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Neuron type-specific mRNA translation programs provide a gateway for memory consolidation.

ABSTRACT: Long-term memory consolidation is a dynamic process that requires a heterogeneous ensemble of neurons, each with a highly specialized molecular signature. Considerable effort has been devoted to identifying molecular changes that accompany the process of consolidation, but mostly hours or days after training, when memory consolidation is already complete. Studies have shown that protein synthesis is elevated during the early stages of consolidation, but how this increase impacts neuronal function remains unclear. We hypothesize that mRNAs translated during the early stages of consolidation could provide information on how diverse neurons involved in memory formation restructure their molecular signatures to support memory. Here, we generate a landscape of the translatome of three neuron types in the dorsal hippocampus during the first hour of contextual memory consolidation. Our results reveal that translation programs associated with consolidation are different among neurons, fueling the reconfiguration of specific biological processes. We further demonstrate the patterned translation of mRNAs in different neuron types during consolidation is explained by features hard-coded in the mRNA sequence, suggesting ubiquitous mechanisms controlling activity-induced neuronal translation. Altogether, our work uncovers previously unknown mechanisms controlling activity-induced translation in neurons and provides a large, readily available resource for scientists interested in the role of memory formation in health and disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE300675 | GEO | 2026/05/07

REPOSITORIES: GEO

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Engram-specific transcriptome profiling of contextual memory consolidation

Project description:Sparse populations of neurons in the dentate gyrus (DG) of the hippocampus are causally implicated in the encoding of contextual fear memories. However, engram-specific molecular mechanisms underlying memory consolidation remain largely unknown. Here we perform unbiased RNA sequencing of DG engram neurons 24h after contextual fear conditioning to identify transcriptome changes specific to memory consolidation. DG engram neurons exhibit a highly distinct pattern of gene expression, in which CREB-dependent transcription features prominently (P=6.2x10-13), including Atf3 (P=2.4x10-41), Penk (P=1.3x10-15), and Kcnq3 (P=3.1x10-12). Moreover, we validate the functional relevance of the RNAseq findings by establishing the causal requirement of intact CREB function specifically within the DG engram during memory consolidation, and identify a novel group of CREB target genes involved in the encoding of long-term memory.

2019-03-30 | GSE129024 | GEO

A Bioinformatics Analysis of Memory Consolidation Reveals Involvement of the Transcription Factor c-Rel

Project description:Consolidation of long-term memory (LTM) is a complex process requiring synthesis of new mRNAs and proteins. Many studies have characterized the requirement for de novo mRNA and protein synthesis; however, few studies have comprehensively identified genes regulated during LTM consolidation. We show that consolidation of long-term contextual memory in the hippocampus triggers altered expression of numerous genes encompassing many aspects of neuronal function. Like contextual memory formation, this altered gene expression required NMDA receptor activation and was specific for situations in which the animal formed an association between a physical context and a sensory stimulus. Using a bioinformatics approach, we found that regulatory elements for several transcription factors are over-represented in the upstream region of genes regulated during consolidation of LTM. Using a knock-out mouse, we found that c-rel, one of the transcription factors identified in our bioinformatics study, is necessary for hippocampus-dependent long-term memory formation. Keywords: other

2005-03-30 | GSE1782 | GEO

Synaptically recruited lncRNA SLAMR facilitates structural plasticity in fear memory consolidation by modulatin translation

Project description:LncRNAs are involved in critical processes for cell homeostasis and function. However, it remains largely unknown whether and how the transcriptional regulation of long noncoding RNAs results in activity-dependent changes at the synapse and facilitate formation of long-term memories. Here, we report the identification of a novel lncRNA, SLAMR, that becomes enriched in CA1- but not in CA3-hippocampal neurons upon contextual fear conditioning. SLAMR is transported to dendrites via the molecular motor KIF5C and recruited to the synapse in response to stimulation. Loss of function of SLAMR reduced dendritic complexity and impaired activity-dependent changes in spine structural plasticity. Interestingly, the gain of function of SLAMR enhanced dendritic complexity, and spine density through enhanced translation. Analyses of the SLAMR interactome revealed its association with CaMKIIa protein through a 220-nucleotide element and its modulation of CaMKIIa activity. Furthermore, loss-of-function of SLAMR in CA1 selectively impairs consolidation but neither acquisition, recall, nor extinction of fear memory and spatial memory. Together, these results establish a new mechanism for activity dependent changes at the synapse and consolidation of contextual fear memory.

2023-03-13 | MSV000091477 | MassIVE

The clock gene Per1 may exert diurnal control over hippocampal memory consolidation

Project description:The circadian system influences many different biological processes, including memory performance. While the suprachiasmatic nucleus (SCN) functions as the brain’s central pacemaker, downstream “satellite clocks” may also regulate local functions based on the time of day. Within the dorsal hippocampus (DH), for example, local molecular oscillations may contribute to time-of-day effects on memory. Here, we used the hippocampus-dependent Object Location Memory task to determine how memory is regulated across the day/night cycle in mice. First, we systematically determined which phase of memory (acquisition, consolidation, or retrieval) is modulated across the 24h day. We found that mice show better long-term memory performance during the day than at night, an effect that was specifically attributed to diurnal changes in memory consolidation, as neither memory acquisition nor memory retrieval fluctuated across the day/night cycle. Using RNA-sequencing we identified the circadian clock gene Period1 (Per1) as a key mechanism capable of supporting this diurnal fluctuation in memory consolidation, as Per1 oscillates in tandem with memory performance. We then show that local knockdown of Per1 within the DH has no effect on either the circadian rhythm or sleep behavior, although previous work has shown this manipulation impairs memory. Thus, Per1 may independently function within the DH to regulate memory in addition to its known role in regulating the circadian system within the SCN. Per1 may therefore exert local diurnal control over memory consolidation within the DH.

2024-01-12 | GSE222744 | GEO

eIF2α pathway controls memory consolidation via excitatory and somatostatin inhibitory neurons

Project description:eIF2α pathway controls memory consolidation via excitatory and somatostatin inhibitory neurons

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Dexmedetomidine Inhibits Fear Memory Consolidation via the Astrocyte-Specific Srebf1-Phgdh Pathway in the Prelimbic Prefrontal Cortex

Project description:Background Post-traumatic stress disorder (PTSD) is a common mental disorder for which effectiveinterventions remain limited. Therefore, we set out to study whether anestheticdexmedetomidine could mitigate fear memory consolidation, part of PTSD, in mice andexplored underlying mechanisms. Methods Adult C57BL/6 male mice received dexmedetomidine (40 μg kg-1, i.p.) immediately following fear conditioning. An auditory-cued memory test in a different context wasconducted next day. RNA sequencing and neuromolecular analyses of prelimbicprefrontal cortex were performed. Molecular pathways were validated using specific gene knockdown, coupled with detailed phenotype analysis. Results Dexmedetomidine significantly reduced freezing time in mice during the auditory-cued memory test compared to control condition (15 [11.73] % vs. 59.67 [14.46] %,P=0.0018) and decreased concentrations of synaptic-related proteins (10.69 [1.27]vs. 7.97 [1.29], P<0.0001) and levels of dendritic spine density. Additionally, dexmedetomidine alleviated anxiety-like behavior and sensorimotor gating function impairment in mice after fear conditioning. These effects correlated with reduced nuclear translocation of sterol regulatory element-binding protein 1 (Srebf1) in astrocytes, but not neurons nor microglia, within the prelimbic prefrontal cortex of mice, leading to downregulation of phosphoglycerate dehydrogenase (Phgdh), a downstream target gene. Specific knockdown of Srebf1 or Phgdh in astrocytes without the treatment of dexmedetomidine inhibited fear memory consolidation and the associated synaptic plasticity in mice. Conclusions Dexmedetomidine mitigated PTSD-like behavior in mice by inhibiting fear memory consolidation through the astrocyte-specific Srebf1-Phgdh pathway in the prelimbic prefrontal cortex. These findings will promote more research toward to understanding of using anesthetic to treat PTSD and the underlying mechanism

2025-03-01 | GSE290477 | GEO

Early life exercise primes the neural epigenome to facilitate gene expression and hippocampal memory consolidation [RNA-seq]

Project description:Aerobic exercise is well known to promote neuroplasticity and hippocampal memory. In the developing brain, early-life exercise (ELE) can lead to lasting improvements in hippocampal function, yet molecular mechanisms underlying this phenomenon have not been fully explored. In this study, adolescent transgenic mice harboring the “NuTRAP” (Nuclear tagging and Translating Ribosome Affinity Purification) cassette in Emx1 expressing neurons (“Emx1-NuTRAP” mice) undergo ELE followed by a hippocampal learning task, in order to determine the molecular underpinnings of exercise contributing to improved hippocampal memory performance. We simultaneously isolate and sequence translating mRNA and nuclear chromatin from a single hippocampus in a cell-type specific manner (excitatory neurons), demonstrate validity of our new technical approach, and couple multi-omics sequencing data to evaluate histone modifications H4K8ac and H3K27me3 and their influence on gene expression after ELE. We then evaluate new gene expression – histone modification relationships specifically during hippocampal memory consolidation that may play a critical role in facilitated memory after ELE. Our data reveal novel candidate gene-histone modification interactions and implicate gene regulatory pathways involved in ELE’s impact on hippocampal learning and memory.

2022-10-18 | GSE208714 | GEO

Early life exercise primes the neural epigenome to facilitate gene expression and hippocampal memory consolidation [CUT&RUN]

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Reactivation of memory-encoding dentate gyrus neurons during memory consolidation is associated with subregion-specific, learning- and sleep-mediated biosynthetic changes [spatial protein expression level]

Project description:Post-learning sleep plays an important role in hippocampal memory processing, including contextual fear memory (CFM) consolidation. Here, we used targeted recombination in activated populations (TRAP) to label context-encoding engram neurons in the hippocampal dentate gyrus (DG) and assessed reactivation of these neurons during post-learning sleep. We find that post-learning sleep deprivation (SD), which impairs CFM consolidation, selectively disrupts reactivation in inferior blade DG engram neurons. This change was linked to more general suppression of neuronal activity markers in the inferior, but not superior, DG blade by SD. To further characterize how learning and subsequent sleep or SD affect these (and other) hippocampal subregions, we used subregion-specific spatial profiling of transcripts and proteins. We found that transcriptomic responses to sleep loss differed greatly between hippocampal regions CA1, CA3, and DG inferior blade, superior blade, and hilus. Critically, learning-driven transcriptomic changes, measured 6 h following contextual fear learning, were limited to the two DG blades, differed dramatically between the blades, and were absent from all other regions. Similarly, protein abundance in these hippocampal subregions were differentially impacted by sleep vs. SD and by prior learning, with the majority of alterations to protein expression restricted to DG. Together, these data suggest that the DG plays an essential role in the consolidation of hippocampal memories, and that the effects of sleep and sleep loss on the brain are highly subregion-specific, even within the DG itself.

2024-03-01 | GSE229081 | GEO

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