c-Rel, an NF- B family transcription factor, is required for hippocampal long-term synaptic plasticity and memory formation

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

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Synaptic plasticity-dependent competition rule influences memory formation

Nature Communications ◽

10.1038/s41467-021-24269-4 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yire Jeong ◽

Hye-Yeon Cho ◽

Mujun Kim ◽

Jung-Pyo Oh ◽

Min Soo Kang ◽

...

Keyword(s):

Synaptic Plasticity ◽

Fear Conditioning ◽

Long Term Potentiation ◽

Memory Formation ◽

Specific Pattern ◽

Memory Encoding ◽

Competition Rule ◽

Term Potentiation ◽

Input Activity

AbstractMemory is supported by a specific collection of neurons distributed in broad brain areas, an engram. Despite recent advances in identifying an engram, how the engram is created during memory formation remains elusive. To explore the relation between a specific pattern of input activity and memory allocation, here we target a sparse subset of neurons in the auditory cortex and thalamus. The synaptic inputs from these neurons to the lateral amygdala (LA) are not potentiated by fear conditioning. Using an optogenetic priming stimulus, we manipulate these synapses to be potentiated by the learning. In this condition, fear memory is preferentially encoded in the manipulated cell ensembles. This change, however, is abolished with optical long-term depression (LTD) delivered shortly after training. Conversely, delivering optical long-term potentiation (LTP) alone shortly after fear conditioning is sufficient to induce the preferential memory encoding. These results suggest a synaptic plasticity-dependent competition rule underlying memory formation.

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The HDAC inhibitor CI-994 acts as a molecular memory aid by facilitating synaptic and intra-cellular communication after learning

10.1101/2021.09.21.460970 ◽

2021 ◽

Author(s):

Allison M Burns ◽

Mélissa Farinelli-Scharly ◽

Sandrine Hugues-Ascery ◽

Jose Vicente Sanchez-Mut ◽

Giulia Santoni ◽

...

Keyword(s):

Synaptic Plasticity ◽

Hdac Inhibitor ◽

Brain Region ◽

Mode Of Action ◽

Memory Formation ◽

Epigenetic Modifications ◽

Fear Learning ◽

Cognitive Enhancers ◽

Hdaci Treatment

AbstractLong-term memory formation relies on synaptic plasticity, activity-dependent transcription and epigenetic modifications. Multiple studies have shown that HDAC inhibitor (HDACi) treatments can enhance individual aspects of these processes, and thereby act as putative cognitive enhancers. However, their mode of action is not fully understood. In particular, it is unclear how systemic application of HDACis, which are devoid of substrate specificity, can target pathways that promote memory formation. In this study, we explore the electrophysiological, transcriptional and epigenetic responses that are induced by CI-994, a class I HDAC inhibitor, combined with contextual fear conditioning (CFC) in mice. We show that CI-994-mediated improvement of memory formation is accompanied by enhanced long-term potentiation in the hippocampus, a brain region recruited by CFC, but not in the striatum, a brain region not primarily implicated in contextual memory formation. Furthermore, using a combination of bulk and single cell RNA sequencing, we find that synaptic plasticity-promoting gene expression cascades are more strongly engaged in the hippocampus than in the striatum, but only when HDACi treatment co-occurred with CFC, and not by either treatment alone. Lastly, using ChIP-sequencing, we show that the combined action of HDACi application and conditioning is required to elicit enhancer histone acetylation in pathways that may underlie improved memory performance. Together, our results indicate that systemic HDACi administration amplifies brain-region specific processes that are naturally induced by learning. These findings shed light onto the mode of action of HDACis as cognitive enhancers.Significance StatementMemory formation relies on a plethora of functions, including epigenetic modifications. Over the past years, multiple studies have indicated the potential of HDAC inhibitors (HDACi) to act as cognitive enhancers, but their mode of action is not fully understood. Here, we tested whether HDACi treatment improves memory formation via “cognitive epigenetic priming”, stipulating that HDACis – without inherent target specificity – specifically enhance plasticity-related processes. We found that combining HDACi with fear learning, but not either treatment alone, enhances synaptic plasticity as well as memory-promoting transcriptional signaling in the hippocampus, a brain area known to be recruited by fear learning, but not in others. These results lend experimental support to the theory of “cognitive epigenetic priming”.

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Nr4a2 Transcription Factor in Hippocampal Synaptic Plasticity, Memory and Cognitive Dysfunction: A Perspective Review

Frontiers in Molecular Neuroscience ◽

10.3389/fnmol.2021.786226 ◽

2021 ◽

Vol 14 ◽

Author(s):

Judit Català-Solsona ◽

Alfredo J. Miñano-Molina ◽

José Rodríguez-Álvarez

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Synaptic Plasticity ◽

Nuclear Receptor ◽

Molecular Mechanisms ◽

Expression Profiles ◽

Gene Expression Profiles ◽

Memory Formation ◽

Synaptic Dysfunction ◽

Hippocampal Synaptic Plasticity

Long-lasting changes of synaptic efficacy are largely mediated by activity-induced gene transcription and are essential for neuronal plasticity and memory. In this scenario, transcription factors have emerged as pivotal players underlying synaptic plasticity and the modification of neural networks required for memory formation and consolidation. Hippocampal synaptic dysfunction is widely accepted to underlie the cognitive decline observed in some neurodegenerative disorders including Alzheimer’s disease. Therefore, understanding the molecular pathways regulating gene expression profiles may help to identify new synaptic therapeutic targets. The nuclear receptor 4A subfamily (Nr4a) of transcription factors has been involved in a variety of physiological processes within the hippocampus, ranging from inflammation to neuroprotection. Recent studies have also pointed out a role for the activity-dependent nuclear receptor subfamily 4, group A, member 2 (Nr4a2/Nurr1) in hippocampal synaptic plasticity and cognitive functions, although the underlying molecular mechanisms are still poorly understood. In this review, we highlight the specific effects of Nr4a2 in hippocampal synaptic plasticity and memory formation and we discuss whether the dysregulation of this transcription factor could contribute to hippocampal synaptic dysfunction, altogether suggesting the possibility that Nr4a2 may emerge as a novel synaptic therapeutic target in brain pathologies associated to cognitive dysfunctions.

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Non-selective COX inhibitors impair memory formation and short-term but not long-term synaptic plasticity

Naunyn-Schmiedeberg s Archives of Pharmacology ◽

10.1007/s00210-021-02092-4 ◽

2021 ◽

Author(s):

Soomaayeh Heysieattalab ◽

Jafar Doostmohammadi ◽

Mahgol Darvishmolla ◽

Negin Saeedi ◽

Narges Hosseinmardi ◽

...

Keyword(s):

Synaptic Plasticity ◽

Memory Formation ◽

Short Term ◽

Cox Inhibitors

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Reading Memory Formation from the Eyes

10.1101/268490 ◽

2018 ◽

Author(s):

Anne Bergt ◽

Anne E. Urai ◽

Tobias H. Donner ◽

Lars Schwabe

Keyword(s):

Synaptic Plasticity ◽

Memory Formation ◽

Pupil Dilation ◽

Long Term Memory ◽

Term Memory ◽

Pupil Response ◽

Rapid Formation ◽

The Brain

At any time, we are processing thousands of stimuli, but only few of them will be remembered hours or days later. Is there any way to predict which ones? Here, we show that the pupil response to ongoing stimuli, an indicator of physiological arousal, is a reliable predictor of long-term memory for these stimuli, over at least one day. Pupil dilation was tracked while participants performed visual and auditory encoding tasks. Memory was tested immediately after encoding and 24 hours later. Irrespective of the encoding modality, trial-by-trial variations in pupil dilation predicted which stimuli were recalled in the immediate and 24 hours-delayed tests. These results show that our eyes may provide a window into the formation of long-term memories. Furthermore, our findings underline the important role of central arousal systems in the rapid formation of memories in the brain, possibly by gating synaptic plasticity mechanisms.

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Suppression of CHOP Reduces Neuronal Apoptosis and Rescues Cognitive Impairment Induced by Intermittent Hypoxia by Inhibiting Bax and Bak Activation

Neural Plasticity ◽

10.1155/2021/4090441 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Linhao Xu ◽

Yanli Bi ◽

Yizhou Xu ◽

Yihao Wu ◽

Xiaoxue Du ◽

...

Keyword(s):

Transcription Factor ◽

Synaptic Plasticity ◽

Signaling Pathway ◽

Intermittent Hypoxia ◽

Specific Chemical ◽

Activating Transcription Factor ◽

Induced Apoptosis

Our previous study showed that growth arrest- and DNA damage-inducible gene 153 (GAD153/CHOP) plays an important role in intermittent hypoxia- (IH-) induced apoptosis and impaired synaptic plasticity. This study is aimed at determining which signaling pathway is activated to induce CHOP and the role of this protein in mitochondria-dependent apoptosis induced by IH. In the in vivo study, mice were placed in IH chambers for 8 h daily over a period of 2 weeks; the IH chambers had oxygen (O2) concentrations that oscillated between 10% and 21%, cycling every 90 s. In the in vitro study, PC12 cells were exposed to 21% O2 (normoxia) or 8 IH cycles (25 min at 21% O2 and 35 min at 0.1% O2 for each cycle). After 2 weeks of IH treatment, we observed that the expression levels of phosphorylated protein kinase-like endoplasmic reticulum kinase (p-PERK), activating transcription factor 4 (ATF-4) and phosphorylated eukaryotic initiation factor 2 alpha (p-elf2α), were increased, but the levels of activating transcription factor 6 (ATF-6) and inositol-requiring enzyme 1 (IRE-1) were not increased. GSK2606414, a specific chemical inhibitor of the PERK pathway, reduced the expression of p-PERK, ATF-4, p-elf2α, and CHOP and rescued ER structure. In addition, Bax and Bak accumulated in the mitochondria after IH treatment, which induced cytochrome c release and initiated apoptosis. These effects were prevented by GSK2606414 and CHOP shRNA. Finally, the impaired long-term potentiation and long-term spatial memory in the IH group were rescued by GSK2606414. Together, the data from the in vitro and in vivo experiments indicate that IH-induced apoptosis and impaired synaptic plasticity were mediated by the PERK-ATF-4-CHOP pathway. Suppressing PERK-ATF-4-CHOP signaling pathway attenuated mitochondria-dependent apoptosis by reducing the expression of Bax and Bak in mitochondria, which may serve as novel adjunct therapeutic strategy for ameliorating obstructive sleep apnea- (OSA-) induced neurocognitive impairment.

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BDNF and Control of Synaptic Plasticity in the Adult Brain

European Psychiatry ◽

10.1016/s0924-9338(09)70554-1 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1

Author(s):

C. Bramham

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Antidepressant Drugs ◽

Long Term Potentiation ◽

Memory Formation ◽

Adult Brain ◽

Early Gene ◽

Perforant Path ◽

Mammalian Brain

Experience-dependent changes in synaptic connectivity are thought to play a vital role not only in memory formation, but also in long-term adaptive responses involved in mood regulation, reward behavior, and pain control. The neurotrophin, brain-derived neurotrophic factor (BDNF), which has recently been implicated in memory formation and aspects of major depression, is also an important regulator of long-term synaptic plasticity in the adult mammalian brain. We have investigated BDNF function in the dentate gyrus, a brain region implicated in depression and the action of antidepressant drugs. Local infusion of BDNF into the dentate gyrus generated a long-term potentiation (LTP) of synaptic efficacy at medial perforant path-granule cell synapses. This LTP is associated with expression of the immediate early gene, Arc, in postsynaptic granule cells and transport of Arc mRNA to synaptic regions on dendrites. Using local infusion of antisense oligodeoxynucleotides to block Arc synthesis, we show that Arc is required for the induction and time-dependent consolidation of BDNF-induced LTP. The sustained synthesis of Arc during a critical time-window is required for local expansion of the actin cytoskeletal network in dendritic spines. These results identify Arc as a critical mediator of BDNF in long-term synaptic plasticity in the adult brain. Microarray expression profiling has further revealed a panel of genes that, like Arc, are strongly upregulated following acute BDNF infusion or chronic treatment with the antidepressant fluoxetine.

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The relation of transcription to memory formation.

Acta Biochimica Polonica ◽

10.18388/abp.2003_3668 ◽

2003 ◽

Vol 50 (3) ◽

pp. 775-782 ◽

Cited By ~ 17

Author(s):

Edward Korzus

Keyword(s):

Transcription Factor ◽

Memory Consolidation ◽

Memory Formation ◽

Information Storage ◽

Long Term Memory ◽

Behavioral Studies ◽

Activation Of Transcription ◽

Element Binding Protein ◽

Downstream Processes

A distinction between short-term memories lasting minutes to hours and long-term memories lasting for many days is that the formation of long-term memories requires new gene expression. In this review, the focus is on the current understanding of the relation of transcription to memory consolidation based on the data collected from behavioral studies performed primarily on genetically altered animals. Studies in Drosophila and Aplysia indicate that the transcription factor cAMP/Ca(2+) response element binding protein (CREB) is critical in mediating the conversion from short- to long-term memory. More recent genetic studies in mice also demonstrated CREB and inducible transcription factor Zif268 involvement in information storage processes. Transcription seems to play essential role in memory formation but the mechanisms for activation of transcription and downstream processes during memory consolidation remain unclear.

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Transcription of a plasticity gene is activated by neuronal hyperpolarization

10.1101/636878 ◽

2019 ◽

Author(s):

Zhonghua Zhu ◽

Tamara Sanchez Ortiz ◽

Shaul Mezan ◽

Sebastian Kadener ◽

Justin Blau

Keyword(s):

Transcription Factor ◽

Synaptic Plasticity ◽

Neuronal Activity ◽

Mushroom Body ◽

Transcriptional Factors ◽

List Type ◽

Circadian Pacemaker ◽

Pacemaker Neurons ◽

Rhythmic Expression

SummaryLong term synaptic plasticity requires transcription in response to changes in neuronal activity. While genes induced by neuronal activity have been extensively studied, genes induced by hyperpolarization are largely unknown. We focused on Pura, a Rho1 GEF whose rhythmic expression drives the daily retraction of the projections of Drosophila LNv circadian pacemaker neurons. We found that Pura transcription is repressed by activity and induced by hyperpolarization in LNvs – the opposite of typical activity-regulated genes. Pura is repressed by activity-regulated transcriptional factors including Mef2 and Sr (fly Egr-1) and activated by Toy, a Pax6 transcription factor. toy transcription is also induced by inactivity. Thus toy and Pura represent a class of genes induced by hyperpolarization.HighlightsHyperpolarization activates transcription of Pura, a plasticity geneThis phenomenon occurs in circadian pacemaker neurons and mushroom body neuronsThe Pura enhancer integrates recent neuronal activity to regulate transcriptionHyperpolarization activates transcription of toy (Pax-6), which then activates Pura

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