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Optogenetic induction of cortical spreading depression in anesthetized and freely behaving mice
Thijs Houben1, Inge Cm Loonen2, Serapio M Baca3
11 Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands.
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.
Insights
Researchers developed a novel, less invasive optogenetic method to study cortical spreading depression, a key factor in neurological disorders. This new technique allows for precise, repeatable induction and study of cortical spreading depression in mice.
Area of Science:
- Neuroscience
- Optogenetics
- Neurological Disorders
Background:
- Cortical spreading depression (CSD) is implicated in various neurological conditions.
- Traditional CSD models rely on highly invasive experimental techniques.
- A need exists for less invasive and more controlled CSD research models.
Purpose of the Study:
- To develop and validate a relatively non-invasive optogenetic model for inducing cortical spreading depression (CSD).
- To compare optogenetically induced CSD with traditional methods in terms of physiological and behavioral outcomes.
- To assess the utility of this model in both anesthetized and freely behaving mice.
Main Methods:
- Utilized transcranial stimulation of channelrhodopsin-2 in cortical layer 5 neurons to induce CSD.
- Employed intracortical DC-potentials, multi-unit activity, laser Doppler flowmetry, and optical intrinsic signal imaging for monitoring.
- Evaluated CSD characteristics and behavioral effects in anesthetized and freely behaving mice.
Main Results:
- Optogenetic CSD induction thresholds and propagation rates were comparable to invasive methods.
- CSD induced vascular and parenchymal optical intrinsic signal changes similar to KCl-evoked CSD.
- CSD in freely behaving mice showed comparable characteristics to anesthetized mice, with a shorter duration.
- CSD transiently suppressed spontaneous behavior and motor function.
Conclusions:
- Optogenetic induction offers a less invasive, cell type-selective, and repeatable method for CSD research.
- This model provides a valuable tool for studying CSD's role in neurological disorders.
- The model effectively captures key CSD features and associated behavioral deficits.
