Response Properties of Meningeal Afferents in Health and Migraine

The cranial meninges, which provide a physical and immunological barrier to protect the brain, are innervated by a network of trigeminal primary afferent sensory neurons. A large body of indirect evidence points to meningeal afferents' involvement in migraine headache genesis. However, we do not yet have a clear understanding of the normal sensory function of meningeal afferents and how they become engaged in migraine. Our current knowledge about the response properties of meningeal afferents has been almost exclusively derived from single-unit recordings of dural afferents from their TG somata in anesthetized rats with surgically exposed and depressurized meninges. Yet, these recordings have only provided a coarse description of the stimuli sensed by the diversity of meningeal afferents. To better understand the function of meningeal afferents, we recently developed a two-photon, GCaMP-based Ca2+ imaging approach to monitor their responses to a large set of complex physiological and pathological stimuli in the intact intracranial space of awake mice. By imaging the activity of meningeal afferent fibers in naïve mice via a closed cranial window, we made the surprising observations that despite their presumed nociceptive function, a large subset of afferents becomes activated during brief locomotion bouts and displays distinct dynamics to various levels of meningeal deformations that occur in response to locomotion. We now propose to leverage our newly developed imaging approach to advance our understanding of the sensory function of meningeal afferents and how their response properties are modulated under conditions that have been implicated in migraine headaches in humans Studies in Aim 1 will investigate the novel idea that the meningeal sensory system is tuned to sense a wide range of interoceptive mechanical stimuli, including physiological meningeal vasodilation and intracranial pressure elevations. In Aim 2, we will test the prediction that migraine triggers amplify these normal sensory responses. Aim 3 is to explore the relative contribution of the mechanosensitive Piezo2 channel in mediating the afferents' responses to normal intracranial interoceptive signals and their amplification following the administration of migraine triggers. Our proposed studies and innovative approach to image the activity of meningeal afferents could provide a dramatically better understanding of the role of the meningeal sensory system in homeostasis and under pathophysiological conditions that lead to migraine. Advances made could accelerate preclinical translational headache research.