Optogenetic cortical spreading depression originating from the primary visual cortex induces migraine-like pain and anxiety behaviors in freely moving C57BL/6 J mice.

Background: Migraine is the second disabling neurological disorder with a high prevalence. Aura occurs in one-third of migraineurs and visual aura accounts for over 90%. Cortical spreading depression (CSD) underlies aura and might trigger migraine headaches. Compared with CSD induction by invasive electrical, chemical, or mechanical stimulation, optogenetics avoids direct influences on meninges in the stimulation process. However, previous optogenetic CSD models mainly use Thy1-ChR2-YFP or CaMKIIα-cre transgenic mice. They are limited when the pathogenesis study requires transgenic mice to express other specific promotor, such as the dopamine or serotonin transporter promotor. In addition, reported behavioral paradigms were based on CSD induction under anesthesia. This study aimed to establish an optogenetic CSD-induced migraine model originating in the primary visual cortex (VISp) in C57BL/6 J mice and presented the behavioral paradigm when CSD induction was under awake condition.

Methods: We performed viral transduction for the expression of light-sensitive channelrhodopsin-2 in pyramidal neurons of VISp in C57BL/6 J mice. Regional cerebral blood flow (rCBF) was measured by laser speckle flowmetry to confirm CSD induction. The von Frey, light-dark box, elevated plus maze, and open field test were conducted to verify migraine-related behaviors in freely moving mice.

Results: An optogenetic stimulus induced typical spreading triphasic rCBF change with a reduction of over 20%, confirming CSD induction. A single unilateral CSD in freely moving C57BL/6 J mice triggered bilateral periorbital and hind-paw allodynia lasting for 4-24 h. Notably, the ipsilateral periorbital mechanical threshold was significantly lower than the contralateral at 1 h. It also generated photophobia and anxiety behaviors persisting for 24-48 h. Furthermore, cutaneous allodynia and anxiety behaviors were alleviated by sumatriptan.

Conclusions: This study proposes an optogenetic CSD-induced migraine model originating from VISp in awake and freely moving C57BL/6 J mice and presents the behavioral paradigm in detail. The CSD model in wild-type mice is promising to be wildly used to study the pathogenesis of MwA.