{"doi":"10.1101/2024.06.19.599720","title":"Restoring the loss of consciousness under sevoflurane anesthesia in states of anxiety and depression by potently activating serotonergic pathways in brain","abstract":"Abstract Preoperative anxiety and depression are significant risk factors for prolonged general anesthesia emergence, raising postoperative complications and mortality. However, the neural mechanisms underlying this association remain unclear, limiting effective interventions and development of effective preventive and therapeutic strategies. Previous studies have shown that sleep-wakefulness neural circuit is closely related to neural circuitry of anesthesia recovery, with 5-Hydroxytryptamine (5-HT) playing a pivotal role of anesthesia arousal. Herein, we utilized pharmacology, optogenetics, chemogenetics, fiber photometry and retrograde tracing to demonstrate that activation of the 5-HTergic neural circuit between the central amygdala (CeA) and medial prefrontal cortex (mPFC) accelerates recovery from sevoflurane anesthesia. Particularly for individuals with anxiety- and depression-like symptoms, who exhibit more severe delayed emergence, it is necessary to enhance 5-HT neuronal activity by further optimizing parameters. To further validate the reliability of our findings and the specificity of viral tools, we successfully bred TPH2-Cre transgenic mice and repeated key experiments, which robustly confirmed all original conclusions. Pharmacological experiments further demonstrated that both 5-HT₁A and 5-HT₂A receptors mediate the pro-arousal function of this circuit. Collectively, our study identifies a key CeA-mPFC serotonergic pathway linking emotional disorders to abnormal anesthetic emergence, providing potential targets for optimizing anesthesia management in vulnerable patients. Highlights Boosting the 5-HTergic neural circuit between the CeA and mPFC promotes emergence from sevoflurane anesthesia, with 5-HT 1 A and 5-HT 2 A receptors playing a critical role in modulating consciousness transitions. Preoperative anxiety and depression exacerbate delayed emergence from anesthesia, highlighting the need for targeted interventions. Deciphering the aberrant neurocircuitry mechanisms underlying delayed emergence to inversely deduce the neurocircuitry principles of normal physiology represents a pathological-to-physiological research paradigm. Stepwise enhancement of intervention parameters reverses delayed emergence in pathological states. Tailored activation of the 5-HTergic circuit offers a novel approach to mitigate complications from delayed emergence in vulnerable patient populations. Graphical Abstract","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":498728,"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":0.9545,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1345325,"name":"Yue Yang","orcid":"0000-0003-2188-6077","position":1,"is_corresponding":false},{"id":1345650,"name":"YaXuan Wu","orcid":null,"position":2,"is_corresponding":false},{"id":1345326,"name":"Xiaoxia Xu","orcid":"0009-0005-3699-235X","position":3,"is_corresponding":false},{"id":531464,"name":"Qing Xu","orcid":"0000-0002-9804-3222","position":4,"is_corresponding":false},{"id":1345651,"name":"ZiWen Zhang","orcid":null,"position":5,"is_corresponding":false},{"id":1345652,"name":"XuanYi Di","orcid":null,"position":6,"is_corresponding":false},{"id":1345327,"name":"Honghai Zhang","orcid":"0000-0003-3530-2060","position":7,"is_corresponding":false},{"id":325174,"name":"Lu Liu","orcid":"0009-0003-6744-9427","position":8,"is_corresponding":false},{"id":504320,"name":"Hui Wu","orcid":"0000-0003-2818-756X","position":11,"is_corresponding":false},{"id":1231774,"name":"Dandan Yan","orcid":null,"position":12,"is_corresponding":false},{"id":495708,"name":"Yue Shen","orcid":"0000-0002-6415-2439","position":13,"is_corresponding":false},{"id":1345653,"name":"XinZhong Chen","orcid":null,"position":14,"is_corresponding":false},{"id":1345324,"name":"Yuling Wang","orcid":"0000-0002-2079-3568","position":0,"is_corresponding":true}],"reference_count":50,"raw_metadata":null,"created_at":"2026-07-19T02:09:42.181447Z","pmid":null,"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":[]}