# MECHANISMS OF CSD-EVOKED PERSISTENT ACTIVATION OF MENINGEAL NOCICEPTORS

> **NIH NIH R01** · BETH ISRAEL DEACONESS MEDICAL CENTER · 2020 · $410,463

## Abstract

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.

## Key facts

- **NIH application ID:** 9934285
- **Project number:** 5R01NS078263-07
- **Recipient organization:** BETH ISRAEL DEACONESS MEDICAL CENTER
- **Principal Investigator:** DAN LEVY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,463
- **Award type:** 5
- **Project period:** 2013-07-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934285

## Citation

> US National Institutes of Health, RePORTER application 9934285, MECHANISMS OF CSD-EVOKED PERSISTENT ACTIVATION OF MENINGEAL NOCICEPTORS (5R01NS078263-07). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9934285. Licensed CC0.

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