scholarly journals Learning and Sleep Have Divergent Effects on Cytosolic and Membrane-Associated Ribosomal mRNA Profiles in Hippocampal Neurons

2020 ◽  
Author(s):  
James Delorme ◽  
Lijing Wang ◽  
Varna Kodoth ◽  
Yifan Wang ◽  
Jingqun Ma ◽  
...  
Keyword(s):  
Memory Consolidation ◽  
Hippocampal Neurons ◽  
Affinity Purification ◽  
Ribosomal Subunit ◽  
Sleep Loss ◽  
Contextual Fear Conditioning ◽  
Cellular Mechanisms ◽  
Prior Learning ◽  
Contextual Fear ◽  
Transcript Profiles

AbstractThe hippocampus plays an essential role in consolidating transient experiences into long-lasting memories. Memory consolidation can be facilitated by post-learning sleep, although the underlying cellular mechanisms are undefined. Here, we addressed this question using a mouse model of hippocampally-mediated, sleep-dependent memory consolidation (contextual fear memory; CFM), which is known to be disrupted by post-learning sleep loss. We used translating ribosome affinity purification (TRAP) to quantify ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different hippocampal cell populations (either whole hippocampus, Camk2a+ excitatory neurons, or highly active neurons expressing phosphorylated ribosomal subunit S6 [pS6+]). Using RNA-seq, we examined how these transcript profiles change as a function of sleep vs. sleep deprivation (SD) and as a function of prior learning (contextual fear conditioning; CFC). Surprisingly, we found that while many mRNAs on cytosolic ribosomes were altered by sleep loss, almost none were altered by learning. Of the few changes in cytosolic ribosomal transcript abundance following CFC, almost all were occluded by subsequent SD. This effect was particularly pronounced in pS6+ neurons with the highest level of neuronal activity following CFC, suggesting SD-induced disruption of post-learning transcript changes in putative “engram” neurons. In striking contrast, far fewer transcripts on membranebound (MB) ribosomes were altered by SD, and many more mRNAs (and lncRNAs) were altered on MB ribosomes as a function of prior learning. For hippocampal neurons, cellular pathways most significantly affected by CFC were involved in structural remodeling. Comparisons of post-CFC transcript profiles between freely-sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons, and increased protein synthesis capacity in pS6+ neurons, as biological processes disrupted by post-learning sleep loss.

scholarly journals Hippocampal neurons’ cytosolic and membrane-bound ribosomal transcript profiles are differentially regulated by learning and subsequent sleep

2021 ◽  
Vol 118 (48) ◽  
pp. e2108534118
Author(s):  
James Delorme ◽  
Lijing Wang ◽  
Varna Kodoth ◽  
Yifan Wang ◽  
Jingqun Ma ◽  
...  
Keyword(s):  
Memory Consolidation ◽  
Hippocampal Neurons ◽  
Affinity Purification ◽  
Ribosomal Subunit ◽  
Neuronal Cell ◽  
Subcellular Compartment ◽  
Contextual Fear ◽  
Highly Active ◽  
Membrane Bound ◽  
Transcript Profiles

The hippocampus is essential for consolidating transient experiences into long-lasting memories. Memory consolidation is facilitated by postlearning sleep, although the underlying cellular mechanisms are largely unknown. We took an unbiased approach to this question by using a mouse model of hippocampally mediated, sleep-dependent memory consolidation (contextual fear memory). Because synaptic plasticity is associated with changes to both neuronal cell membranes (e.g., receptors) and cytosol (e.g., cytoskeletal elements), we characterized how these cell compartments are affected by learning and subsequent sleep or sleep deprivation (SD). Translating ribosome affinity purification was used to profile ribosome-associated RNAs in different subcellular compartments (cytosol and membrane) and in different cell populations (whole hippocampus, Camk2a+ neurons, or highly active neurons with phosphorylated ribosomal subunit S6 [pS6+]). We examined how transcript profiles change as a function of sleep versus SD and prior learning (contextual fear conditioning; CFC). While sleep loss altered many cytosolic ribosomal transcripts, CFC altered almost none, and CFC-driven changes were occluded by subsequent SD. In striking contrast, SD altered few transcripts on membrane-bound (MB) ribosomes, while learning altered many more (including long non-coding RNAs [lncRNAs]). The cellular pathways most affected by CFC were involved in structural remodeling. Comparisons of post-CFC MB transcript profiles between sleeping and SD mice implicated changes in cellular metabolism in Camk2a+ neurons and protein synthesis in highly active pS6+ (putative “engram”) neurons as biological processes disrupted by SD. These findings provide insights into how learning affects hippocampal neurons and suggest that the effects of SD on memory consolidation are cell type and subcellular compartment specific.

scholarly journals 028 Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

SLEEP ◽  
2021 ◽  
Vol 44 (Supplement_2) ◽  
pp. A12-A13
Author(s):  
James Delorme ◽  
Lijing Wang ◽  
Femke Kuhn ◽  
Varna Kodoth ◽  
Jingqun Ma ◽  
...  
Keyword(s):  
Memory Consolidation ◽  
Dorsal Hippocampus ◽  
Affinity Purification ◽  
Ribosomal Subunit ◽  
Sleep Loss ◽  
Contextual Fear Conditioning ◽  
Cell Type ◽  
Single Trial ◽  
Contextual Fear ◽  
Cell Type Specific

Abstract Introduction Sleep loss profoundly disrupts consolidation of hippocampus-dependent memory. To better characterize effects of learning and sleep loss on the hippocampal circuit, we quantified activity-dependent phosphorylation of ribosomal subunit S6 (pS6) across the dorsal hippocampus of mice. Methods We first measured pS6 throughout the hippocampus after learning (single trial contextual fear conditioning; CFC), and after subsequent sleep or sleep deprivation (SD). To characterize cell populations with activity affected by SD, we used translating ribosome affinity purification (TRAP)-seq to identify cell type-specific transcripts on pS6 ribosomes after SD vs. sleep. We next used pharmacogenetics to mimic the effects of SD, selectively activating hippocampal Sst+ interneurons or cholinergic inputs to hippocampus from the medial septum (MS) while mice slept in the hours following CFC. We also inhibited these neuronal populations to assess effects on memory consolidation. Results We find that pS6 in enhanced in the dentate gyrus (DG) following single-trial CFC, but is reduced throughout the hippocampus after brief SD – a manipulation which disrupts contextual fear memory (CFM) consolidation. Cell type-specific enrichment analysis (CSEA) of these transcripts revealed that hippocampal somatostatin-expressing (Sst+) interneurons, and cholinergic and orexinergic inputs to hippocampus, are selectively activated after SD. We used TRAP targeted to hippocampal Sst+ interneurons to identify cellular mechanisms mediating SD-driven Sst+ interneuron activation. . We find that activation of Sst+ interneurons is sufficient to disrupt CFM consolidation, by gating activity in surrounding pyramidal neurons, while inhibition of Sst+ interneurons enhances memory consolidation. Similarly, pharmacogenetic activation of cholinergic input to hippocampus from the MS disrupted CFM. Inhibition of MS cholinergic neurons promoted CFM consolidation and disinhibited neurons in the DG, increasing pS6 expression among DG granule cells. Conclusion Our data suggest that state-dependent gating of DG activity during SD is mediated by cholinergic input. Together these data provide evidence for an inhibitory gate on hippocampal information processing, which is activated by sleep loss. Support (if any) R01-NS118440 to SJA from NINDS, DP2-MH104119 to SJA from the NIH Director’s Office, and a Human Frontiers Science Program Young Investigator Award

scholarly journals Sleep loss disrupts hippocampal memory consolidation via an acetylcholine- and somatostatin interneuron-mediated inhibitory gate

2020 ◽  
Author(s):  
James Delorme ◽  
Femke Roig Kuhn ◽  
Lijing Wang ◽  
Varna Kodoth ◽  
Jingqun Ma ◽  
...  
Keyword(s):  
Dorsal Hippocampus ◽  
Affinity Purification ◽  
Ribosomal Subunit ◽  
Enrichment Analysis ◽  
Sleep Loss ◽  
Contextual Fear Conditioning ◽  
Cell Type ◽  
Cellular Mechanisms ◽  
Contextual Fear ◽  
Cell Type Specific

AbstractSleep loss profoundly disrupts consolidation of hippocampus-dependent memory. To better characterize effects of learning and sleep loss on the hippocampal circuit, we quantified activity-dependent phosphorylation of ribosomal subunit S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 in enhanced in the dentate gyrus (DG) following single-trial contextual fear conditioning (CFC), but is reduced throughout the hippocampus after brief sleep deprivation (SD) – a manipulation which disrupts contextual fear memory (CFM) consolidation. To characterize cell populations with activity affected by SD, we used translating ribosome affinity purification (TRAP)-seq to identify cell type-specific transcripts on pS6 ribosomes after SD vs. sleep. Cell type-specific enrichment analysis (CSEA) of these transcripts revealed that hippocampal somatostatin-expressing (Sst+) interneurons, and cholinergic and orexinergic inputs to hippocampus, are selectively activated after SD. We used TRAP targeted to hippocampal Sst+ interneurons to identify cellular mechanisms mediating SD-driven Sst+ interneuron activation. We next used pharmacogenetics to mimic the effects of SD, selectively activating hippocampal Sst+ interneurons while mice slept in the hours following CFC. We find that activation of Sst+ interneurons is sufficient to disrupt CFM consolidation, by gating activity in surrounding pyramidal neurons. Pharmacogenetic inhibition of cholinergic input to hippocampus from the medial septum (MS) promoted CFM consolidation and disinhibited neurons in the DG, increasing pS6 expression. This suggests that state-dependent gating of DG activity is mediated by cholinergic input during SD. Together these data provide evidence for an inhibitory gate on hippocampal information processing, which is activated by sleep loss.

scholarly journals Sleep loss drives acetylcholine- and somatostatin interneuron–mediated gating of hippocampal activity to inhibit memory consolidation

2021 ◽  
Vol 118 (32) ◽  
pp. e2019318118
Author(s):  
James Delorme ◽  
Lijing Wang ◽  
Femke Roig Kuhn ◽  
Varna Kodoth ◽  
Jingqun Ma ◽  
...  
Keyword(s):  
Cell Population ◽  
Granule Cells ◽  
Dorsal Hippocampus ◽  
Affinity Purification ◽  
Enrichment Analysis ◽  
Sleep Loss ◽  
Contextual Fear Conditioning ◽  
Cell Type ◽  
Contextual Fear ◽  
Cell Type Specific

Sleep loss disrupts consolidation of hippocampus-dependent memory. To characterize effects of learning and sleep loss, we quantified activity-dependent phosphorylation of ribosomal protein S6 (pS6) across the dorsal hippocampus of mice. We find that pS6 is enhanced in dentate gyrus (DG) following single-trial contextual fear conditioning (CFC) but is reduced throughout the hippocampus after brief sleep deprivation (SD; which disrupts contextual fear memory [CFM] consolidation). To characterize neuronal populations affected by SD, we used translating ribosome affinity purification sequencing to identify cell type–specific transcripts on pS6 ribosomes (pS6-TRAP). Cell type–specific enrichment analysis revealed that SD selectively activated hippocampal somatostatin-expressing (Sst+) interneurons and cholinergic and orexinergic hippocampal inputs. To understand the functional consequences of SD-elevated Sst+ interneuron activity, we used pharmacogenetics to activate or inhibit hippocampal Sst+ interneurons or cholinergic input from the medial septum. The activation of either cell population was sufficient to disrupt sleep-dependent CFM consolidation by gating activity in granule cells. The inhibition of either cell population during sleep promoted CFM consolidation and increased S6 phosphorylation among DG granule cells, suggesting their disinhibition by these manipulations. The inhibition of either population across post-CFC SD was insufficient to fully rescue CFM deficits, suggesting that additional features of sleeping brain activity are required for consolidation. Together, our data suggest that state-dependent gating of DG activity may be mediated by cholinergic input and local Sst+ interneurons. This mechanism could act as a sleep loss–driven inhibitory gate on hippocampal information processing.

scholarly journals Hippocampus-retrosplenial cortex interaction is increased during phasic REM and contributes to memory consolidation

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Daniel Gomes de Almeida-Filho ◽  
Bruna Del Vechio Koike ◽  
Francesca Billwiller ◽  
Kelly Soares Farias ◽  
Igor Rafael Praxedes de Sales ◽  
...  
Keyword(s):  
Rem Sleep ◽  
Memory Consolidation ◽  
Retrosplenial Cortex ◽  
Contextual Fear Conditioning ◽  
Oscillatory Activity ◽  
Theta Oscillation ◽  
Contextual Fear ◽  
Before And After ◽  
Freely Behaving ◽  
Phasic Rem Sleep

AbstractHippocampal (HPC) theta oscillation during post-training rapid eye movement (REM) sleep supports spatial learning. Theta also modulates neuronal and oscillatory activity in the retrosplenial cortex (RSC) during REM sleep. To investigate the relevance of theta-driven interaction between these two regions to memory consolidation, we computed the Granger causality within theta range on electrophysiological data recorded in freely behaving rats during REM sleep, both before and after contextual fear conditioning. We found a training-induced modulation of causality between HPC and RSC that was correlated with memory retrieval 24 h later. Retrieval was proportional to the change in the relative influence RSC exerted upon HPC theta oscillation. Importantly, causality peaked during theta acceleration, in synchrony with phasic REM sleep. Altogether, these results support a role for phasic REM sleep in hippocampo-cortical memory consolidation and suggest that causality modulation between RSC and HPC during REM sleep plays a functional role in that phenomenon.

scholarly journals Treadmill Running Regulates Adult Neurogenesis, Spatial and Non-Spatial Learning by ErbB4 Signaling

2020 ◽  
Author(s):  
Yandong Yi ◽  
Yuanlong Song ◽  
Bo Liu ◽  
Yisheng Lu
Keyword(s):  
Cognitive Impairment ◽  
Discrimination Learning ◽  
Spatial Learning ◽  
Hippocampal Neurons ◽  
Reference Memory ◽  
Contextual Fear Conditioning ◽  
Treadmill Running ◽  
Spatial Learning And Memory ◽  
Contextual Fear ◽  
Adult Hippocampus

Abstract Recent studies have shown exercise is effective for adult hippocampus neurogenesis and memory. However, the molecular mechanism of exercise is unclear. In this study, AG1478, an ErbB4 inhibitor, was used to explore the involvement of ErbB4 receptors. Four weeks post-running, cognitive impairment was analyzed using T-maze, Morris water maze (MWM) and contextual fear discrimination learning tests, followed by histological assessment of the proliferation and survival of hippocampal neurons using Ki67, NeuN and BrdU immunostaining respectively. Expression of total and phosphate ErbB4 protein level was evaluated by Western blotting. The results showed that AG1478 significantly impaired the performances in T-maze and MWM (spatial learning and memory), contextual fear conditioning and discrimination learning paradigm (non-spatial working and reference memory), enhanced neurogenesis loss, downregulated the expression of p-ErbB4 and total ErbB4 protein, which could be reversed by running. Taken together, our study suggested that running ameliorates cognitive impairment and neurogenesis via ErbB4 signaling.

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