抑郁症的神经免疫假说认为，小胶质细胞神经免疫M1（炎性）状态和M2（抗炎修复）状态的平衡是抑郁症治疗的关键。云南中药灵芝中的主要有效成分灵芝酸A对免疫系统有很强的调节作用。本项目拟研究灵芝酸A通过激活其大脑中的法尼醇X受体（FXR）产生抗抑郁作用的分子机制。首先用灵芝酸A注射的小鼠，观察灵芝酸A在抑郁症动物行为模型游泳、悬尾、旷野实验中的抗抑郁效果。并用灵芝酸A受体FXR的特异拮抗剂GW9662和FXR敲除鼠来观察灵芝酸A的抗抑郁作用是否由FXR受体介导。及是否能够调节小胶质细胞免疫炎症M1状态向抗炎修复M2状态转变，从而引起了抗炎细胞因子（IL-4、IL-10、TGF-β、BDNF）和促炎细胞因子（TNF-α、IL-6、IL-1β）表达变化。还拟揭示灵芝酸A对神经树突密度和神经突触兴奋性AMPA受体的调节作用。研究将发现灵芝酸A抗抑郁的神经免疫-神经可塑性的新机制。

It is commonly accepted that the balance of immune M1 (inflammatory) status and M2 (anti-inflammatory and repairing) status of microglia is the key for the treatment of depression. Ganoderic acid A is the main active ingredient of Yunnan traditional Chinese medicine Ganoderma lucidum, and has a strong regulatory effect on the immune system. This project aims to study whether Ganoderic acid A exerts an antidepressant through the activation of its receptor farnesoid X (FXR) in the brain, and its related molecular mechanism. First of all, the mice would be injected with Ganoderic acid A to observe the antidepressant effect in the animal model of depression, such as forced swimming, tail suspension, and open field tests. Whether the antidepressant effect of Ganoderic acid A is mediated by the FXR receptor would be determined with the specific antagonist of FXR GW9662 and the FXR knockout mice. Whether Ganoderic acid A could adjust inflammatory M1 status to anti-inflammatory M2 status, and regulate the expression of anti-inflammatory cytokines (IL-4, IL-10, TGF-β, and BDNF) and inflammatory cytokines (TNF-α, IL-6, IL-1β) in the prefrontal cortex and hippocampus would be determined. The research is also going to reveal the regulatory role of Ganoderic acid A on the synaptic protein expression, dendritic branch density, and excitatory AMPA receptors at the synapses. This study shed light to find Ganoderic acid A as a novel antidepressant with mechanism regulating neuroimmune and neuroplasticity.