Han Chorong, Lim Ji Ye, Koike Nobuya, Kim Sun Young, Ono Kaori, Tran Celia K, Mangutov Elizaveta, Kim Eunju, Zhang Yanping, Li Lingyong, Pradhan Amynah A, Yagita Kazuhiro, Chen Zheng, Yoo Seung-Hee, Burish Mark J
Department of Biochemistry and Molecular Biology, UTHealth Houston, Houston, Texas, USA.
Department of Physiology and Systems Bioscience, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Headache. 2024 Feb;64(2):195-210. doi: 10.1111/head.14670. Epub 2024 Jan 30.
To characterize the circadian features of the trigeminal ganglion in a mouse model of headache.
Several headache disorders, such as migraine and cluster headache, are known to exhibit distinct circadian rhythms of attacks. The circadian basis for these rhythmic pain responses, however, remains poorly understood.
We examined trigeminal ganglion ex vivo and single-cell cultures from Per2::LucSV reporter mice and performed immunohistochemistry. Circadian behavior and transcriptomics were investigated using a novel combination of trigeminovascular and circadian models: a nitroglycerin mouse headache model with mechanical thresholds measured every 6 h, and trigeminal ganglion RNA sequencing measured every 4 h for 24 h. Finally, we performed pharmacogenomic analysis of gene targets for migraine, cluster headache, and trigeminal neuralgia treatments as well as trigeminal ganglion neuropeptides; this information was cross-referenced with our cycling genes from RNA sequencing data to identify potential targets for chronotherapy.
The trigeminal ganglion demonstrates strong circadian rhythms in both ex vivo and single-cell cultures, with core circadian proteins found in both neuronal and non-neuronal cells. Using our novel behavioral model, we showed that nitroglycerin-treated mice display circadian rhythms of pain sensitivity which were abolished in arrhythmic Per1/2 double knockout mice. Furthermore, RNA-sequencing analysis of the trigeminal ganglion revealed 466 genes that displayed circadian oscillations in the control group, including core clock genes and clock-regulated pain neurotransmitters. In the nitroglycerin group, we observed a profound circadian reprogramming of gene expression, as 331 of circadian genes in the control group lost rhythm and another 584 genes gained rhythm. Finally, pharmacogenetics analysis identified 10 genes in our trigeminal ganglion circadian transcriptome that encode target proteins of current medications used to treat migraine, cluster headache, or trigeminal neuralgia.
Our study unveiled robust circadian rhythms in the trigeminal ganglion at the behavioral, transcriptomic, and pharmacogenetic levels. These results support a fundamental role of the clock in pain pathophysiology.
Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24-hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day.
在头痛小鼠模型中表征三叉神经节的昼夜节律特征。
已知几种头痛疾病，如偏头痛和丛集性头痛，发作具有明显的昼夜节律。然而，这些节律性疼痛反应的昼夜节律基础仍知之甚少。
我们对来自Per2::LucSV报告基因小鼠的三叉神经节进行体外和单细胞培养，并进行免疫组织化学分析。使用三叉神经血管和昼夜节律模型的新组合研究昼夜行为和转录组学：一种硝酸甘油小鼠头痛模型，每6小时测量一次机械阈值，以及三叉神经节RNA测序，每4小时测量一次，持续24小时。最后，我们对偏头痛、丛集性头痛和三叉神经痛治疗的基因靶点以及三叉神经节神经肽进行了药物基因组学分析；这些信息与我们从RNA测序数据中获得的循环基因进行交叉参考，以确定时辰疗法的潜在靶点。
三叉神经节在体外和单细胞培养中均表现出强烈的昼夜节律，在神经元和非神经元细胞中均发现了核心昼夜节律蛋白。使用我们的新行为模型，我们发现硝酸甘油处理的小鼠表现出疼痛敏感性的昼夜节律，而在无节律的Per1/2双敲除小鼠中这种节律消失。此外，三叉神经节的RNA测序分析显示，对照组中有466个基因表现出昼夜振荡，包括核心生物钟基因和生物钟调节的疼痛神经递质。在硝酸甘油组中，我们观察到基因表达的深刻昼夜重编程，因为对照组中331个昼夜节律基因失去了节律，另有584个基因获得了节律。最后，药物遗传学分析在我们的三叉神经节昼夜转录组中鉴定出10个基因，这些基因编码用于治疗偏头痛、丛集性头痛或三叉神经痛的当前药物的靶蛋白。
我们的研究在行为、转录组和药物遗传学水平上揭示了三叉神经节强大的昼夜节律。这些结果支持生物钟在疼痛病理生理学中的基本作用。
几种头痛疾病，如偏头痛和丛集性头痛，每天在同一时间发作。我们了解到，三叉神经节是几种头痛疾病中的重要疼痛结构，它有一个24小时的周期，可能与这种每日头痛周期有关。我们的基因分析表明，一些药物在一天中的特定时间服用时，可能对治疗偏头痛和丛集性头痛更有效。
