终纹床核-腹侧被盖区环路调控巨噬细胞功能障碍在脓毒症免疫抑制中的作用及机制研究

脓毒症免疫抑制(SAIS)是脓毒症患者高死亡率的重要原因。巨噬细胞功能障碍严重影响SAIS的发展与结局，但SAIS进程中巨噬细胞功能障碍的中枢调控机制尚不清楚。中脑腹侧被盖区(VTA)多巴胺能神经元可增强固有免疫，预实验也发现SAIS小鼠VTA多巴胺能神经元活动降低；抑制终纹床核卵圆核区(ovBNST)GABA能神经元可减轻肺损伤并改善巨噬细胞功能。故推测在SAIS进程中，ovBNST的GABA能神经元持续激活导致VTA多巴胺能神经元活动受抑制，从而促进巨噬细胞功能障碍并加重SAIS。为此，本研究拟建立“二次打击”SAIS小鼠模型，在Cre小鼠运用光遗传学、药理学、光纤钙信号、跨突触病毒示踪和流式细胞术等多种方法，明确BNST-VTA神经环路对SAIS进程及巨噬细胞功能障碍的调控作用。本研究将拓展多巴胺能神经系统对免疫调控的神经环路理论，为脓毒症免疫抑制的脑内机制研究提供新依据。

Sepsis-associated immunosuppression (SAIS) is the leading cause of high mortality in sepsis patients. One key hallmark of SAIS is macrophage dysfunction. However, the underlying mechanisms of SAIS and macrophage dysfunction are unclear. The present research project hypothesizes that γ-aminobutyrate (GABAergic) neurons in the oval nucleus of the bed nucleus of the stria terminals (ovBNST) are activated in the progress of SAIS. The activated ovBNST GABAergic neurons subsequently inhibit the activity of dopamine neurons in the ventral tegmental area (VTA), which then exacerbate the progress of SAIS. With the combined use of optogenetics, chemogenetics, pharmacological, flow cytometry, molecular biology and animal models, the research project aims to address the following questions: 1) the role of dopaminergic neurons in the VTA in the macrophage dysfunction and SAIS progress; 2) the neural circuits between ovBNST GABAergic and VTA dopaminergic neurons; 3) the role of the ovBNST GABAergic neurons in the progress of SAIS and macrophage function; 4) the role of ovBNST-VTA neural circuits in the progress of SAIS and macrophage dysfunction. Dissection of the research project would shed light on the central modulation of macrophage function in the progress of SAIS and provide new evidence for the study of brain mechanism in sepsis immunosuppression.