Stimulation of CGRP-expressing neurons in the medial cerebellar nucleus induces light and touch sensitivity in mice.
Stimulation of CGRP-expressing neurons in the medial cerebellar nucleus induces light and touch sensitivity in mice.
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DOI：
10.1016/j.ynpai.2022.100098
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发表时间：
2022-08
期刊：
影响因子：
--
通讯作者：
Sowers, Levi P.
中科院分区：
文献类型：
--
作者：
Wang, Mengya;Castonguay, William C.;Duong, Thomas L.;Huebner, Michael W.;Flinn, Harold C.;Greenway, Agatha M.;Russo, Andrew F.;Sowers, Levi P.
小脑内侧核中的CGRP神经元诱导偏头痛样症状。小脑CGRP神经元仅在雌性小鼠中诱导恐惧症，在两种性别中诱导触觉敏感性。降钙素基因相关肽（CGRP）被认为是偏头痛病理生理学的主要参与者。然而，CGRP在偏头痛中的作用的位置和机制尚不清楚。一个尚待回答的重要问题是：中枢CGRP信号传导在偏头痛中发挥作用吗？一个候选部位是小脑，它作为感觉和运动整合中心，在偏头痛患者中被激活。小脑在中枢神经系统中具有最多的CGRP结合位点，并且小脑深部核，即内侧核（MN），表达CGRP（MNCGRP）。先前的研究表明，CGRP递送到小脑诱导偏头痛样行为。我们假设，MNCGRP神经元的刺激可能会诱导偏头痛样行为。为了验证这一假设，我们使用了一种光遗传学策略，使用CalcaCre/+小鼠来选择性地驱动小脑MN中CGRP神经元中通道视紫红质-2的Cre依赖性表达。进行一系列行为测试以评估作为偏头痛症状的替代物的临床前行为，包括当MNCGRP神经元被光学刺激时的光厌恶、皮肤异常性疼痛和自发性疼痛。运动功能也进行了评估。MNCGRP神经元的光学刺激减少了在光下停留的时间，这与在黑暗中休息的时间增加相结合，但在光下休息的时间却没有增加。这些变化仅在雌性小鼠中显著。两种性别的同侧爪的足底触觉敏感性增加，但对侧爪的数据不太清楚。焦虑样行为、自发性疼痛（斜视）或步态变化无显著增加。这些发现表明，MNCGRP神经元可能有助于偏头痛样感觉过敏的光和触摸。
CGRP neurons in the medial nucleus of the cerebellum induce migraine-like symptoms. Cerebellar CGRP neurons induce photophobia only in female mice, and tactile sensitivity in both sexes. Calcitonin gene-related peptide (CGRP) is considered a major player in migraine pathophysiology. However, the location and mechanisms of CGRP actions in migraine are not clearly elucidated. One important question yet to be answered is: Does central CGRP signaling play a role in migraine? One candidate site is the cerebellum, which serves as a sensory and motor integration center and is activated in migraine patients. The cerebellum has the most CGRP binding sites in the central nervous system and a deep cerebellar nucleus, the medial nucleus (MN), expresses CGRP (MNCGRP). A previous study demonstrated that CGRP delivery into the cerebellum induced migraine-like behaviors. We hypothesized that stimulation of MNCGRP neurons might induce migraine-like behaviors. To test the hypothesis, we used an optogenetic strategy using CalcaCre/+ mice to drive Cre-dependent expression of channelrhodopsin-2 selectively in CGRP neurons in the cerebellar MN. A battery of behavioral tests was done to assess preclinical behaviors that are surrogates of migraine symptoms, including light aversion, cutaneous allodynia, and spontaneous pain when MNCGRP neurons were optically stimulated. Motor functions were also assessed. Optical stimulation of MNCGRP neurons decreased the time spent in the light, which was coupled to increased time spent resting in the dark, but not the light. These changes were only significant in female mice. Plantar tactile sensitivity was increased in the ipsilateral paws of both sexes, but contralateral paw data were less clear. There was no significant increase in anxiety-like behavior, spontaneous pain (squint), or changes in gait. These discoveries reveal that MNCGRP neurons may contribute to migraine-like sensory hypersensitivity to light and touch.
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