Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice
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| Název: | Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice |
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| Autoři: | David V. C. Brito, Janina Kupke, Rostilav Sokolov, Sidney Cambridge, Martin Both, C. Peter Bengtson, Andrei Rozov, Ana M. M. Oliveira |
| Přispěvatelé: | Sapientia |
| Zdroj: | Mol Psychiatry |
| Informace o vydavateli: | Cold Spring Harbor Laboratory, 2023. |
| Rok vydání: | 2023 |
| Témata: | Male, 0301 basic medicine, Conditioning, Classical, Storage, Hippocampus, Receptors, N-Methyl-D-Aspartate, Article, Extinction, Psychological, 38/77, Mice, Inbred C57BL [MeSH], Receptors, N-Methyl-D-Aspartate/genetics [MeSH], Neuronal Plasticity/physiology [MeSH], Memory/physiology [MeSH], 631/80, Male [MeSH], Memory Consolidation/physiology [MeSH], Conditioning, Classical/physiology [MeSH], 42/44, Genes, Immediate-Early [MeSH], Extinction, Psychological/physiology [MeSH], Basic Helix-Loop-Helix Transcription Factors/metabolism [MeSH], Hippocampus/metabolism [MeSH], 13/1, Receptors, N-Methyl-D-Aspartate/metabolism [MeSH], Animals [MeSH], 64/60, Mice [MeSH], Basic Helix-Loop-Helix Transcription Factors/genetics [MeSH], 38, Fear/physiology [MeSH], 631/378, article, Persistence, Mice, 03 medical and health sciences, Messenger-RNA, Memory, Basic Helix-Loop-Helix Transcription Factors, Animals, Genes, Immediate-Early, Memory Consolidation, 0303 health sciences, Neuronal Plasticity, Neuronal ensemles, Activity-dependent transcription, Enhancement, Imparments, Fear, Long-term-memory, Mice, Inbred C57BL, Recognition, BDNF |
| Popis: | Long-term memories are believed to be encoded by unique transcriptional signatures in the brain. The expression of immediate early genes (IEG) promotes structural and molecular changes required for memory consolidation. Recent evidence has shown that the brain is equipped with mechanisms that not only promote, but actively constrict memory formation. However, it remains unknown whether IEG expression may play a role in memory suppression. Here we uncovered a novel function of the IEG neuronal PAS domain protein 4 (Npas4), as an inducible memory suppressor gene of highly salient aversive experiences. Using a contextual fear conditioning paradigm, we found that low stimulus salience leads to monophasic Npas4 expression, while highly salient learning induces a biphasic expression of Npas4 in the hippocampus. The later phase requires NMDA receptor activity and is independent of dopaminergic neurotransmission. Ourin vivopharmacological and genetic manipulation experiments suggested that the later phase of Npas4 expression restricts the consolidation of a fear memory and promote behavioral flexibility, by facilitating fear extinction and the contextual specificity of fear responses. Moreover, immunofluorescence and electrophysiological analysis revealed a concomitant increase in synaptic input from cholecystokinin (CCK)-expressing interneurons. Our results demonstrate how salient experiences evoke unique temporal patterns of IEG expression that fine-tune memory consolidation. Moreover, our study provides evidence for inducible gene expression associated with memory suppression as a possible mechanism to balance the consolidation of highly salient memories, and thereby to evade the formation of maladaptive behavior. |
| Druh dokumentu: | Article Other literature type |
| Popis souboru: | application/pdf |
| ISSN: | 1476-5578 1359-4184 |
| DOI: | 10.1101/2023.11.17.567527 |
| DOI: | 10.1038/s41380-024-02454-3 |
| Přístupová URL adresa: | https://pubmed.ncbi.nlm.nih.gov/38347124 https://hdl.handle.net/10400.1/20474 https://repository.publisso.de/resource/frl:6494530 |
| Rights: | CC BY |
| Přístupové číslo: | edsair.doi.dedup.....1e38050dc5cdcad3bd152a7d09893e93 |
| Databáze: | OpenAIRE |
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Nájsť tento článok vo Web of Science | Abstrakt: | Long-term memories are believed to be encoded by unique transcriptional signatures in the brain. The expression of immediate early genes (IEG) promotes structural and molecular changes required for memory consolidation. Recent evidence has shown that the brain is equipped with mechanisms that not only promote, but actively constrict memory formation. However, it remains unknown whether IEG expression may play a role in memory suppression. Here we uncovered a novel function of the IEG neuronal PAS domain protein 4 (Npas4), as an inducible memory suppressor gene of highly salient aversive experiences. Using a contextual fear conditioning paradigm, we found that low stimulus salience leads to monophasic Npas4 expression, while highly salient learning induces a biphasic expression of Npas4 in the hippocampus. The later phase requires NMDA receptor activity and is independent of dopaminergic neurotransmission. Ourin vivopharmacological and genetic manipulation experiments suggested that the later phase of Npas4 expression restricts the consolidation of a fear memory and promote behavioral flexibility, by facilitating fear extinction and the contextual specificity of fear responses. Moreover, immunofluorescence and electrophysiological analysis revealed a concomitant increase in synaptic input from cholecystokinin (CCK)-expressing interneurons. Our results demonstrate how salient experiences evoke unique temporal patterns of IEG expression that fine-tune memory consolidation. Moreover, our study provides evidence for inducible gene expression associated with memory suppression as a possible mechanism to balance the consolidation of highly salient memories, and thereby to evade the formation of maladaptive behavior. |
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| ISSN: | 14765578 13594184 |
| DOI: | 10.1101/2023.11.17.567527 |