难治性抑郁临床治疗十分棘手，发生机制不清。既往研究显示，炎症因素可能在其中扮演了重要角色。我们前期应用慢性不可预见性温和刺激诱导小鼠抑郁模型，发现：海马IL-1β表达明显增高组对氟西汀治疗反应性差；临床试验显示：难治性抑郁患者外周血IL-1β的表达亦明显升高；而IL-1β的高表达与脑白质髓鞘损害程度呈显著正相关（部分结果已发表）。据此推测：异常增高的IL-1β可能通过损伤少突胶质细胞引起脑白质脱髓鞘损害进而导致难治性抑郁的形成。为进一步验证该假说，本研究拟采用慢性不可预见性温和刺激诱导抑郁模型，首先，应用免疫组化和分子生物学方法在体观察氟西汀疗效不佳抑郁小鼠脑内IL-1β及脑白质髓鞘表达情况；其次，通过转基因动物模型进一步验证IL-1β在氟西汀难治性抑郁形成中的关键作用，最后从脑白质髓鞘异常角度探讨其作用机制。预计本课题将为难治性抑郁发生机制提供理论依据，为抗抑郁药物治疗提供新靶点。

Treatment resistant depression（TRD）is one of the most exciting and challenging topics in the world. However, its molecular mechanism and effective treatment are still unknown. Indeed, studies have demonstrated a certain role of inflammatory process in the etiology and pathophysiology of TRD. The previous research in our group had also found that 1)the depressive mice with higher expression of IL-1β exhibited lower responsive to fluoxetine treatment；2) The higher expression of IL-1β can also be investigated in clinical treatment resistant depression；3)the level of IL-1β and white matter/demyelination have a significantly positive corelation. Based on those data, we hypothesized that IL-1β may play a key role in the pathophysiology of depression or in the treatment resistance by white matter/demyelination. In the present study, we used the neurobiological methods, behavioral analysis and molecular biological techniques to further investigate the key role of IL-1β in the pathophysiology of CUMS-induced depression in transgenic mice and explore the possible underlying mechanism.Thus, we hope to shed light on more detailed understanding of potential mechanisms in the depression and treatment resistance and provide a newly target for the antidepressant treatment.