Optogenetic Spreading Depression Elicits Trigeminal Pain and Anxiety Behavior

Abstract

Objective Cortical spreading depression (SD) is an intense depolarization underlying migraine aura. Despite the weight of evidence linking SD to the pain phase of migraine, controversy remains over a causal role of SD in cephalgia because of the invasive nature of previous SD induction methods. To overcome this problem, we used a novel minimally invasive optogenetic SD induction method and examined the effect of SD on behavior. Methods Optogenetic SD was induced as a single event or repeatedly every other day for 2 weeks. End points, including periorbital and hindpaw mechanical allodynia, mouse grimace, anxiety, and working memory, were examined in male and female mice. Results A single SD produced bilateral periorbital mechanical allodynia that developed within 1 hour and resolved within 2 days. Sumatriptan prevented periorbital allodynia when administered immediately after SD. Repeated SDs also produced bilateral periorbital allodynia that lasted 4 days and resolved within 2 weeks after the last SD. In contrast, the hindpaw withdrawal thresholds did not change after repeated SDs suggesting that SD‐induced allodynia was limited to the trigeminal region. Moreover, repeated SDs increased mouse grimace scores 2 days after the last SD, whereas a single SD did not. Repeated SDs also increased thigmotaxis scores as a measure of anxiety. In contrast, neither single nor repeated SDs affected visuospatial working memory. We did not detect sexual dimorphism in any end point. Interpretation Altogether, these data show a clinically congruent causal relationship among SD, trigeminal pain, and anxiety behavior, possibly reflecting SD modulation of hypothalamic, thalamic, and limbic mechanisms. ANN NEUROL 2021;89:99–110

Continuous long‐term recording and triggering of brain neurovascular activity and behaviour in freely moving rodents

“…It has been used for decades as a translational model of migraine (Charles & Baca, 2013). The majority of studies of CSD in rodents have been performed under anaesthesia, and those that have been performed in unanaesthetized animals have involved significantly more invasive methods than those described in the current study (Houben et al 2017;Harriott et al 2020). The ability to trigger and record CSD repeatedly in a freely behaving animal over extended time periods represents a new opportunity to examine the effects of CSD on physiological and behavioural parameters, in addition to examining the effects of genetic, hormonal, circadian factors on CSD susceptibility and its clinical characteristics.…”

Kcnq2/Kv7.2 controls the threshold and bi-hemispheric symmetry of cortical spreading depolarization

“… 11 , 12 Spreading depolarization may remain clinically silent, or promote malignant neurovascular inflammation that may contribute to longer lasting neurological deficits. 13 , 14 …”

Review and Hypothesis: A Potential Common Link Between Glial Cells, Calcium Changes, Modulation of Synaptic Transmission, Spreading Depression, Migraine, and Epilepsy—H+

“…Migraines are a heterogenous set of headache-related maladies reported to occur in many different parts of the brain and appear to involve widespread changes in multiple neuronal pathways and involve a number of neurochemical mediators [Davidoff, 2002;Charles, 2013; Headache Classification Committee of the International Headache Society (IHS) ( 2013)]. The aura perceived in certain migraines has been suggested to result from the initial spreading depolarizing wave that precedes the profound suppression of neuronal responses characteristic of spreading depression (Lauritzen, 1994;Cui et al, 2014;Charles, 2018;Major et al, 2020;Harriott et al, 2021). The pain in certain migraines following an aura might then result in part from the excessive and prolonged release of H + from glia during the period of synaptic inhibition occurring during the depression that follows the spreading depolarization.…”