Determinants of Optogenetic Cortical Spreading Depolarizations
Determinants of Optogenetic Cortical Spreading Depolarizations
复制标题
DOI：
10.1093/cercor/bhy021
复制
发表时间：
2019-03-01
期刊：
影响因子：
3.7
通讯作者：
Ayata, Cenk
中科院分区：
文献类型：
--
作者：
Chung, David Y.;Sadeghian, Homa;Ayata, Cenk
皮层扩散性去极化（SD）是偏头痛先兆背后的电生理事件，也是脑损伤后继发性损害的关键因素。SD的实验模型已经在偏头痛和脑损伤研究中使用了几十年;然而，它们具有高度侵入性，通常会导致原发性组织损伤，从而降低了它们的转化价值。在这里，我们提出了一种非侵入性的方法来触发SD使用光诱导的去极化在转基因小鼠表达通道视紫红质-2的神经元（Thy 1-ChR 2-YFP）。使用光纤通过完整颅骨的焦点照明（470 nm，1-10 mW）引起功率依赖性的稳定细胞外电位偏移和细胞外[K+]的局部升高，当功率超过阈值时，其在SD中达到顶点。使用该模型，我们表明纯合子小鼠对SD明显更敏感（即，更低的光阈值）。此外，我们发现SD的易感性显着不同的皮质分区（电机，晶须桶，感觉，视觉，在敏感性降序），这与相对通道视紫红质-2的表达。此外，NMDA受体拮抗剂MK-801阻断向SD的转变，而不减少细胞外电位偏移。总之，我们的数据表明，光遗传学SD模型非常适合于在急性和纵向研究中检查SD的生理或药理学调节。
Cortical spreading depolarization (SD) is the electrophysiological event underlying migraine aura, and a critical contributor to secondary damage after brain injury. Experimental models of SD have been used for decades in migraine and brain injury research; however, they are highly invasive and often cause primary tissue injury, diminishing their translational value. Here we present a non-invasive method to trigger SDs using light-induced depolarization in transgenic mice expressing channelrhodopsin-2 in neurons (Thy1-ChR2-YFP). Focal illumination (470 nm, 1-10 mW) through intact skull using an optical fiber evokes power-dependent steady extracellular potential shifts and local elevations of extracellular [K+] that culminate in an SD when power exceeds a threshold. Using the model, we show that homozygous mice are significantly more susceptible to SD (i.e., lower light thresholds) than heterozygous ChR2 mice. Moreover, we show SD susceptibility differs significantly among cortical divisions (motor, whisker barrel, sensory, visual, in decreasing order of susceptibility), which correlates with relative channelrhodopsin-2 expression. Furthermore, the NMDA receptor antagonist MK-801 blocks the transition to SD without diminishing extracellular potential shifts. Altogether, our data show that the optogenetic SD model is highly suitable for examining physiological or pharmacological modulation of SD in acute and longitudinal studies.