Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice

Brito, David V.C.; Kupke, Janina; Sokolov, Rostilav; Cambridge, Sidney; Both, Martin; Bengtson, C. Peter; Rozov, Andrei; Oliveira, Ana M. M.

Publication

Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice

2024-02Journal article

dc.contributor.author	Brito, David V.C.
dc.contributor.author	Kupke, Janina
dc.contributor.author	Sokolov, Rostilav
dc.contributor.author	Cambridge, Sidney
dc.contributor.author	Both, Martin
dc.contributor.author	Bengtson, C. Peter
dc.contributor.author	Rozov, Andrei
dc.contributor.author	Oliveira, Ana M. M.
dc.date.accessioned	2024-03-04T13:38:39Z
dc.date.available	2024-03-04T13:38:39Z
dc.date.issued	2024-02
dc.description.abstract	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 N-methyl-D-aspartate (NMDA) receptor activity and is independent of dopaminergic neurotransmission. Our in vivo pharmacological 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.	pt_PT
dc.description.sponsorship	Grant numbers OL 437/1, OL 437/2, OL 437/3 and OL 437/4 to AMMO and BE 7081/2-1 to CPB; RSF 22-15-00293; contract no. 075-15-2022-293	pt_PT
dc.description.version	info:eu-repo/semantics/publishedVersion	pt_PT
dc.identifier.doi	10.1038/s41380-024-02454-3	pt_PT
dc.identifier.eissn	1476-5578
dc.identifier.uri	http://hdl.handle.net/10400.1/20474
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.publisher	Springer Nature	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	pt_PT
dc.subject	Long-term-memory	pt_PT
dc.subject	Activity-dependent transcription	pt_PT
dc.subject	Neuronal ensemles	pt_PT
dc.subject	Messenger-RNA	pt_PT
dc.subject	Persistence	pt_PT
dc.subject	Storage	pt_PT
dc.subject	BDNF	pt_PT
dc.subject	Enhancement	pt_PT
dc.subject	Recognition	pt_PT
dc.subject	Imparments	pt_PT
dc.title	Biphasic Npas4 expression promotes inhibitory plasticity and suppression of fear memory consolidation in mice	pt_PT
dc.type	journal article
dspace.entity.type	Publication
oaire.citation.title	Molecular Psychiatry	pt_PT
person.familyName	Vilhena Catarino Brito
person.givenName	David
person.identifier.ciencia-id	7918-F771-8F47
person.identifier.orcid	0000-0002-2726-9347
rcaap.rights	openAccess	pt_PT
rcaap.type	article	pt_PT
relation.isAuthorOfPublication	24607876-f29a-41fa-be64-425f26ac67b5
relation.isAuthorOfPublication.latestForDiscovery	24607876-f29a-41fa-be64-425f26ac67b5