Inflammatory mechanisms in a two-hit mouse model of neurodevelopmental disease

越来越多的证据表明，早期生活编程效应可能在神经精神疾病的发病机制中发挥重要作用，这些疾病包括精神分裂症、自闭症和双相情感障碍等大脑发育异常的组成部分。利用翻译小鼠模型，我们最近表明，联合暴露于产前免疫挑战和青春期应激对成人行为功能和神经化学产生协同的病理效应。在这个两次打击的模型中，受到两种环境侮辱的后代显示出明显的神经炎症迹象，其特征是小胶质细胞过度激活和脑炎性细胞因子的过度分泌。拟议项目的总体目标是调查炎症对行为异常和神经病理变化发展的贡献，长期目标是确定神经精神疾病的潜在预防方法或治疗目标。我们的一般假设是，炎症在神经发育疾病的启动中起着关键作用，因此，在这一模型中，在产前免疫挑战期间使用细胞因子中和抗体或在青春期应激暴露期间使用核因子-kB激活的选择性抑制剂来干预炎症事件具有保护作用。

Increasing evidence suggests that early-life programming effects may play an essential role in the pathogenesis of neuropsychiatric diseases that comprise components of abnormal brain development, including schizophrenia, autism, and bipolar disorder. Using a translational mouse model, we have recently shown that combined exposure to prenatal immune challenge and peripubertal stress induces synergistic pathological effects on adult behavioral functions and neurochemistry. In this two-hit model, offspring subjected to both environmental insults showed marked signs of neuroinflammation characterized by microglia overactivation and hypersecretion of brain inflammatory cytokines. The overall objective of the proposed project is to investigate the contribution of inflammation to the development of behavioral abnormalities and neuropathological changes, with the long-term goal to identify potential preventative approaches or therapeutic targets for neuropsychiatric diseases. Our general hypothesis is that inflammation plays a key role in the priming of neurodevelopmental disease and, accordingly, interference with inflammatory events by using either cytokine-neutralizing antibodies during prenatal immune challenge or a selective inhibitor of NF-kB activation during peripubertal stress exposure has protective effects in this model.