Fizyolojik Uyarılarla Kortikal Yayılan Depresyonun Oluşturulması

Abstract

Migraine is a primary headache disorder with an annual prevalence of 12-15% in the general population, causing considerable disability and productivity loss. Migraine aura is associated with cortical spreading depression (CSD) waves occurring in the brain. Recent studies showed that CSD itself triggers headache, which follows aura within 60 minutes. Hence, CSD has been widely used to model migraine in experimental research. However, the methods to induce CSD in animals involve direct mechanical, electrical or chemical stimuli to the brain, which do not constitute a proper representation of the actual attack initiation in migraineurs. On the other hand, it is well known that a migraine attack can be triggered by a variety of factors such as stress, intense light exposure, exercise, fasting, certain foods, sleep disturbances and hormonal imbalance. Therefore, in this study, we hypothesized that CSD can be induced by intense sensory stimulation in the susceptible mouse brain. We applied ouabain, a Na+-K+ ATPase blocker, topically to the relevant sensory cortex (visual or somatosensory) to make mouse brain susceptible to CSD (migraine), and used intense photic or whisker stimulation to trigger CSD. Increasing doses of ouabain were found to be associated with higher frequencies of spontaneous CSDs, and the threshold concentration to induce CSD was determined as 0.1 mM. Photic or whisker stimulation started at least 30 minutes after the last spontaneous CSD following the ouabain application were found to increase the CSD incidence significantly. Furthermore, we visualized extracellular potassium increases with a florescent potassium indicator, APG-4, during the CSD and sensory stimulation. Taken together, these findings show that CSD (aura) can be triggered in the susceptible mouse brain (like in migraineurs) with intense sensory stimulation, and this induction is possibly caused by extracellular potassium rise. This thesis study therefore lends support to the role of CSD in migraine pathophysiology, and also opens new avenues for the development of more realistic and physiologic experimental migraine models. Better understanding of CSD initiation and propagation mechanisms will eventually lead to more efficient preventive and therapeutic interventions in migraine.