作用于神经递质系统的抗抑郁剂只能治愈50%的患者, 为此抑郁症的炎症假说独辟蹊径。我们已证明炎症能够导致抑郁和神经退行性病变，如刺激HPA轴释放应激激素、减少神经递质合成、抑制神经营养因子（NTFs）功能和神经发生。反之，慢性应激能驱动胶质细胞的炎症反应而导致抑郁。我们也证明细胞膜成分Omega-3 fatty acids (FAs）能够治疗抑郁并改善认知和记忆，其机制为抗炎、抗氧化以及调节神经递质和NTFs的功能。 待解决的重要问题是：慢性应激如何改变1）胶质细胞活性从而将M1和M2表型转向炎症反应；2）细胞膜促炎和抗炎FAs浓度与细胞膜流动性和功能之间的关系；3）膜胆固醇的浓度及与炎症和HPA功能的关系；4）FAs敏感受体和离子通道的的功能；6）FAs治疗抑郁的膜机制。本研究以慢性应激诱导的大鼠模型为对象，用精神神经免疫学的理念，结合行为学、药理学和分子生物学方法，揭示以上关键的机制。

Classic hypotheses of depression or neurodegeneration, such as Alzheimer's disease (AD) were based on neurotransmitter deficits, dysfunction of hypothalamic-pituitary-adrenal (HPA) axis and neurotoxic deposition. Therefore, current treatments focus on neurotransmitter synthesis, uptake, metabolism and receptors, as well as on the antagonist of glucocorticoids or receptors. Due to most ineffective treatments with many side-effects, the exploration of new mechanisms and treatments are urgent. In the past 20 years, we have demonstrated that increased innate (non-specific) inflammatory response, neurotrophin dysfunction and omega (n)-3 unsaturated fatty acid (FA) deficits may play crucial roles in the onset and progress of depression and neurodegenerative diseases. In animal models, we showed that stress could trigger inflammatory response, while inflammation could stimulate stress hormone release. Furthermore, we revealed that n-3 FA exerted antidepressant and neuroprotective effects via anti-inflammation, anti-oxidants and normalizing neurotransmitter and neurotrophic systems. However, several important mechanisms are unknown: 1) whether and how chronic stress induces neuroinflammation through activating brain glial cells, which triggers specific microglia M1 and M2，then promote inflammatory response; 2) the relationship between chronic stress/inflammation and membrane functions, such as FA profile, membrane fluidity and raft function; 3) how stress/inflammation-induced changes cause the dysfunction of the HPA axis and neurotransmitter systems by distributing membrane FAs and cholesterols; 4) whether and how stress changes the function of "FA sensitive receptors", such as neuronal ion channel proteins, G-proteins and peroxisome proliferator-activated proteins. Thus, the present project aims to answer these questions. In chronic and multiple stressors induced rodent model and normal controls, the studies will step by step carry out from FA profile, membrane fluidity, cholesterol concentrations, then membrane associated changes in microglia-modulated neuroinflammation and astrocytes modulated neurotrophin functions, to the activity of the HPA axis and function of neurotransmitters, finally to depression and AD-like behavioural output. Upon the new discoveries, the membrane mechanism by which n-3 FA treat depression and AD will be explored. The study will reveal new mechanisms of these brain diseases and open a new direction for drug treatments.