Harriott, Andrea M.Chung, David Y.Uner, AylinBozdayi, Refik O.Morais, AndreiaTakizawa, TsubasaQin, TaoAyata, Cenk2021-04-192021-04-1920200364-5134http://hdl.handle.net/11727/5742Objective 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 2020enginfo:eu-repo/semantics/closedAccessCENTRAL TRIGEMINOVASCULAR NEURONSANTERIOR CINGULATE CORTEXCUTANEOUS ALLODYNIAFOS EXPRESSIONNUCLEUS CAUDALISMIGRAINEMODELACTIVATIONHEADACHEAURAarticle891991100005843030000012-s2.0-85093917474