Oxytocin alleviates cognitive and memory impairments by decreasing hippocampal microglial activation and synaptic defects via OXTR/ERK/STAT3 pathway in a mouse model of sepsis-associated encephalopathy

Junliang Jiang; Yue Zou; Chuantong Xie; Miaoxian Yang; Qiuping Tong; Mimi Yuan; Xu Pei; Shuixiang Deng; Mi Tian; Lei Xiao; Ye Gong

doi:10.1016/j.bbi.2023.08.023

Oxytocin alleviates cognitive and memory impairments by decreasing hippocampal microglial activation and synaptic defects via OXTR/ERK/STAT3 pathway in a mouse model of sepsis-associated encephalopathy

Brain Behav Immun. 2023 Nov:114:195-213. doi: 10.1016/j.bbi.2023.08.023. Epub 2023 Aug 28.

Authors

Junliang Jiang¹, Yue Zou², Chuantong Xie³, Miaoxian Yang³, Qiuping Tong³, Mimi Yuan³, Xu Pei³, Shuixiang Deng³, Mi Tian³, Lei Xiao⁴, Ye Gong⁵

Affiliations

¹ Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China; Department of Orthopedics & Traumatology, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China.
² Yunnan Eye Institute & Key Laboratory of Yunnan Province, Yunnan Eye Disease Clinical Medical Center, Affiliated Hospital of Yunnan University, Yunnan University, Kunming, China.
³ Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China.
⁴ Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: leixiao@fudan.edu.cn.
⁵ Department of Critical Care Medicine and Neurosurgery of Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Fudan University, Shanghai, China. Electronic address: gong_ye@fudan.edu.cn.

PMID: 37648002
DOI: 10.1016/j.bbi.2023.08.023

Abstract

Background: Sepsis-associated encephalopathy (SAE) is a diffuse brain dysfunction, characterized by cognitive and memory impairments closely linked to hippocampal dysfunction. Though it is well-known that SAE is a diffuse brain dysfunction with microglial activation, the pathological mechanisms of SAE are not well established and effective clinical interventions are lacking. Oxytocin (OXT) is reported to have anti-inflammatory and neuroprotective roles. However, the effects of OXT on SAE and the underlying mechanisms are not clear.

Methods: SAE was induced in adult C57BL/6J male mice by cecal ligation and perforation (CLP) surgery. Exogenous OXT was intranasally applied after surgery. Clinical score, survivor rate, cognitive and memory behaviors, and hippocampal neuronal and non-neuronal functions were evaluated. Cultured microglia challenged with lipopolysaccharide (LPS) were used to investigate the effects of OXT on microglial functions, including inflammatory cytokines release and phagocytosis. The possible intracellular signal pathways involved in the OXT-induced neuroprotection were explored with RNA sequencing.

Results: Hippocampal OXT level decreases, while the expression of OXT receptor (OXTR) increases around 24 h after CLP surgery. Intranasal OXT application at a proper dose increases mouse survival rate, alleviates cognitive and memory dysfunction, and restores hippocampal synaptic function and neuronal activity via OXTR in the SAE model. Intraperitoneal or local administration of the OXTR antagonist L-368,899 in hippocampal CA1 region inhibited the protective effects of OXT. Moreover, during the early stages of sepsis, hippocampal microglia are activated, while OXT application reduces microglial phagocytosis and the release of inflammatory cytokines, thereby exerting a neuroprotective effect. OXT may improve the SAE outcomes via the OXTR-ERK-STAT3 signaling pathway.

Conclusion: Our study uncovers the dysfunction of the OXT signal in SAE and shows that intranasal OXT application at a proper dose can alleviate SAE outcomes by reducing microglial overactivation, suggests that OXT may be a promising therapeutic approach in managing SAE patients.

Keywords: Microglial activation; Neuroinflammation; Oxytocin; Sepsis-associated encephalopathy; Synapse.