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OBJECTIVE To investigate the role of the complement C3/C3aR signaling pathway in the prefrontal cortex and colon neuroglia cell interactions during meth-amphetamine(METH)addiction,to observe the effects of TLR4 inhibitors as well as complement C3 elimination on METH reward and relapse behavior,and to explore the neuroinflammatory mechanisms of complement C3 acti-vation in METH addiction.METHODS ①A 14 d and 28 d rat METH addiction model was established to observe the effects of TLR4 antagonist ibudilast 3 mg·kg-1 and 10 mg·kg-1 on self-administration,reward motivation,relapse,and natural reward behavior in METH-trained 14 d rats and the effects of 0.02 mg·kg-1 complement C3 antago-nist on self-administration behavior in METH-trained 28 d rats.② Differences in the expression of TLR4,NF-κB,GRP94,C3,cathepsin L,CD68,and GFAP in the pre-frontal cortex of each group were examined using West-ern blotting.③ In addition,the expression of ATF6 in the prefrontal cortex of each group and the effects on neuro-nal and microglia/macrophage INOS,CD206 GRP94,and complement C3/C3aR.RESULTS ① Endoplasmic reticulum stress occurred in neurons and microglia after METH exposure depending on GRP94 and unfolded pro-tein responses to the ATF6 pathway.In addition,it acti-vates the TLR4-NF-κB pathway.② Microglia with high complement C3/C3aR expression in the prefrontal cortex were recruited to synaptic pruning and phagocytic responses around neurons with high GRP94,comple-ment C3/C3aR expression and these effects were blocked by complement C3 antagonists.③ In the rec-tum,GRP94 functions as a molecular chaperone for com-plement C3 and cathepsin L.Crosstalk occurs between enteric neurons high in GRP94,complement C3,and macrophages high in C3aR,located in the submucosa,lamina propria,and muscular,respectively,and all of these effects are blocked by complement C3 antago-nists.④ Treatment with the TLR4 antagonist ibudilast inhibits self-administration,reward motivation,and cue-or METH-priming in METH-trained 14 d rats,but fails to affect natural reward behavior.Ibudilast treatment attenu-ates the TLR4-NF-κB inflammatory pathway and comple-ments C3/C3aR pathway in the prefrontal cortex.CON-CLUSION Activation of the complement C3/C3aR signal-ing pathway by TLR4-NF-κB inflammatory signaling in the prefrontal cortex mediates the METH addiction pro-cess,providing an experimental basis for the clinical treatment of METH addiction,and targeting TLR4/NF-κB inflammatory signaling and complement C3/C3aR may be a new way to intervene in METH addiction.
ABSTRACT
Objective@#To investigate association between adolescent depressive symptoms with circadian rhythm and emotion regulation strategies, and to provide the basis for mental health education for depression.@*Methods@#CES-D, Morning and Evening Questionnaire-5 (MEQ-5) and Emotion Regulation scale (ERS) were administered to 2 398 students from 6 middle schools in Chengdu, Langzhong and Leshan of Sichuan Province. SPSS 21.0 was used to data processing and anlysis.@*Results@#About 37.9% (909/2 398) of adolescents reported depressive symptoms. Prevalence of depressive symptom was higher in female students( χ 2= 25.15 , P <0.01), rural adolescents( χ 2=15.45, P <0.01), adolescents aged 15-18 compared to aged 12-14( χ 2=187.24, P < 0.01 ). There was significant difference in rate of depressive symptoms among adolescents with different circadian rhythms( χ 2= 55.19 , P < 0.01 ), with definite evening rhythm preference was the highest(57.1%). Prevalence of depressive symptoms significantly varied by sleep duration( χ 2=141.99, P <0.01), and were highest in adolescents with sleep duration <6 h(69.4%). The scores of suppression dimension in depressed adolescents were significantly higher than that of non depressive group, while the scores of reappraisal dimension were significantly higher in non depressive group than that of depressive group. Multivariate Logistic regression analysis showed that gender( OR =1.60), age( OR=2.29), suppression( OR = 1.13 ), sleep duration <6 h( OR =5.17), sleep duration 6-8 h ( OR =2.88) were positively associated with depressive symptoms in adolescents. Moderate type( OR =0.53), morning type ( OR =0.55) and cognitive reappraisal ( OR =0.90) were associated with lower rate of depressive symptoms( P <0.05).@*Conclusion@#Sleep rhythm delay, lack of sleep and emotion suppression in adolescents are associated with higher risk for depression. Regular sleep habits and reasonable emotion regulation might help to prevent adolescent depression.