Journal Club: Systemic CGRP injection makes mice sound- and motion-sensitive, recreating vestibular migraine–like symptoms.

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Today's journal article

Rahman SM, Faucher S, Jonnala R, Holt JC, Lee C, Luebke AE. Systemic calcitonin gene-related peptide modifies auditory and vestibular end organ electrical potentials, and increases sensory hypersensitivities. 

Why I picked this article

Migraine is a chronic brain disorder that affects many people (more women than men). One type of migraine is vestibular migraine, which can include episodes of vertigo, motion sensitivity, and balance problems in addition to headache. 

A signalling molecule called CGRP (calcitonin gene–related peptide) is linked to migraine and has been extensively researched to date. CGPR administration can trigger headaches in people with migraine, and medicines that block CGRP can help with headaches. CGRP is also present at efferent (brain-to-ear) synapses in the cochlea and vestibular organs, however, whether increased CGRP in the body can directly affect inner ear (cochlea and vestibular system) is unknown. 

This research used mouse model to test if the hearing function and vestibular functions are impacted at the inner ear level by CGRP administration. 

Some of the research findings

Animal model and testing: 
  • Wild-type C57BL/6J mice (Jackson Laboratory JAX no.664) 
  • Equal mixture of male and female mice, 2.3-6 months of age. 
  • Systemic adminsitration by ntraperitoneal injection: CGRP(0.1 mg/kg, rat
  • a-CGRP, Sigma). 
  • each animal received 1 injection per testing day at approx. 100 μL.
  • mice were tested approximately 20 min after intraperitoneal delivery of either vehicle or CGRP.
  • Hearing check: auditory brainstem responses (ABRs) to sound
  • Balance check: vestibular sensory evoked potentials (VsEPs) to jerk stimuli 
  • Behavioural testing: acoustic startle reflex for sound sensitivity (80 - 130 dB SPL). 
  • Balance check: postural sway for static balance.
Finding: 
  • Injection of CGPR increased the amplitude of the ABR wave (I) in female mice. This suggests that CGPR may impact the peripheral auditory nerve to make them hypersensitive. 
  • Injection of CGPR decreased the VsEP amplitude in male mice, and overall, as the group (more variable in females). This suggests that the CGPR also affect the peripheral vestibular nerve activity. This may explain the balance problem with vestibular migraine. 
  • Injection of CGRP increased the startle response in both quiet and noisy backgrounds at all sound levels tested. 
  • Postural sway was also increased in the CGRP-treated group.
Systemic CGRP can modulate both cochlear and vestibular end-organ signals and produce behaviours that resemble phonophobia and postural instability seen in vestibular migraine.
Figure 2A. The experimental design for the startle response. Rahman et al. 

Haruna's takeaway

What's interesting is how the same molecule, linked to migraine, has a different impact on the hearing (cochlea) and balance (vestibular) system. Data seem to suggest that some peripheral changes could be happening at the location in the inner ear or between the inner ear and the brainstem. Sex-based difference is expected based on what we know about migraines in humans. It seems like a very simple animal model using CGRP injection to recreate some aspect of the vestibular migraine. 

Vestibular migraine is very difficult to distinguish from other diseases that cause vertigo, like Meniere's disease and BPPV. It would be great if this animal model could be used to research new treatment or diagnostic methodologies for vestibular migraines. 

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This is Haruna's 51/100 of the 100-day challenge to post a science blog article every day! I love inner ear biology & cochlear physiology.