The Role Of HMGB1 In Depressive Disorder Induced By Maternal Separation In Mice

Early life stress disrupts the normal immune function of an individual’s brain and can have a major impact on behavioral abilities later in life.Negative events experienced by an individual in early life can affect immune cells in the brain through some signals,which in turn regulates the response level of the nervous system when the individual is stressed in later life,making the individual susceptible to mental disorders such as depression and anxiety.Maternal separation is a commonly used model of early life stress,and studies have shown that rodents undergoing repeated maternal separation have activated neuroimmune system in early adolescence,and are susceptible to depressive-like behaviors in response to secondary stress in later life.However,the molecular mechanism by which maternal separation induces adverse effects is not well understood.Recent studies have indicated that endogenous danger-associated molecular patterns（DAMPs）are closely related to stress-induced neuroinflammatory responses and depressive disorders,and microglia can sense the stress through DAMPs.High mobility group box-1（HMGB1）is one kind of DAMPs,which plays a key role in stress-induced neuroinflammation and abnormal behaviors.We hypothesized that HMGB1 mediated neuroinflammation and behavioral abnormalities in offspring in adolescence and adulthood mice subjected to maternal separation.In this study,we constructed a maternal separation model in C57/BL6 mice and used the HMGB1 inhibitor glycyrrhizic acid as an intervention to explore the mechanism of HMGB1 in the short-and long-term adverse effects induced by maternal separation.Behavioral tests were carried to evaluate the the depressive state of mice,and RT-q PCR was performed to detect the proinflammatory cytokines in brain,and morphology parameters of microglia were analyzed by immunofluorescence.The results showed that inhibition of HMGB1 blocked maternal separation-induced microglial activation,neuroinflammation and depression-like behaviors in early adolescent offspring.Meanwhile,early inhibition of HMGB1 attenuated the enhanced neuroinflammation and significant behavioral disturbances induced by lipopolysaccharide injection in adult mice subjected to maternal separation.In vitro experiments further showed that primary microglia could be directly activated by HMGB1 to induce immune responses,while pre-activation of microglia by HMGB1 enhanced inflammatory response upon secondary stimulation by lipopolysaccharide.We conducted a preliminary exploration of the role of HMGB1 in the adverse effects induced by maternal separation.HMGB1 mediated depressive disorders in offspring mice subjected to maternal separation by activating microglia and regulating neuroinflammatory response.