最近临床证据表明，神经炎症是抑郁症的易感因素，但机制不清。且目前的抗炎药物副作用大，不适于抗抑郁长期治疗。申请人前期研究发现，抑郁症大鼠内侧前额叶皮质（mPFC）小胶质细胞激活，炎症因子IL-1β表达增加。进一步研究发现神经元成熟树突棘比例降低、突触数量减少，并伴随切丝蛋白Cofilin的激活；电生理结果显示神经元兴奋性突触后电流幅度降低，呈长时程压抑。而敲减mPFC区的IL-1β或阻断其受体均有显著的抗抑郁作用。以上结果表明IL-1β可能通过调控神经元突触可塑性而介导抑郁症的发生。因此本项目拟利用膜片钳、光遗传调控及Cre-loxp条件性基因敲除等技术，结合分子生物学和行为检测等方法，研究：1）IL-1β调控神经元突触可塑性的神经及分子机制；2）IL-1β调控神经元突触可塑性在抑郁症发病中的作用。从而阐明神经炎症介导抑郁症发病的机理，为抑郁症的抗炎治疗策略提供新的药物靶点和理论依据。

Recently, neuroinflammation is considered as an important factor leading to brain dysfunction in depression. The current anti-inflammatory drug has more side effects which inadequate for antidepression therapies. We have investigated and reported the important role of synaptic plasticity in the infralimbic cortex of prefrontal cortex in chronic unpredicted mild stress induced depression animal model. Recently, we found that the activated microglia and the level of inflammatory factor such as IL-1β is increased and involved in the neuronal synaptic plasticity in chronic stressed rats, while knockdown IL-1β could improve synaptic plasticity, and thus ameliorated the depression-like behaviors. Further study found that overexpression of IL-1β activated cofilin which associated with synaptic plasticity while companied with decreased EPSC and induction of LTD. These results suggested that IL-1β may contribute to the induction of depression via modulating neuronal synaptic plasticity. Therefore, based on the previous findings, we will use virus injection, optogenetics and Cre-loxp conditional gene knockout methods to further investigate the following aspects: (1) investigate the role of IL-1β signaling pathway on the function of neuronal circuit and the mechanism of IL-1β on regulating the neuronal plasticity; (2) illustrate the mechanisms by which IL-1β signaling pathway could contribute to the synaptic plasticity in vivo and as well as depression-like disorders in chronic stress induced depressive rats. Controlling the expression of this pathway could improve mental disorders therapy and provide the new target for drug discovery and development.