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Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice.

ABSTRACT: Cortical spreading depression, which plays an important role in multiple neurological disorders, has been studied primarily with experimental models that use highly invasive methods. We developed a relatively non-invasive optogenetic model to induce cortical spreading depression by transcranial stimulation of channelrhodopsin-2 ion channels expressed in cortical layer 5 neurons. Light-evoked cortical spreading depression in anesthetized and freely behaving mice was studied with intracortical DC-potentials, multi-unit activity and/or non-invasive laser Doppler flowmetry, and optical intrinsic signal imaging. In anesthetized mice, cortical spreading depression induction thresholds and propagation rates were similar for invasive (DC-potential) and non-invasive (laser Doppler flowmetry) recording paradigms. Cortical spreading depression-related vascular and parenchymal optical intrinsic signal changes were similar to those evoked with KCl. In freely behaving mice, DC-potential and multi-unit activity recordings combined with laser Doppler flowmetry revealed cortical spreading depression characteristics comparable to those under anesthesia, except for a shorter cortical spreading depression duration. Cortical spreading depression resulted in a short increase followed by prolonged reduction of spontaneous active behavior. Motor function, as assessed by wire grip tests, was transiently and unilaterally suppressed following a cortical spreading depression. Optogenetic cortical spreading depression induction has significant advantages over current models in that multiple cortical spreading depression events can be elicited in a non-invasive and cell type-selective fashion.

SUBMITTER: Houben T

PROVIDER: S-EPMC5435281 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice.

Houben Thijs T Loonen Inge Cm IC Baca Serapio M SM Schenke Maarten M Meijer Johanna H JH Ferrari Michel D MD Terwindt Gisela M GM Voskuyl Rob A RA Charles Andrew A van den Maagdenberg Arn Mjm AM Tolner Else A EA

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20160101 5

Cortical spreading depression, which plays an important role in multiple neurological disorders, has been studied primarily with experimental models that use highly invasive methods. We developed a relatively non-invasive optogenetic model to induce cortical spreading depression by transcranial stimulation of channelrhodopsin-2 ion channels expressed in cortical layer 5 neurons. Light-evoked cortical spreading depression in anesthetized and freely behaving mice was studied with intracortical DC- ...[more]

PMID: 27107026

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Project description:BackgroundMigraine 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.MethodsWe 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.ResultsAn 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.ConclusionsThis 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.

Dataset Information

Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice.

Publications

Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice.

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