Migraine is often a chronic and progressive disorder with important hormonal, vascular and genetic modulating factors. Among the important experimental advances has been the development of mouse models of migraine expressing human mutations in implicated genes, as well as data implicating cortical spreading depression (CSD) in migraine aura. Preliminary data show that mouse models with mutations in genes implicated in severe and progressive migraine are more susceptible to CSD as well as to stroke. Furthermore, sex modulates CSD susceptibility in female mutant mice that is lost after gonadectomy or when estrus cycling ceases. Particularly underappreciated is that migraineurs are more susceptible to white matter changes and are at higher risk for stroke, and that vascular as well as brain parenchymal mechanisms are important to migraine pathophysiology. This application proposes to examine important questions about mechanisms of migraine aura that are relevant to understand the susceptibility for increasing headache frequency and progression (see RFA).
Aim 1 will test the hypothesis that CSD susceptibility is increased by mutations linked to migraine (2 mutations in the 11A subunit of CaV2.1 channel, and in the blood vessel specific Notch3 receptor), further supporting the notion that CSD susceptibility is a common pathophysiological mechanism.
Aim 1 also proposes to test whether female mice harboring mutations in two different genes (CaV2.1 and Notch3) and in two distinct loci in the CaV2.1 channel are more susceptible to CSD compared to males and whether enhanced susceptibility in females is sex hormone but not gender specific.
Aim 2 will attempt to establish a link between these mutations implicated in migraine, and susceptibility to stroke and white matter lesions. We will test the hypothesis that vascular and metabolic mechanisms linked to increased CSD susceptibility promote greater flow- metabolism mismatch in mutants than in controls, as determined using novel optical imaging methods (CBF, oxygenation), autoradiography, and molecular stress markers.
Aim 3 will further study these mutations by testing the hypothesis that CSD susceptibility conferred by genetic mechanisms renders the brain more sensitive to the development of stroke, and of white matter lesions in the presence of mild ischemia. Taken together these experiments are intended to examine mechanisms underlying progression of migraine and its neuropathological consequences. Migraine is a highly prevalent neurological disorder that is clinically associated with increased risk of brain injury such as stroke. This research will help identify the mechanisms by which risk factors for migraine predispose individuals to stroke and other types of brain injury, and open new avenues of research to prevent these long term progressive and cumulative complications of migraine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS061505-05
Application #
8213639
Study Section
Special Emphasis Panel (ZNS1-SRB-R (30))
Program Officer
Porter, Linda L
Project Start
2008-01-15
Project End
2013-12-31
Budget Start
2012-01-01
Budget End
2013-12-31
Support Year
5
Fiscal Year
2012
Total Cost
$357,530
Indirect Cost
$140,614
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Chen, Shih-Pin; Ay, Ilknur; de Morais, Andreia Lopes et al. (2016) Vagus nerve stimulation inhibits cortical spreading depression. Pain 157:797-805
Seidel, Jessica L; Escartin, Carole; Ayata, Cenk et al. (2016) Multifaceted roles for astrocytes in spreading depolarization: A target for limiting spreading depolarization in acute brain injury? Glia 64:5-20
von Bornstädt, Daniel; Houben, Thijs; Seidel, Jessica L et al. (2015) Supply-demand mismatch transients in susceptible peri-infarct hot zones explain the origins of spreading injury depolarizations. Neuron 85:1117-31
Mawet, Jerome; Kurth, Tobias; Ayata, Cenk (2015) Migraine and stroke: in search of shared mechanisms. Cephalalgia 35:165-81
Srinivasan, Vivek J; Yu, Esther; Radhakrishnan, Harsha et al. (2015) Micro-heterogeneity of flow in a mouse model of chronic cerebral hypoperfusion revealed by longitudinal Doppler optical coherence tomography and angiography. J Cereb Blood Flow Metab 35:1552-60
Mawet, Jerome; Eikermann-Haerter, Katharina; Park, Kwang-Yeol et al. (2015) Sensitivity to acute cerebral ischemic injury in migraineurs: A retrospective case-control study. Neurology 85:1945-9
Eikermann-Haerter, Katharina; Lee, Jeong Hyun; Yalcin, Nilufer et al. (2015) Migraine prophylaxis, ischemic depolarizations, and stroke outcomes in mice. Stroke 46:229-36
Blasi, Francesco; Whalen, Michael J; Ayata, Cenk (2015) Lasting pure-motor deficits after focal posterior internal capsule white-matter infarcts in rats. J Cereb Blood Flow Metab 35:977-84
Eikermann-Haerter, Katharina; Arbel-Ornath, Michal; Yalcin, Nilufer et al. (2015) Abnormal synaptic Ca(2+) homeostasis and morphology in cortical neurons of familial hemiplegic migraine type 1 mutant mice. Ann Neurol 78:193-210
Sakadžić, Sava; Lee, Jonghwan; Boas, David A et al. (2015) High-resolution in vivo optical imaging of stroke injury and repair. Brain Res 1623:174-92

Showing the most recent 10 out of 42 publications