Dysregulation of the hypothalamic paraventricular nucleusOXT-locus coeruleusOXTR system involved in anesthesia recovery and postoperative neurocognitive disorders in aged mice
LI Yiyao
JIANG Wenrui
YANG Ziyi
ZHANG Mingming
Abstract：Objective To investigate the impact of aging on the function of the oxytocin(OXT)system and to determine whether it mediates impairments in anesthesia recovery and postoperative neurocognitive disorders(PND)through the oxytocin receptor(OXTR)in the locus coeruleus(LC).Methods Adult(2-3 months old)and aged(18-24 months old)C57BL/6 mice were selected.Immunofluorescence staining was employed to assess changes in the activity of OXT neurons in the hypothalamic paraventricular nucleus(PVN)and the co-distribution of OXTR with tyrosine hydroxylase(TH)in the LC.Isoflurane inhalation was used to record both the anesthesia induction period and arousal period.The loss of righting reflex and recovery of righting reflex following anesthesia in mice were measured.The Y-maze and novel object recognition tests were conducted to evaluate postoperative neurocognitive function.Chemogenetic recombinant adeno-associated viruses were injected into the PVN and LC respectively to observe the intervention effect of specific activation or inhibition of the PVNOXT-LCOXTR neural pathway on aged mice.Results Compared with adult mice,aged mice showed no significant difference in the number of OXT neurons in the PVN.However,the number(P＜0.000 1)and proportion(P＜0.001)of OXT/FOS double-labeled neurons were significantly reduced.In the LC,the number(P＜0.000 1)and proportion(P＜0.001)of OXTR/TH double-labeled neurons were significantly increased,while the number(P＜0.01)and proportion(P＜0.01)of TH/FOS double-labeled neurons were significantly decreased.Additionally,the number of OXTR/TH/FOS triple-labeled neurons was markedly reduced(P＜0.01).Behaviorally,aged mice exhibited a shorter anesthesia induction period(P＜0.01)and a longer arousal period(P＜0.01)compared to adult mice,accompanied by significant PND symptoms.Chemogenetic-specific activation of PVNOXT neurons projecting to the LC or inhibition of LCOXTR neurons receiving projections from PVN resulted in shortened anesthesia recovery period and improved PND.However,these interventions did not affect anesthesia induction period.Conclusion The attenuation of OXT signaling from the PVN in aged mice results in diminished activation of LC noradrenergic neurons,accompanied by a compensatory overexpression of OXTR.This phenomenon represents a critical mechanism underlying anesthesia recovery disorders and PND.Targeted modulation of the PVNOXT-LCOXTR neural pathway potentially enhances anesthesia recovery and cognitive function in aged mice.
Keywords：oxytocinoxytocin receptorhypothalamic paraventricular nucleuslocus coeruleusanesthesiaarousalpostoperative neurocognitive disordersneural pathway
Publication Date：2026-02-28
Online Publishing Date：2026-08-26(First online date of this platform, not the publication date of the document)
Pages：9( 231-239 )