Engram-specific transcriptome profiling of contextual memory consolidation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA529794 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8809610.fastq.gz | Fastqsanger.gz | |||
| SRR8809620.fastq.gz | Fastqsanger.gz | |||
| SRR8809630.fastq.gz | Fastqsanger.gz | |||
| SRR8809640.fastq.gz | Fastqsanger.gz | |||
| SRR8809611.fastq.gz | Fastqsanger.gz |
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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.
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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.
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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.
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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 24 h 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 = 6.2 × 10-13), including Atf3 (P = 2.4 × 10-41), Penk (P = 1.3 × 10-15), and Kcnq3 (P = 3.1 × 10-12). 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.
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Project description:Hippocampal DNA methylation promote memory persistence by facilitating systems consolidation and cortical engram stabilization
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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.
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Project description:Adult rats (male Lister hooded) received a single unsignaled scrambled footshock (0.5 mA for 2 s) 2 min into a 3min exposure to a novel context. One half rats received bilateral microinfusions (1 microlitre/hemisphere) of 2 nmol/microlitre BDNF antisense ODN (BDNFASO, 5’-TCTTCCCCTTTTAATGGT-3’ in PBS, pH 7.4) or BDNF missense ODN (BDNFMSO, 5’ -ATACTTTCTGTTCTTGCC-3’ in PBS, pH 7.4) into the dorsal hippocampus (AP -3.50, relative to bregma), 90 min before contextual fear conditioning (CFC). Infusions were made in awake rats via previously surgically implanted indwelling stainless steel cannula. Rats were housed in the home cages at all times outside the conditioning procedure. Rats were killed by CO2 inhalation 2 hours after CFC. CA1 enriched dorsal hippocampus was immediately dissected on ice before rapid freezing and storage at -80oC. The BDNFASO-infused group represent consolidation-impaired rats.
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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
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