Abstract Details

Environmental and Genetic Circadian Disruption Increases Migraine-Associated Phenotypes in Mice
Headache
S1 - Headache 1 (1:48 PM-2:00 PM)
005

Migraine is linked to circadian rhythms with attack onset disproportionately in the morning, jet lag is a known trigger, and a mutation in the clock regulatory kinase, casein kinase 1δ (CK1δ), is comorbid for migraine with aura and Familial Advance Sleep Phase (FASP). Here, we sought to explore the effect of circadian rhythms on periorbital (PO) mechanosensitivity in mice and characterize migraine-like phenotypes in transgenic mice harboring the CK1δ mutation or a second mutation for FASP affecting the clock specific protein Per2.

To investigate the role of environmental and genetic perturbations of circadian rhythms on migraine pathophysiology.

In C57bl/6J (n=24), PO mechosensitivity was measured using the von Frey assay at zeitgeber time (ZT) 0, 6, 12, 18; chronic jet lag was modelled by changing light cycles and mechanosensitivity assessed at ZT0 and 12. Migraine-like phenotypes including cortical spreading depression (CSD) and nitroglycerin-induced PO mechanosensitivity were assessed in CK1δ-T44A (n=24), Per2-S662G (n=25) and WT littermates (n=47). CSD was chemically induced (1M KCl) in anaesthetized mice and recorded for 1hr. Mechanosensitivity was measured at baseline and 2hrs post nitroglycerin (5mg/kg i.p.).

PO mechanosensitivity exhibits circadian variation (F2,26=25.40; p<0.0001). Additionally, thresholds were significantly lower at both time points after changing light cycles (ZT0: t44 = 2.74, p<0.05; ZT12: t44 = 5.87, p<0.0001). Both transgenic lines showed increased CSD susceptibility (WT=7, CK1δ-T44A=10; U=12, p<0.0001) (WT=6, Per2-S662G=7; U=30, p<0.05). Transgenics also showed increased PO mechanosensitivity following nitroglycerin (WT vs CK1δ-T44A: F1,22=41.61; p<0.0001; WT vs Per2-S662G: F1,22=32.13; p<0.0001)

C57bl/6J exhibit circadian variation in PO mechanosensitivity suggestive of a rhythmicity in sensory processing that could underlie the circadian nature of migraine. Additionally, changing light cycles seems to impact migraine-relevant pain processing. Furthermore, disruption to Per2 is, at least in part, sufficient to induce migraine-like phenotypes, implicating a purely circadian gene in migraine pathophysiology for the first time.

Authors/Disclosures
Lauren Strother (King s College London)
PRESENTER
No disclosure on file
Louis J. Ptacek, MD (UCSF - HHMI) Dr. Ptacek has nothing to disclose.
Peter Goadsby, MD, PhD, FRS (University of California, Los Angeles) Dr. Goadsby has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Abbvie. Dr. Goadsby has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Eli-Lilly. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Aurene. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Teva Pharmaceuticals. Dr. Goadsby has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Lundbeck. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Satsuma. Dr. Goadsby has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Pfizer. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Shiratronics. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for CoolTech LLC. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Linpharma. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for PureTech Health LLC. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Vial. Dr. Goadsby has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Aeon Biopharma. Dr. Goadsby has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Massachusetts Medical Society. The institution of Dr. Goadsby has received research support from NIHR. The institution of Dr. Goadsby has received research support from Kallyope. Dr. Goadsby has received publishing royalties from a publication relating to health care. Dr. Goadsby has received publishing royalties from a publication relating to health care. Dr. Goadsby has a non-compensated relationship as a Trustee with Migraine Trust that is relevant to AAN interests or activities. Dr. Goadsby has a non-compensated relationship as a Trustee with Organisation for Understanding Cluster Headache (UK) that is relevant to AAN interests or activities. Dr. Goadsby has a non-compensated relationship as a Executive roles with American Headache Society that is relevant to AAN interests or activities.
No disclosure on file