Restoring the loss of consciousness under sevoflurane anesthesia in states of anxiety and depression by potently activating serotonergic pathways in brain

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-HTA 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. HighlightsO_LIBoosting the 5-HTergic neural circuit between the CeA and mPFC promotes emergence from sevoflurane anesthesia, with 5-HT1A and 5-HT2A receptors playing a critical role in modulating consciousness transitions. C_LIO_LIPreoperative anxiety and depression exacerbate delayed emergence from anesthesia, highlighting the need for targeted interventions. C_LIO_LIDeciphering the aberrant neurocircuitry mechanisms underlying delayed emergence to inversely deduce the neurocircuitry principles of normal physiology represents a pathological-to-physiological research paradigm. C_LIO_LIStepwise enhancement of intervention parameters reverses delayed emergence in pathological states. C_LIO_LITailored activation of the 5-HTergic circuit offers a novel approach to mitigate complications from delayed emergence in vulnerable patient populations. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=172 SRC="FIGDIR/small/599720v3_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@589b26org.highwire.dtl.DTLVardef@13204fforg.highwire.dtl.DTLVardef@e6374dorg.highwire.dtl.DTLVardef@38cac0_HPS_FORMAT_FIGEXP M_FIG C_FIG