Department of Neurology, Xuanwu Hospital, Capital Medical University, Beijing, China.
Beijing Key Laboratory of Neuromodulation, Beijing, China.
J Cell Mol Med. 2019 Oct;23(10):6822-6834. doi: 10.1111/jcmm.14566. Epub 2019 Aug 6.
Hypocretin 1 and hypocretin 2 (orexin A and B) regulate sleep, wakefulness and emotion. Tumour necrosis factor alpha (TNF-α) is an important neuroinflammation mediator. Here, we examined the effects of TNF-α treatment on hypocretin expression in vivo and behaviour in mice. TNF-α decreased hypocretin 1 and hypocretin 2 expression in a dose-dependent manner in cultured hypothalamic neurons. TNF-α decreased mRNA stability of prepro-hypocretin, the single precursor of hypocretin 1 and hypocretin 2. Mice challenged with TNF-α demonstrated decreased expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in hypothalamus. In response to TNF-α, prepro-hypocretin mRNA decay was increased in hypothalamus. TNF-α neutralizing antibody restored the expression of prepro-hypocretin, hypocretin 1 and hypocretin 2 in vivo in TNF-α challenged mice, supporting hypocretin system can be impaired by increased TNF-α through decreasing hypocretin expression. Repeated TNF-α challenge induced muscle activity during rapid eye movement sleep and sleep fragmentation, but decreased learning, cognition and memory in mice. TNF-α neutralizing antibody blocked the effects of TNF-α; in contrast, hypocretin receptor antagonist enhanced the effects of TNF-α. The data support that TNF-α is involved in the regulation of hypocretin expression, sleep and cognition. The findings shed some lights on the role of neuroinflammation in neurodegenerative diseases including Alzheimer's disease and Parkinson's disease.
下丘脑泌素 1 和下丘脑泌素 2（食欲素 A 和 B）调节睡眠、觉醒和情绪。肿瘤坏死因子-α（TNF-α）是一种重要的神经炎症介质。在这里，我们研究了 TNF-α 处理对体内下丘脑泌素表达和小鼠行为的影响。TNF-α 以剂量依赖的方式减少培养的下丘脑神经元中下丘脑泌素 1 和下丘脑泌素 2 的表达。TNF-α 降低了前下丘脑泌素的 mRNA 稳定性，即下丘脑泌素 1 和下丘脑泌素 2 的单一前体。接受 TNF-α 挑战的小鼠表现出下丘脑前下丘脑泌素、下丘脑泌素 1 和下丘脑泌素 2 表达减少。对 TNF-α的反应增加了下丘脑前下丘脑泌素 mRNA 的降解。TNF-α 中和抗体在 TNF-α 挑战的小鼠体内恢复了前下丘脑泌素、下丘脑泌素 1 和下丘脑泌素 2 的表达，支持通过降低下丘脑泌素表达，增加的 TNF-α 可以损害下丘脑泌素系统。重复 TNF-α 挑战诱导快速眼动睡眠期间的肌肉活动和睡眠碎片化，但减少了小鼠的学习、认知和记忆。TNF-α 中和抗体阻断了 TNF-α 的作用；相反，下丘脑泌素受体拮抗剂增强了 TNF-α 的作用。这些数据支持 TNF-α 参与下丘脑泌素表达、睡眠和认知的调节。研究结果揭示了神经炎症在包括阿尔茨海默病和帕金森病在内的神经退行性疾病中的作用。
