Project Summary/Abstract: This is a five-year career development proposal examining sex differences in
gonadal hormone and hypothalamic involvement in migraine with aura using cortical spreading depression as a
model. The candidate is an Instructor at Harvard Medical School and a physician at the Massachusetts General
Hospital in the Department Neurology, Division of Headache and Neuropathic Pain. This proposal advances the
candidate’s prior experience with a combination of optogenetic, chemogenetic, machine learning and
transcriptomic approaches to studying sex differences in migraine mechanisms in vivo. This proposal also
interfaces with the candidate’s clinical expertise in treating migraine and other disabling headache disorders.
The training plan focuses on enhancing the candidate’s aptitude in the field of sex differences migraine research
and gaining discrete skills in cutting edge experimental methods through an intensive supervised training
experience incorporating the expert knowledge of co-mentors Prof. Cenk Ayata, MD PhD who specializes in
spreading depression and Prof. Ursula Kaiser, MD who specializes in hypothalamic, sex and gonadal hormones.
The training program will enable the candidate’s transition to an independent research career whose long-term
goal is to discover sex dependent mechanisms of migraine.
Migraine accounts for considerable global suffering and disproportionately affects women. Cortical spreading
depression (SD), a slow wave of neuronal and glial depolarization, is responsible for migraine with aura and is
widely used as a preclinical migraine model. SD can activate meningeal nociceptors and sensitize second order
neurons in the trigeminal nucleus caudalis (TNC). Furthermore, minimally invasive optogenetic SD produces
periorbital allodynia and increases mouse grimace, behavioral evidence of trigeminal nociceptive activation. That
migraine starts after menarche, worsens during menstruation, and abates after menopause implicates gonadal
hormones in migraine. Moreover, a growing body of evidence supports a role for the hypothalamus, one of the
most sexually dimorphic regions of the brain, in migraine. Activation of hypothalamic neurons, including those
expressing neuropeptide orexin, could act to mitigate the impact of SD on trigeminal pain via descending
inhibition of TNC neurons. However, sex differences in gonadal hormone modulation of migraine-relevant
behavior or the role of the hypothalamus has not been systematically investigated. Specifically, this proposal
aims to (1) investigate sex differences in female and male gonadal hormone modulation of SD-induced migraine-
relevant behaviors, (2) examine sex and hormonal influences on SD-induced lateral hypothalamic gene
expression and (3) examine sex differences in orexinergic modulation of SD-induced trigeminal pain behavior.
At the end of the proposed experiments, study results are expected to enhance the fundamental understanding
of mechanisms of sex differences in migraine with aura and contribute to uncovering putative targets for
subsequent mechanistic studies of sex specific hypothalamic neuronal involvement in migraine.