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

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”.

scholarly journals Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

2015 ◽  
Vol 210 (5) ◽  
pp. 771-783 ◽  
Author(s):  
Norbert Bencsik ◽  
Zsófia Szíber ◽  
Hanna Liliom ◽  
Krisztián Tárnok ◽  
Sándor Borbély ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Protein Kinase ◽  
Dendritic Spines ◽  
Morphological Changes ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Protein Kinase D

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.

scholarly journals Synaptic plasticity-dependent competition rule influences memory formation

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.

scholarly journals Neurotrophin signalling in amygdala-dependent cued fear learning

2020 ◽  
Vol 382 (1) ◽  
pp. 161-172 ◽  
Author(s):  
Susanne Meis ◽  
Thomas Endres ◽  
Volkmar Lessmann
Keyword(s):  
Synaptic Plasticity ◽  
Learning And Memory ◽  
Neurotrophic Factor ◽  
Memory Formation ◽  
Fear Learning ◽  
Mammalian Brain ◽  
Pavlovian Fear Conditioning ◽  
Cortical Afferents ◽  
Trkb Receptors ◽  
Tropomyosin Related Kinase B

Abstract The amygdala is a central hub for fear learning assessed by Pavlovian fear conditioning. Indeed, the prevailing hypothesis that learning and memory are mediated by changes in synaptic strength was shown most convincingly at thalamic and cortical afferents to the lateral amygdala. The neurotrophin brain-derived neurotrophic factor (BDNF) is known to regulate synaptic plasticity and memory formation in many areas of the mammalian brain including the amygdala, where BDNF signalling via tropomyosin-related kinase B (TrkB) receptors is prominently involved in fear learning. This review updates the current understanding of BDNF/TrkB signalling in the amygdala related to fear learning and extinction. In addition, actions of proBDNF/p75NTR and NGF/TrkA as well as NT-3/TrkC signalling in the amygdala are introduced.

Isoflurane Impairs Learning and Hippocampal Long-term Potentiation via the Saturation of Synaptic Plasticity

2014 ◽  
Vol 121 (2) ◽  
pp. 302-310 ◽  
Author(s):  
Kazuhiro Uchimoto ◽  
Tomoyuki Miyazaki ◽  
Yoshinori Kamiya ◽  
Takahiro Mihara ◽  
Yukihide Koyama ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Western Blotting ◽  
Field Potential ◽  
Inhibitory Avoidance ◽  
Long Term Potentiation ◽  
Fear Learning ◽  
Male Rats ◽  
Avoidance Task ◽  
Term Potentiation

Abstract Background: General anesthesia induces long-lasting cognitive and learning deficits. However, the underlying mechanism remains unknown. The GluA1 subunit of AMPAR is a key molecule for learning and synaptic plasticity, which requires trafficking of GluA1-containing AMPARs into the synapse. Methods: Adult male rats were exposed to 1.8% isoflurane for 2 h and subjected to an inhibitory avoidance task, which is a hippocampus-dependent contextual fear learning paradigm (n = 16 to 39). The in vitro extracellular field potential of hippocampal synapses between the Schaffer collateral and the CA1 was evaluated using a multielectrode recorder (n = 6 per group). GluA1 expression in the synaptoneurosome was assessed using Western blotting (n = 5 to 8). The ubiquitination level of GluA1 was evaluated using immunoprecipitation and Western blotting (n = 7 per group). Results: Seven days after exposure to 1.8% isoflurane for 2 h (Iso1.8), the inhibitory avoidance learning (control vs. Iso1.8; 294 ± 34 vs. 138 ± 28, the mean ± SEM [%]; P = 0.002) and long-term potentiation (125.7 ± 6.1 vs. 105.7 ± 3.3; P < 0.001) were impaired. Iso1.8 also temporarily increased GluA1 in the synaptoneurosomes (100 ± 9.7 vs. 138.9 ± 8.9; P = 0.012) and reduced the GluA1 ubiquitination, a main degradation pathway of GluA1 (100 ± 8.7 vs. 71.1 ± 6.1; P = 0.014). Conclusions: Isoflurane impairs hippocampal learning and modulates synaptic plasticity in the postanesthetic period. Increased GluA1 may reduce synaptic capacity for additional GluA1-containing AMPARs trafficking.

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

2021 ◽  
Author(s):  
Soomaayeh Heysieattalab ◽  
Jafar Doostmohammadi ◽  
Mahgol Darvishmolla ◽  
Negin Saeedi ◽  
Narges Hosseinmardi ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Memory Formation ◽  
Short Term ◽  
Cox Inhibitors

Regional and Postnatal Heterogeneity of Activity-Dependent Long-Term Changes in Synaptic Efficacy in the Dorsal Striatum

2000 ◽  
Vol 84 (3) ◽  
pp. 1422-1429 ◽  
Author(s):  
John G. Partridge ◽  
Ka-Choi Tang ◽  
David M. Lovinger
Keyword(s):  
Synaptic Plasticity ◽  
Nmda Receptor ◽  
Brain Region ◽  
High Frequency ◽  
Long Term Potentiation ◽  
Rat Striatum ◽  
Synaptic Efficacy ◽  
Dependent Form ◽  
Activity Dependent

High-frequency activation of excitatory striatal synapses produces lasting changes in synaptic efficacy that may contribute to motor and cognitive functions. While some of the mechanisms responsible for the induction of long-term potentiation (LTP) and long-term depression (LTD) of excitatory synaptic responses at striatal synapses have been characterized, much less is known about the factors that govern the direction of synaptic plasticity in this brain region. Here we report heterogeneous activity-dependent changes in the direction of synaptic strength in subregions of the developing rat striatum. Neurons in the dorsolateral region of the anterior striatum tended to express LTD after high-frequency afferent stimulation (HFS) in slices from animals aged P15–P34. However, HFS in dorsolateral striatum from P12-P14 elicited an N-methyl-d-aspartate (NMDA) receptor-dependent form of LTP. Synapses in the dorsomedial anterior striatum exhibited a propensity to express an NMDA-receptor dependent form of LTP across the entire developmental time period examined. The NMDA receptor antagonist (±)-2-amino-5-phosphopentanoic acid (APV) inhibited evoked excitatory postsynaptic potentials recorded in striatum obtained from P12–P15 rats but had little effect in striatum from older animals. The expression of multiple forms of synaptic plasticity in the striatum suggests mechanisms by which this brain region plays pivotal roles in the acquisition or encoding of some forms of motor sequencing and stereotypical behaviors.

scholarly journals Reading Memory Formation from the Eyes

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.

BDNF and Control of Synaptic Plasticity in the Adult Brain

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.

scholarly journals Transcription Factors in Long-Term Memory and Synaptic Plasticity

2009 ◽  
Vol 89 (1) ◽  
pp. 121-145 ◽  
Author(s):  
Cristina M. Alberini
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Synaptic Plasticity ◽  
Memory Formation ◽  
Long Term Memory ◽  
Term Memory ◽  
Molecular Neuroscience ◽  
And Function ◽  
Expression Evidence

Transcription is a molecular requisite for long-term synaptic plasticity and long-term memory formation. Thus, in the last several years, one main interest of molecular neuroscience has been the identification of families of transcription factors that are involved in both of these processes. Transcription is a highly regulated process that involves the combined interaction and function of chromatin and many other proteins, some of which are essential for the basal process of transcription, while others control the selective activation or repression of specific genes. These regulated interactions ultimately allow a sophisticated response to multiple environmental conditions, as well as control of spatial and temporal differences in gene expression. Evidence based on correlative changes in expression, genetic mutations, and targeted molecular inhibition of gene expression have shed light on the function of transcription in both synaptic plasticity and memory formation. This review provides a brief overview of experimental work showing that several families of transcription factors, including CREB, C/EBP, Egr, AP-1, and Rel, have essential functions in both processes. The results of this work suggest that patterns of transcription regulation represent the molecular signatures of long-term synaptic changes and memory formation.

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