Cortical pain induced by optogenetic cortical spreading depression: from whole brain activity mapping

Abstract

Background Cortical spreading depression (CSD) is an electrophysiological event underlying migraine aura. Traditional CSD models are invasive and often cause injuries. The aim of the study was to establish a minimally invasive optogenetic CSD model and identify the active networks after CSD using whole-brain activity mapping. Methods CSD was induced in mice by light illumination, and their periorbital thresholds and behaviours in the open field, elevated plus-maze and light-aversion were recorded. Using c-fos, we mapped the brain activity after CSD. The whole brain was imaged, reconstructed and analyzed using the Volumetric Imaging with Synchronized on-the-fly-scan and Readout technique. To ensure the accuracy of the results, the immunofluorescence staining method was used to verify the imaging results. Results The optogenetic CSD model showed significantly decreased periorbital thresholds, increased facial grooming and freezing behaviours and prominent light-aversion behaviours. Brain activity mapping revealed that the somatosensory, primary sensory, olfactory, basal ganglia and default mode networks were activated. However, the thalamus and trigeminal nucleus caudalis were not activated. Conclusions Optogenetic CSD model could mimic the behaviours of headache and photophobia. Moreover, the optogenetic CSD could activate multiple sensory cortical regions without the thalamus or trigeminal nucleus caudalis to induce cortical pain.

Connection between right-to-left shunt and photosensitivity: a community-based cross-sectional study

“…Hypersensitivity to light was also associated with cortical hypersensitivity within the visual cortex ( 32 ). Animal experimental research verified that air micro-emboli could trigger CSD in the posterior region of the mice's brain and induce obvious photophobia in mice ( 10 , 33 ). Moreover, functional magnetic resonance imaging (fMRI) studies described the activation of the trigeminothalamic pathway including central changes in individuals with high photosensitivity ( 34 ).…”

The effect of sex and estrus cycle stage on optogenetic spreading depression induced migraine-like pain phenotypes

“…While time spent in a light–dark box is a reliable measure of photosensitivity, it is also used to test anxiety [ 49 ] with recent studies that have attempted to address how to distinguish between the two [ 48 ]. Since our prior results demonstrate opto-SD induced anxiety-related behavior [ 24 ], and others have demonstrated freezing and reduced locomotor activity in light following opto-SD [ 35 ], we used grimace to reduce potential confounders in the interpretation of photophobia-like responses. There was increased grimace with increased light intensity for all groups except MD sham animals.…”

Optogenetic cortical spreading depolarization induces headache-related behaviour and neuroinflammatory responses some prolonged in familial hemiplegic migraine type 1 mice

“…Our optogenetic approach to induce CSD events, unlike the mostly used invasive procedures, was uniquely combined with the assessment of CSD consequences in freely behaving mice over a long period of time. In other studies optogenetics has been used to induce CSD but only the behavioural consequences typically within the first half hour were investigated [ 24 – 26 ] and focus was on immediate behavioural responses, such as locomotion, freezing, head shaking and grooming, but not on longer lasting headache-relevant behaviour. Only the study of Harriott et al .…”

“…A recent advancement to overcome such caveats is the development of a minimally invasive method to induce CSD events using optogenetics in mice that express blue light sensitive channelrhodopsin-2 in cortical neurons [ 23 ]. Only a few studies have investigated consequences of optogenically induced CSD, be it on neuroinflammation [ 20 ] or behaviour [ 24 – 26 ]. Until now, behavioural consequences were studied only shortly after (a few min to 30 min) optogenetic-induced CSD, for instance in the context of sleep-wake states [ 24 ], and typical behavioural features – abnormal locomotion, increased freezing, head shaking, prolonged facial grooming –, earlier reported with KCl-induced CSD, were also observed [ 24 , 26 ].…”

“…Only a few studies have investigated consequences of optogenically induced CSD, be it on neuroinflammation [ 20 ] or behaviour [ 24 – 26 ]. Until now, behavioural consequences were studied only shortly after (a few min to 30 min) optogenetic-induced CSD, for instance in the context of sleep-wake states [ 24 ], and typical behavioural features – abnormal locomotion, increased freezing, head shaking, prolonged facial grooming –, earlier reported with KCl-induced CSD, were also observed [ 24 , 26 ]. In only one study MGS scores, as a pain mimic, were investigated and found to be increased two days after repeated (two weeks, every other day) – but not single – induction of CSD, with the caveat that mice had coverslips placed over large craniotomies and were kept under anaesthesia every time CSDs were induced [ 27 ].…”