{"doi":"10.1101/2025.05.21.655312","title":"Prelimbic cortical excitatory overdrive and inhibitory underdrive accompany environmental suppression of food seeking","abstract":"Cues associated with food, such as fast-food advertising, can provoke food cravings and may lead to unhealthy overeating. Environmental enrichment (EE) that enhances cognitive and physical stimulation can reduce cue-evoked sucrose seeking in mice and recruitment of sucrose cue-reactive neurons or 'neuronal ensembles' in the prelimbic cortex (PL), which regulates appetitive behaviors. Hence, EE provides us with a behavioral model and neuronal targets to identify 'anti-craving' relevant mechanisms. Here, we investigated in the PL how EE modulated neuronal excitability and activity patterns in cue-reactive neuronal populations. Chemogenetic inhibition of cue-reactive neurons in PL blocked cue-evoked sucrose seeking, thereby confirming the function of these neurons in sucrose cue memory. EE boosted the baseline excitability of 'originally', or before EE exposure, cue-reactive, excitatory pyramidal cells in PL. Furthermore, their sucrose cue-specificity was lost - resulting in their persistent activation and non-cue selective activation or 'excitatory overdrive'. Furthermore, EE reduced recruitment of cue-reactive, inhibitory interneurons reflecting 'inhibitory underdrive'. Taken together, impaired neuronal food cue processing due to simultaneous prefrontal cortical excitatory 'overdrive' and inhibitory 'underdrive' likely underlies EE's anti-craving action, thereby serving as potential neurophysiological targets to develop novel medications that help control food cravings.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":558006,"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":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9583,"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":1449797,"name":"Zuzana Pedan","orcid":null,"position":1,"is_corresponding":false},{"id":1449798,"name":"Romarua Agbude","orcid":null,"position":2,"is_corresponding":false},{"id":1095854,"name":"Emily Woods","orcid":"0000-0003-2349-2688","position":3,"is_corresponding":false},{"id":1449369,"name":"Oliver G. Steele","orcid":"0000-0003-4789-9773","position":4,"is_corresponding":false},{"id":711527,"name":"Nobuyoshi Suto","orcid":"0000-0002-8994-2592","position":5,"is_corresponding":false},{"id":1449799,"name":"Scott B. Kinghorn","orcid":null,"position":6,"is_corresponding":false},{"id":1449370,"name":"Olga Tsaponina","orcid":"0000-0003-3002-8103","position":7,"is_corresponding":false},{"id":980606,"name":"Eisuke Koya","orcid":"0000-0002-5039-4875","position":8,"is_corresponding":false},{"id":626475,"name":"Kate Z. Peters","orcid":"0000-0003-2473-1644","position":0,"is_corresponding":true}],"reference_count":48,"raw_metadata":null,"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40475591","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":[]}