Development of a multi-modal mouse model of cluster headache

About This Grant

PROJECT SUMMARY / ABSTRACT Cluster headache (CH), which affects about 1 in 1,000 people, is a severe and debilitating primary headache disorder characterized by repeated attacks occurring in clusters over weeks or months. CH has clearly defined features: severe pain (worse than childbirth), facial autonomic changes (such as a watery eye), restlessness, and a striking circadian pattern of attacks (at the same time each day like clockwork in approximately 70.5% of patients). CH also has a well-defined pathophysiology of 3 systems: the trigeminovascular pain system, the autonomic nervous system, and the hypothalamic system (in particular the posterior hypothalamus, the first brain area activated during an attack). Despite the well-known features and systems involved in CH, no disease- specific treatments are available: all CH treatments are repurposed medications from other diseases. This lack of CH-specific treatments is due in large part to the lack of a viable animal model that faithfully recapitulates the aforementioned CH features. To develop a specific animal model for CH, we previously studied a trigeminovascular headache model (repeated nitroglycerin injections), and discovered a circadian pattern of pain responses that reflects the clockwork-like pattern of attacks in CH patients. Furthermore, our analysis also identified a recently discovered CH modifier gene Mertk (MER proto-oncogene, tyrosine receptor kinase) to be highly rhythmically expressed in the trigeminal ganglion. Deletion of Mertk (Mertk-KO) altered the normal circadian rhythm of pain sensitivity by increasing pain sensitivity over 24 hours. Finally, activation of the posterior hypothalamus (via c-Fos staining) was observed after NTG administration in wild-type mice. Based on these exciting preliminary findings, we hypothesize that a combination of trigeminovascular (nitroglycerin), genetic (Mertk-KO), and hypothalamic (direct optogenetic activation of the posterior hypothalamus) manipulations will generate the first multi-modal animal model of CH. In Aim 1 (the R61 phase), we will determine the contributions of each aspect of our combined model, alone or in combination (a 4x2 grid of NTG or control, Mertk KO mouse or wild-type control, and optogenetic injection or control). Our milestone for progression to the R33 phase will be significant differences in at least two pain behaviors in our model compared to controls. In Aims 2 and 3 (the R33 phase), we will validate our model through face validity (lacrimation and restlessness), construct validity (CGRP, PACAP, and VIP in the trigeminal ganglion and hypothalamus), and predictive validity (ability of first-line and new treatments to ameliorate the pain behaviors of our model). This project is highly significant and innovative, addressing a profound need for a specific and comprehensive animal model for this devastating yet understudied disease. With the unique combination of complementary expertise in CH (laboratory and clinical), circadian biology, pharmacology, optogenetics and pain, we are ideally suited to generate this combined CH model with the goal of providing insights into CH pathophysiology and developing novel therapeutics.