青少期应激诱发抑郁症认知功能障碍的中枢免疫机制及干预新策略

Both human and animal studies have shown that adverse social stressors during adolescence which prime developing brain areas, especially the prefrontal cortex (PFC) such that emotional and cognitive dysfunctions regulated by PFC during adulthood causes the higher risk of the occurrence of psychiatric disorders, such as depression. The biological mechanisms causally underlying this procedure, especially the involvement of central immunity, are still unclear, and therefore the development of novel effective antidepressant treatment is hindered. Our recent studies demonstrated that social stress exposure during early adolescence induced a developmental impairment in cortically - mediated cognitive flexibility and stress coping ability in adult mice, but not adolescents. Based on this, using behavioral, genetic, molecular biological, electrophysiological methods, this project aimed to systematically investigate: 1) dynamic effects of adolescent social stress on the activity of microglia in the PFC and tumor necrosis factor alpha (TNF) secreted by it, and its causal relationship with the onset of cognitive impairment during adulthood; 2) whether central immune activities mediated the therapeutic effects of behavioral intervention and chronic antidepressant treatment on the cognitive impairment induced by adolescent social stress; 3) the antidepressant effects of immunomodulatory agents on cognitive dysfunction induced by adolescent social stress, and synaptic plasticity mechanisms underlying the rapid relief of cognitive impairment after a single dose of immune modulator treatment. These will be helpful to extend the current knowledge regarding psycho-neuro-immunune interaction mechanisms underlying susceptibility to depression and suggest new treatment and intervention strategies for depression based on immune modulation.

人类和动物实验研究显示青少期社会应激重塑前额叶皮质发育过程从而持久改变成年期该脑区介导的情绪和认知功能并造成抑郁症等精神疾病的发病风险增加。介导这一过程的生物学介质，尤其是中枢免疫的作用尚不清楚。采用拟人类青少期社会应激诱发的抑郁症认知功能障碍动物模型，本项目综合运用行为学、遗传学、分子生物学和电生理方法，通过一系列实验揭示这一阶段社会环境因素对前额叶皮质小胶质细胞及其释放的促炎性细胞因子TNF表达的发展性影响，及其与认知功能障碍发生之间的因果联系；行为干预和抗抑郁药物治疗改善认知功能障碍的中枢免疫介导作用，进而探讨免疫调节剂的认知功能障碍治疗作用及其快速起效的潜在突触可塑性机理。这些工作旨在扩展对于抑郁症易感的心理-神经-免疫交互作用病理机制的认识，建立基于免疫调节的疾病防治新策略。

青少期社会应激重塑前额叶皮质发育过程从而持久改变成年期该脑区介导的情绪和认知功能并造成抑郁症等精神疾病的发病风险增加。介导这一过程的神经生物学介质，尤其是中枢免疫的作用尚不清楚。采用拟人类青少期社会霸凌诱发的抑郁症认知功能障碍动物模型，本项目综合运用行为学、遗传学、药物学、分子生物学和电生理方法，通过一系列实验发现：1）青少期应激后认知功能损害的发生发展与前额叶小胶质细胞激活及相关分子释放的动态改变间存在时间和空间的关系，主要表现在伴随青少期应激诱导前额叶认知转化功能障碍直至成年后（而非青少期）出现的发展延迟性损害，应激诱导内侧前额叶小胶质细胞的功能活动经历应激期间及应激后短暂升高，随后持续降低直至成年后显著低于相应对照组的动态变化过程；2）青少期应激诱导的成年期mPFC小胶质细胞功能不足介导了成年动物的认知转换功能损害。具体来说，mPFC 小胶质细胞数目减少及其相关因子BDNF和炎性因子TNFα释放减少，进而通过相应受体抑制其下游的GABA能神经元信号转导与突触传递过程是导致认知功能损害的重要分子和环路机制；3）社会支持干预和单胺氧化酶抑制剂抗抑郁药物慢性治疗都可以改善青少期应激诱导的抑郁行为和认知功能损害，以及上述免疫分子表达和GABA能突触传递功能的抑制性改变，提示免疫分子在认知功能障碍治疗中的潜力。进一步，成年期直接单次、急性免疫调节剂LPS干预以增加小胶质细胞活动被发现可以快速恢复青少期应激诱导的成年认知功能损害；4）结合应激后免疫活动经历过度激活到逐渐降低直至低于相应对照组的动态改变轨迹，在青少期阶段采用一种免疫抑制剂米洛环素对抗应激诱导的免疫炎性激活，可以阻止成年后认知功能损害的出现，提示发育性免疫紊乱在认知功能障碍发生中的病因学影响。这些工作扩展了对于抑郁症认知功能障碍发生发展的心理-神经-免疫交互作用机理的认识，提出了基于免疫调节的认知功能障碍防治的新策略。