Migraine is the second leading cause of disability worldwide; however, it remains unclear how the headache phase is initiated during a migraine attack. In migraine with aura, a condition that affects about 30% of people with migraine, the leading theory proposes that (a) cortical spreading depression (CSD) is the pathophysiological event that underlies the aura phase, and b) CSD somehow leads to the activation of the meningeal sensory system, resulting in the onset of the headache. Our recent studies, including during the prior grant period, provided a long-missing critical piece of support for the theory by finally showing that CSD does in fact activate meningeal sensory afferents, and can produce a prolonged period of both activation and mechanical sensitization. However, a long-standing problem with the CSD theory has been the paucity of evidence that CSD leads to pain behaviors, as would be expected for an event that supposedly is a potent trigger for headache. Furthermore, efforts to establish a link between CSD, the ensuing meningeal afferent responses, and headache pain have been limited by the challenges of studying the activity of meningeal sensory neurons in awake behaving animals. We have overcome this major obstacle by developing a two- photon calcium imaging approach to monitor the activity of meningeal afferent nerve endings in the awake behaving mouse, during voluntary locomotion via a chronic cranial window.
In Aim 1, we propose to pursue this novel imaging approach to expand upon preliminary data suggesting that as a result of CSD-induced mechanical sensitization, meningeal stretching during voluntary locomotion results in enhanced activation of meningeal afferents, and consequent reduction of locomotion.
Aims 2 and 3 are to explore cellular and molecular mechanisms that contribute to meningeal nociception following CSD. We will build upon preliminary results and use electrophysiology in anesthetized animals, calcium imaging in awake mice and an optogenetic approach to test the hypothesis that cortical astrocytes play a causal role in mediating the enhanced meningeal afferent responses and related decrease in voluntary locomotion following CSD. We will then employ biosensors, electrophysiology, afferent calcium imaging, pharmacological inhibitors and transgenic mice to test the hypothesis that astrocyte-dependent cortical ATP efflux contributes to CSD-evoked meningeal nociception via purinergic P2X7 signaling in meningeal macrophages. These innovative experiments, in addition of establishing a novel powerful platform for studying the responses of meningeal afferents and associated behavioral consequences related to migraine headache, could also shed light on the roles of cortical astrocytes and meningeal purinergic signaling, as well as sex differences in the mechanisms responsible for migraine pain - a key step towards mitigating the painful effects of CSD in migraine with aura.

Public Health Relevance

Migraine is the second leading cause of disability worldwide; however, it remains unclear how the headache phase is initiated during a migraine attack. The proposed project will employ innovative two-photon calcium imaging, electrophysiology, neuropharmacology and optogenetic approaches to explore how cortical spreading depression, which mediates the aura of migraine, also contributes to the onset of the headache in migraine by enhancing the activity and sensitivity of sensory neurons that innervate the intracranial meninges. A detailed understanding of this biological process could lead to new insights and novel therapeutic targets for combating migraine headache.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS078263-07
Application #
9934285
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Oshinsky, Michael L
Project Start
2013-07-15
Project End
2023-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
7
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Levy, Dan; Abdian, Lorin; Dekel-Steinkeller, Michal et al. (2018) Experimental evidence for weaker endogenous inhibition of trigeminal pain than extra-trigeminal pain in healthy individuals. Cephalalgia 38:1307-1315
Zhao, Jun; Levy, Dan (2018) Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset. J Neurosci 38:5053-5066
Bree, Dara; Levy, Dan (2018) Development of CGRP-dependent pain and headache related behaviours in a rat model of concussion: Implications for mechanisms of post-traumatic headache. Cephalalgia 38:246-258
Levy, Dan; Labastida-Ramirez, Alejandro; MaassenVanDenBrink, Antoinette (2018) Current understanding of meningeal and cerebral vascular function underlying migraine headache. Cephalalgia :333102418771350
Zhao, Jun; Levy, Dan (2018) The CGRP receptor antagonist BIBN4096 inhibits prolonged meningeal afferent activation evoked by brief local K+ stimulation but not cortical spreading depression-induced afferent sensitization. Pain Rep 3:e632
Gariepy, Helaine; Zhao, Jun; Levy, Dan (2017) Differential contribution of COX-1 and COX-2 derived prostanoids to cortical spreading depression-Evoked cerebral oligemia. J Cereb Blood Flow Metab 37:1060-1068
Zhao, Jun; Bree, Dara; Harrington, Michael G et al. (2017) Cranial dural permeability of inflammatory nociceptive mediators: Potential implications for animal models of migraine. Cephalalgia 37:1017-1025
Levy, Dan; Edut, Shahaf; Baraz-Goldstein, Renana et al. (2016) Responses of dural mast cells in concussive and blast models of mild traumatic brain injury in mice: Potential implications for post-traumatic headache. Cephalalgia 36:915-23
Zhao, Jun; Levy, Dan (2016) Cortical Spreading Depression Promotes Persistent Mechanical Sensitization of Intracranial Meningeal Afferents: Implications for the Intracranial Mechanosensitivity of Migraine. eNeuro 3:
Benromano, T; Defrin, R; Ahn, A H et al. (2015) Mild closed head injury promotes a selective trigeminal hypernociception: implications for the acute emergence of post-traumatic headache. Eur J Pain 19:621-8

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