo Olfatório/citologia , Análise de Célula Única , Sinapses/metabolismo , Transcriptoma , Preferências Alimentares/fisiologia , Preferências Alimentares/psicologiaRESUMO
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.
Assuntos
Astrócitos , Comunicação Celular , Perfilação da Expressão Gênica , Memória de Longo Prazo , Neurônios , Astrócitos/citologia , Astrócitos/metabolismo , Astrócitos/fisiologia , Complexo Nuclear Basolateral da Amígdala/citologia , Complexo Nuclear Basolateral da Amígdala/metabolismo , Complexo Nuclear Basolateral da Amígdala/fisiologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Memória de Longo Prazo/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Neurônios/citologia , Neurônios/metabolismo , Neurônios/fisiologia , Análise de Sequência de RNA , Imagem Individual de Molécula , Análise da Expressão Gênica de Célula Única , UbiquitinaçãoRESUMO
Traumatic events generate some of the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that, in mice, successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes, which is accompanied by higher metabolic, synaptic, and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata.
Assuntos
Medo , Memória de Longo Prazo , Plasticidade Neuronal , Animais , Epigênese Genética , Hipocampo/metabolismo , Histona Desacetilase 2/metabolismo , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Masculino , Memória de Longo Prazo/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , TranscriptomaRESUMO
Systems consolidation-a process for long-term memory stabilization-has been hypothesized to occur in two stages1-4. Whereas new memories require the hippocampus5-9, they become integrated into cortical networks over time10-12, making them independent of the hippocampus. How hippocampal-cortical dialogue precisely evolves during this and how cortical representations change in concert is unknown. Here, we use a skill learning task13,14 to monitor the dynamics of cross-area coupling during non-rapid eye movement sleep along with changes in primary motor cortex (M1) representational stability. Our results indicate that precise cross-area coupling between hippocampus, prefrontal cortex and M1 can demarcate two distinct stages of processing. We specifically find that each animal demonstrates a sharp increase in prefrontal cortex and M1 sleep slow oscillation coupling with stabilization of performance. This sharp increase then predicts a drop in hippocampal sharp-wave ripple (SWR)-M1 slow oscillation coupling-suggesting feedback to inform hippocampal disengagement and transition to a second stage. Notably, the first stage shows significant increases in hippocampal SWR-M1 slow oscillation coupling in the post-training sleep and is closely associated with rapid learning and variability of the M1 low-dimensional manifold. Strikingly, even after consolidation, inducing new manifold exploration by changing task parameters re-engages hippocampal-M1 coupling. We thus find evidence for dynamic hippocampal-cortical dialogue associated with manifold exploration during learning and adaptation.
Assuntos
Hipocampo , Aprendizagem , Córtex Motor , Animais , Hipocampo/fisiologia , Aprendizagem/fisiologia , Consolidação da Memória , Memória de Longo Prazo , Córtex Motor/fisiologia , Fases do Sono/fisiologia , Córtex Pré-Frontal/fisiologiaRESUMO
The phospholipid and free fatty acid (FFA) composition of neuronal membranes plays a crucial role in learning and memory, but the mechanisms through which neuronal activity affects the brain's lipid landscape remain largely unexplored. The levels of saturated FFAs, particularly of myristic acid (C14:0), strongly increase during neuronal stimulation and memory acquisition, suggesting the involvement of phospholipase A1 (PLA1) activity in synaptic plasticity. Here, we show that genetic ablation of the PLA1 isoform DDHD2 in mice dramatically reduces saturated FFA responses to memory acquisition across the brain. Furthermore, DDHD2 loss also decreases memory performance in reward-based learning and spatial memory models prior to the development of neuromuscular deficits that mirror human spastic paraplegia. Via pulldown-mass spectrometry analyses, we find that DDHD2 binds to the key synaptic protein STXBP1. Using STXBP1/2 knockout neurosecretory cells and a haploinsufficient STXBP1+/- mouse model of human early infantile encephalopathy associated with intellectual disability and motor dysfunction, we show that STXBP1 controls targeting of DDHD2 to the plasma membrane and generation of saturated FFAs in the brain. These findings suggest key roles for DDHD2 and STXBP1 in lipid metabolism and in the processes of synaptic plasticity, learning, and memory.
Assuntos
Ácidos Graxos não Esterificados , Memória de Longo Prazo , Proteínas Munc18 , Fosfolipases , Animais , Camundongos , Encéfalo/metabolismo , Ácidos Graxos não Esterificados/metabolismo , Memória/fisiologia , Proteínas Munc18/genética , Fosfolipases/genéticaRESUMO
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.
Assuntos
Amnésia/fisiopatologia , Encéfalo/fisiopatologia , Disfunção Cognitiva/fisiopatologia , Memória de Longo Prazo/fisiologia , Animais , Humanos , Manutenção , Memória de Curto Prazo/fisiologiaRESUMO
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.
Assuntos
Atenção , Imageamento por Ressonância Magnética , Memória de Longo Prazo , Memória de Curto Prazo , Lobo Parietal , Humanos , Atenção/fisiologia , Lobo Parietal/fisiologia , Masculino , Memória de Curto Prazo/fisiologia , Feminino , Memória de Longo Prazo/fisiologia , Adulto , Adulto Jovem , Objetivos , Mapeamento Encefálico , Estimulação Luminosa/métodos , Percepção Visual/fisiologiaRESUMO
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.
Assuntos
Proteínas de Drosophila , Proteínas de Choque Térmico HSP40 , Memória de Longo Prazo , Animais , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Proteínas de Choque Térmico HSP40/metabolismo , Proteínas de Choque Térmico HSP40/genética , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP70/genética , Memória de Longo Prazo/fisiologia , Fatores de Poliadenilação e Clivagem de mRNA/metabolismo , Fatores de Poliadenilação e Clivagem de mRNA/genética , Corpos Pedunculados/metabolismo , Multimerização Proteica , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Chaperonas Moleculares/genética , Chaperonas Moleculares/metabolismoRESUMO
Millions of migratory birds occupy seasonally favourable breeding grounds in the Arctic1, but we know little about the formation, maintenance and future of the migration routes of Arctic birds and the genetic determinants of migratory distance. Here we established a continental-scale migration system that used satellite tracking to follow 56 peregrine falcons (Falco peregrinus) from 6 populations that breed in the Eurasian Arctic, and resequenced 35 genomes from 4 of these populations. The breeding populations used five migration routes across Eurasia, which were probably formed by longitudinal and latitudinal shifts in their breeding grounds during the transition from the Last Glacial Maximum to the Holocene epoch. Contemporary environmental divergence between the routes appears to maintain their distinctiveness. We found that the gene ADCY8 is associated with population-level differences in migratory distance. We investigated the regulatory mechanism of this gene, and found that long-term memory was the most likely selective agent for divergence in ADCY8 among the peregrine populations. Global warming is predicted to influence migration strategies and diminish the breeding ranges of peregrine populations of the Eurasian Arctic. Harnessing ecological interactions and evolutionary processes to study climate-driven changes in migration can facilitate the conservation of migratory birds.
Assuntos
Migração Animal , Falconiformes/fisiologia , Mapeamento Geográfico , Aquecimento Global/estatística & dados numéricos , Memória de Longo Prazo , Animais , Regiões Árticas , Falconiformes/genética , PrevisõesRESUMO
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.
Assuntos
Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Drosophila melanogaster/fisiologia , Rememoração Mental/fisiologia , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/fisiologia , Condicionamento Psicológico , Dendritos/fisiologia , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/citologia , Estimulação Elétrica , Feminino , Memória de Longo Prazo/fisiologia , Corpos Pedunculados/citologia , Corpos Pedunculados/fisiologia , Odorantes , Receptores de Dopamina D1/metabolismo , Fatores de TempoRESUMO
The memory benefit that arises from distributing learning over time rather than in consecutive sessions is one of the most robust effects in cognitive psychology. While prior work has mainly focused on repeated exposures to the same information, in the real world, mnemonic content is dynamic, with some pieces of information staying stable while others vary. Thus, open questions remain about the efficacy of the spacing effect in the face of variability in the mnemonic content. Here, in two experiments, we investigated the contributions of mnemonic variability and the timescale of spacing intervals, ranging from seconds to days, to long-term memory. For item memory, both mnemonic variability and spacing intervals were beneficial for memory; however, mnemonic variability was greater at shorter spacing intervals. In contrast, for associative memory, repetition rather than mnemonic variability was beneficial for memory, and spacing benefits only emerged in the absence of mnemonic variability. These results highlight a critical role for mnemonic variability and the timescale of spacing intervals in the spacing effect, bringing this classic memory paradigm into more ecologically valid contexts.
Assuntos
Memória , Rememoração Mental , Aprendizagem , Memória de Longo Prazo , TempoRESUMO
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.
Assuntos
Fator 4 Ativador da Transcrição , Memória de Longo Prazo , Neurônios , Animais , Camundongos , Fator 4 Ativador da Transcrição/metabolismo , Fator 4 Ativador da Transcrição/genética , Astrócitos/metabolismo , Potenciação de Longa Duração , Memória de Longo Prazo/fisiologia , Camundongos Knockout , Neurônios/metabolismo , Prosencéfalo/metabolismo , MasculinoRESUMO
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.