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Meningeal nociception and migraine-related visual cortex hyperexcitability

Award Number: R21NS147222
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/15/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Meningeal nociception and migraine-related visual cortex hyperexcitability - Migraine is top causes a multifactorial disorder characterized by recurrent attacks of severe headaches and is one of the of global disability. Although the origin of migraine remains unclear, consistent findings of visual cortex hyperexcitability may offer insights into its pathogenesis. Visual cortex hyperexcitability is thought to increase susceptibility to cortical spreading depolarization (CSD), an aberrant neurophysiological event that mediates migraine visual auras and drives trigeminal nociception, producing migraine headache. Visual cortex hyperexcitability is also a common feature of migraine without aura and may trigger migraine headaches independent of CSD. Despite its high prevalence and proposed role in migraine headache triggering, we lack a clear understanding of the factors underlying visual cortex hyperexcitability in migraine. Activation of meningeal nociceptors and the subsequent release of neuropeptides from their peripheral terminals is thought to play a crucial role in the genesis of migraine headaches. Clinical data suggest a potential feedforward mechanism where meningeal nociception drives visual cortex hyperexcitability in migraine. Activated nociceptors regulate tissue immunity, including T cell expansion, and recent work suggests that T cells in the cranial dura mater can directly influence brain neuronal function via the cytokines they produce. In this exploratory project, we will test the novel idea that repeated meningeal nociceptor cortex hyperexcitability, including increased CSD activation linked to multiple migraine attacks promotes visual triggering susceptibility, mediated via dural T cell-to-cortex signaling . We will employ a novel combination of powerful, all-optical, non-invasive methods in transgenic mice, including optogenetic activation of meningeal nociceptors, 2-photon calcium imaging of visual cortex activity, optogenetic CSD-triggering, and pharmacological approaches, using selective antibodies, to target dural T cells and their cytokines. We will first characterize changes in visual cortex responses indicative of cortical hyperexcitability, including a decreased CSD triggering threshold following repeated activation of meningeal nociceptors. We will then explore whether meningeal nociceptor activation affects the dural T cell niche, which in turn mediates the migraine-related visual cortex hyperexcitability. Collectively, this new line of research will fundamentally advance our understanding of migraine pathophysiology and provide an experimental foundation for future explorations of mechanistic insights into the contribution of the meningeal nociceptor-immune axis to sensory cortex dysfunction and headache triggering.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $283,037 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/6/2026	NEW	$283,037
														Subtotal = $283,037

Grand Total All Awards = $283,037

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Meningeal nociception and migraine-related visual cortex hyperexcitability

Award Number: R21NS147222

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/15/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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