Migraine is one of the top leading causes of disability worldwide. Existing treatments remain elusive for many
patients, and development of novel treatments approaches has been limited due to the incomplete understanding
of migraine pathogenesis.
A large body of work now supports the notion that migraine headache involves the
trigeminal sensory system that innervates the cerebral meninges and their related large vessels, but it remains
unclear how this sensory system becomes activated
during a migraine attack. One leading line of evidence
points to the role of cortical dysfunction in triggering migraine headache, and is supported by the findings that
cortical spreading depression (CSD) can cause the activation and sensitization of neurons in the meningeal
nociceptive pathway. However, CSD is thought to trigger the headache in only the small subset of attacks that
are accompanied by aura. Sensory cortex hyperexcitability has also been documented in migraine without aura.
However, it is unclear whether and how such cortical dysfunction, beyond CSD, might lead to meningeal
nociception and the ensuing generation of headache. The notions that (i) cortical hyperexcitability can drive
abnormal activation of cortical astrocytes via their diverse GPCRs, and (ii) that this would result in excessive
release of numerous astrocytic factors with algesic properties that can propagate into the meninges, has led us
to hypothesize that heightened cortical astrocyte GPCR-linked signaling, unrelated to CSD, is sufficient to drive
the meningeal sensory pathway
. To test our working hypothesis, we will first determine whether selective
activation of sensory cortical astrocyte Gq- and Gi-GPCR pathways are sufficient to drive meningeal nociceptors,
and whether enhanced astrocytic GPCRR-linked
Ca2+ signaling plays a role (Aim 1). We will then examine
whether such enhanced cortical astrocyte signaling can also promote migraine-like pain behaviors (Aim 2).
Because calcitonin gene-related peptide (CGRP) is critically involved migraine pathophysiology, but its role is
still not well understood, we will further test whether the cortical astrocyte mediated meningeal nociceptive
responses and related migraine behavioral phenotype involve peripheral CGRP signaling within the intracranial
dura mater (Aim 3). To address these research questions, we will employ a state-of-the-art chemogenetic
DREADD (“designer receptors exclusively activated by designer drugs”) tools, as well as optogenetics, to
selectively promote activation of astrocyte GPCR pathways. We will combine these approaches with in vivo
extracellular single-unit recording , 2-photon calcium imaging, behavioral approaches, as well as genetic
manipulations to interrogate the meningeal nociceptive consequences of enhanced sensory cortical Gq- and Gi-
linked Ca2+ signaling. Taken together, our proposed research could reveal increased astrocyte GPCR signaling
as a key mechanism that links sensory cortex hyperexcitability and headache genesis in in migraine attacks that
do not involve CSD and aura.