Department of Human Genetics, Leiden University Medical Center, Leiden, RC, 2300, The Netherlands.
Department of Anesthesia and Critical Care and Pain Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA, USA.
J Headache Pain. 2023 Jul 26;24(1):96. doi: 10.1186/s10194-023-01628-8.
Cortical spreading depolarization (CSD), the neurophysiological correlate of the migraine aura, can activate trigeminal pain pathways, but the neurobiological mechanisms and behavioural consequences remain unclear. Here we investigated effects of optogenetically-induced CSDs on headache-related behaviour and neuroinflammatory responses in transgenic mice carrying a familial hemiplegic migraine type 1 (FHM1) mutation.
CSD events (3 in total) were evoked in a minimally invasive manner by optogenetic stimulation through the intact skull in freely behaving wildtype (WT) and FHM1 mutant mice. Related behaviours were analysed using mouse grimace scale (MGS) scoring, head grooming, and nest building behaviour. Neuroinflammatory changes were investigated by assessing HMGB1 release with immunohistochemistry and by pre-treating mice with a selective Pannexin-1 channel inhibitor.
In both WT and FHM1 mutant mice, CSDs induced headache-related behaviour, as evidenced by increased MGS scores and the occurrence of oculotemporal strokes, at 30 min. Mice of both genotypes also showed decreased nest building behaviour after CSD. Whereas in WT mice MGS scores had normalized at 24 h after CSD, in FHM1 mutant mice scores were normalized only at 48 h. Of note, oculotemporal stroke behaviour already normalized 5 h after CSD, whereas nest building behaviour remained impaired at 72 h; no genotype differences were observed for either readout. Nuclear HMGB1 release in the cortex of FHM1 mutant mice, at 30 min after CSD, was increased bilaterally in both WT and FHM1 mutant mice, albeit that contralateral release was more pronounced in the mutant mice. Only in FHM1 mutant mice, contralateral release remained higher at 24 h after CSD, but at 48 h had returned to abnormal, elevated, baseline values, when compared to WT mice. Blocking Panx1 channels by TAT-Panx inhibited CSD-induced headache related behaviour and HMGB1 release.
CSDs, induced in a minimally invasive manner by optogenetics, investigated in freely behaving mice, cause various migraine relevant behavioural and neuroinflammatory phenotypes that are more pronounced and longer-lasting in FHM1 mutant compared to WT mice. Prevention of CSD-related neuroinflammatory changes may have therapeutic potential in the treatment of migraine.
皮质扩散性抑制（CSD）是偏头痛先兆的神经生理学相关物，可以激活三叉神经疼痛通路，但神经生物学机制和行为后果仍不清楚。在这里，我们研究了通过光遗传学刺激在携带家族性偏瘫性偏头痛 1 型（FHM1）突变的转基因小鼠中诱发的 CSD 对头痛相关行为和神经炎症反应的影响。
通过对自由活动的野生型（WT）和 FHM1 突变型小鼠的完整头骨进行微创光遗传学刺激，总共诱发了 3 次 CSD 事件。使用小鼠面部表情评分（MGS）评分、头部梳理和筑巢行为分析相关行为。通过免疫组织化学评估 HMGB1 释放和用选择性 Pannexin-1 通道抑制剂预处理小鼠来研究神经炎症变化。
在 WT 和 FHM1 突变型小鼠中，CSD 诱导了头痛相关行为，表现为 MGS 评分增加和眼颞部中风的发生，在 30 分钟时出现。两种基因型的小鼠在 CSD 后也表现出筑巢行为减少。虽然在 WT 小鼠中，CSD 后 24 小时 MGS 评分已恢复正常，但在 FHM1 突变型小鼠中，评分仅在 48 小时后恢复正常。值得注意的是，眼颞部中风行为在 CSD 后 5 小时已经恢复正常，而筑巢行为在 72 小时仍受损；在这两种读数中均未观察到基因型差异。在 CSD 后 30 分钟，FHM1 突变型小鼠皮质中的核 HMGB1 释放在 WT 和 FHM1 突变型小鼠的两侧均增加，尽管在突变型小鼠中对侧释放更为明显。只有在 FHM1 突变型小鼠中，CSD 后 24 小时对侧释放仍然较高，但在 48 小时后，与 WT 小鼠相比，释放又恢复到异常升高的基线值。用 TAT-Panx 阻断 Panx1 通道可抑制 CSD 诱导的头痛相关行为和 HMGB1 释放。
通过光遗传学微创诱导的 CSD 在自由活动的小鼠中进行研究，引起了各种偏头痛相关的行为和神经炎症表型，在 FHM1 突变型小鼠中比 WT 小鼠更明显且持续时间更长。预防 CSD 相关的神经炎症变化可能在偏头痛的治疗中有治疗潜力。
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