{"doi":"10.1016/j.bpsgos.2025.100487","title":"Early-Life Adversity–Induced Epigenetic Reprogramming of Prefrontal Cortex in Rats Subjected to Maternal Separation","abstract":"Early-life adversity (ELA) can lead to long-lasting behavioral and neurobiological changes through epigenetic mechanisms. In this study, we comprehensively mapped genome-wide DNA methylation in the prefrontal cortex of rats following maternal separation (MS). Rat pups were separated from their mother for 180 minutes/day from postnatal days (PNDs) 1 to 14 and tested for depressive- and anxiety-like behavior during adulthood (PNDs 80–89). Genome-wide DNA methylation, corresponding functional analyses, and transcription factor binding sites (TFBSs) were performed using reduced-representation bisulfite sequencing, focusing on differentially methylated cytosines (DMCs), differentially methylated regions (DMRs), and non-CpG sites. Both male and female MS rats showed a significant decrease in sucrose preference. Principal component and multidimensional scaling analyses did not show differences in the methylation data between male and female rats, prompting us to combine them in subsequent analyses. A total of 33,905 DMCs and 151 DMRs were identified in the MS group. The functional analysis of the dysregulated genes by DMCs and DMRs in the promoter or gene body revealed gene enrichment involved in neurodevelopment, synaptic plasticity, and stress response. Key genes with altered methylation included Dnmt3a/b , Notch1 , Mapk14 , and calcium channel subunits. Gene network analysis revealed interactions among ribosomal, MAPK (mitogen-activated protein kinase), and glutamatergic pathway genes. An enrichment of Elk1 TFBSs was particularly noted within the DMR. Additionally, differential non-CpG methylation, specifically at CHH (H = C/T/A) sites, dysregulated the Wnt pathway genes. Our findings expand our understanding of the molecular mechanisms that underlie the long-term effects of ELA and identify potential biomarkers for stress-related psychiatric disorders. Early-life stress (ELS) plays a critical role in the development of various psychiatric disorders in adulthood, including depression. The mechanisms of ELS-induced depression are not clearly understood; however, the role of epigenetic modifications, a process that alters the expression of genes without changing DNA sequences, is under intense investigation. In the current research, we investigated epigenetic changes in the rat brain resulting from maternal separation, a recognized model for early-life stress. Our results showed considerable DNA methylation differences in genes linked to neurodevelopment, synaptic activity, and stress responses in both CpG and non-CpG sites within promoter regions and gene bodies in the cortical area of maternally separated rats who showed anhedonia. The study deepens our understanding of the molecular factors that may play a role in the onset of stress-related psychiatric disorders later in life.","journal":"Biological Psychiatry Global Open Science","year":2025,"id":531225,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9372,"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":1088995,"name":"Lauren A. McKibben","orcid":"0000-0002-7307-6677","position":1,"is_corresponding":false},{"id":303692,"name":"Yogesh Dwivedi","orcid":"0000-0002-5359-4717","position":2,"is_corresponding":false},{"id":1411498,"name":"Aleena Francis","orcid":"0000-0001-9960-758X","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":null,"created_at":"2026-07-19T02:51:14.579161Z","pmid":"40342557","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":[]}