{"doi":"10.1101/2025.05.28.656415","title":"Sequential transcriptional gates in the thalamo-cortical circuit coordinate memory stabilization","abstract":"The molecular mechanisms that enable memories to persist over long time-scales from days to weeks and months are still poorly understood. To develop insights we created a behavioral task where, by varying the frequency of learned associations, mice formed multiple memories but only consolidated some, while forgetting others, over the span of weeks. We then monitored circuit-specific molecular programs that diverge between consolidated and forgotten memories. We identified multiple distinct waves of transcription, i.e., cellular macrostates, specifically in the thalamo-cortical circuit, that defined memory persistence. Notably, a small set of transcriptional regulators orchestrated broad molecular programs that enabled entry into these macrostates. Targeted CRISPR-knockout studies revealed that while these transcriptional regulators had no effects on memory formation, they had prominent, causal, and strikingly time-dependent roles in memory stabilization. In particular, the calmodulin-dependent transcription factor Camta1 was required for initial memory maintenance over days, while Tcf4 and the histone methyl-transferase Ash1l were required later to maintain memory over weeks. These results identify a critical Camta1-Tcf4-Ash1l thalamo-cortical transcriptional cascade required for memory stabilization, and puts forth a model where the sequential, multi-step, recruitment of circuit-specific transcriptional programs enable memory maintenance over progressively longer time-scales.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":566928,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9433,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":241597,"name":"Celine Chen","orcid":"0000-0002-1579-024X","position":1,"is_corresponding":false},{"id":1181417,"name":"Yujin Harada","orcid":"0000-0003-2741-3035","position":2,"is_corresponding":false},{"id":1455819,"name":"Tim Eilers","orcid":"0000-0002-5164-5584","position":3,"is_corresponding":false},{"id":1181789,"name":"Millennium Gebremedhin","orcid":null,"position":4,"is_corresponding":false},{"id":240165,"name":"Richard P. Koche","orcid":"0000-0002-6820-5083","position":5,"is_corresponding":false},{"id":307348,"name":"Pierre-Jacques Hamard","orcid":"0000-0002-2484-6161","position":6,"is_corresponding":false},{"id":1213771,"name":"Roshan Sharma","orcid":"0000-0003-3760-9955","position":7,"is_corresponding":false},{"id":346705,"name":"Priya Rajasethupathy","orcid":null,"position":8,"is_corresponding":false},{"id":458056,"name":"Andrea Terceros","orcid":null,"position":0,"is_corresponding":true}],"reference_count":84,"raw_metadata":null,"created_at":"2026-07-19T02:56:40.491968Z","pmid":"40501559","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}