2023 MSC Poster Contest Presentation: Sex differences in central amygdala response to parabrachial calcitonin gene- related peptide (CGRP) release

The 2023 MSC Emerging Science Contest for Early-Career Investigators took place on December 13, 2023. Below is a written summary of one of the presentations from the contest. Read about other presentations from the event in our Early-Career Science Library.

Category: Special sensory systems/co-morbidities

Runner up: Rebecca Lorsung, MD/PhD student, University of Maryland, US

Title: Sex differences in central amygdala response to parabrachial calcitonin gene- related peptide (CGRP) release.

Hypothesis, methodology, findings and conclusions.

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is linked to chronic pain, and plays a causal role in migraine onset and maintenance. Migraine is far more prevalent in female patients (female-to-male ratio of 3:1). Sex differences in CGRP signaling may underlie this sex difference in migraine susceptibility; my work investigates whether CGRP exerts a sex-dependent effect in key brain regions involved in pain processing.

A prime target for this investigation is the parabrachial nucleus (PB), a major source of CGRP in the central nervous system, which projects to the central amygdala, a processing hub for negative emotions. Previous work suggests that CGRP increases neuronal activity by potentiating neuronal responses to excitatory glutamate. I therefore hypothesized that in the amygdala, female glutamate signaling would be more sensitive to potentiation following parabrachial CGRP release compared to male glutamate signaling.

To test this, I recorded from amygdala neurons while stimulating PB CGRP+ neurons. Whereas in females a single instance of PB CGRP release (lasting ~5 seconds) increased amygdala responsiveness to PB glutamate, male neurons required continuous application of CGRP for ~10 minutes before a similar potentiation occurs. This suggests that the female amygdala is more sensitive to transient elevations in PB CGRP release than the male amygdala. This could lower the threshold for chronic pain development in females, as the PB -> amygdala pathway is more sensitive to strengthening via PB CGRP release.

Implications for understanding migraine disease and/or its comorbidities, or how the research holds promise as a new avenue of future migraine study.

My work suggests that central pain centers, such as the central amygdala, are more sensitive to CGRP-driven hyperactivity in females than in males. Women demonstrate higher incidence, duration, and severity of chronic pain syndromes than men, especially migraine. Women with migraine are also more likely to experience affective comorbidities (e.g., anxiety, depression). My results may provide an important piece to this epidemiological puzzle. After all, even transient changes in CGRP release in females’ central amygdala, a hub of emotional processing, was sufficient to potentiate excitatory activity in this region. If this underlying sex difference in CGRP sensitivity increases the affective (unpleasant, emotional) component of pain processing, this could contribute to the higher psychiatric comorbidities reported in women with migraine. These comorbidities significantly compound the negative effects of migraine on quality of life, and can even worsen future migraine outcomes.