The Role of Cerebellar CGRP in Migraine-like Behavior

Mengya Wang, Master

AHSAM 2020 - Oral session
Published on July 23, 2020

3 minute listen
9 minute read

Key messages

  • Calcitonin gene-related peptide (CGRP) plays a critical role in migraine pathophysiology, but the location and mechanisms of CGRP in migraine are still unknown.
  • Cerebellar CGRP, especially in the fastigial nucleus, may contribute to some migraine-like phenotypes.
  • Background

    What do we already know about this topic?
  • Findings

    What does this study add?
  • Perspectives

    How does this study impact clinical practice?
  • Expert commentary

    by Amynah Pradhan, PhD

Key messages

  • Calcitonin gene-related peptide (CGRP) plays a critical role in migraine pathophysiology, but the location and mechanisms of CGRP in migraine are still unknown.
  • Cerebellar CGRP, especially in the fastigial nucleus, may contribute to some migraine-like phenotypes.

Background

What do we already know about this topic?

  • Previous studies suggest calcitonin gene-related peptide (CGRP) plays a critical role in migraine pathophysiology, but the location and mechanisms of CGRP in migraine are still unknown.
  • A high number of CGRP binding sites are located in the cerebellum, which serves as a sensory and motor integrative center, and is activated during a migraine attack.1
  • CGRP is densely distributed in the Purkinje cells (PCs) and cerebellum medial nucleus, suggesting that CGRP may act on the cerebellum to induce migraine-like behaviors.

How was this study conducted?

  • CGRP expression was measured in the cerebellum of C57BL/6 mice using qPCR and immunohistochemistry, and in calca-cre mice using a cre-dependent viral reporter (AAV-EF1a-DIO-EYFP).
  • The mice were injected with CGRP into the cerebellar vermis V and fastigial nucleus and tested in the light-dark assay to evaluate light aversion.
  • An open field test was used to evaluate anxiety and locomotion, sensitivity to plantar Von Frey filaments, and a squint test was used to evaluate pain.
  • A cerebellar CGRP sensitized mouse model (L7/hRAMP1) was created to further test the role of cerebellar CGRP in migraine.
  • Rats were injected with CGRP into crus I in the cerebellar cortex and were run in an interval estimation task.

Findings

What does this study add?

  • RNAs for both CGRP and its receptor subunits were detected in the cerebellum of C57BL/6 mice.
  • CGRP immunoreactivity was detected in PCs and deep cerebellar nuclei.
  • EYFP was present in fastigial nucleus neurons after injection of AAV-EF1a-DIO-EYFP into calca-cre mice but wasn’t detected in PCs, which suggests that PCs accumulate, but do not produce CGRP.
  • Injection of CGRP to the fastigial nucleus induced light aversion, anxiety, and allodynia, while delivery to the vermis V induced anxiety and a trend towards light aversion.
  • Phenotypes began to present from different time points following injection of CGRP into vermis V and fastigial nucleus, suggesting that light aversion, as well as anxiety, was present.
  • Preliminary data showed that CGRP injection to the fastigial nucleus of L7/hRAMP1 mice and control littermates induced comparable light aversion and anxiety, suggesting that RAMP1 in PCs is not rate-limiting for those CGRP actions.
  • CGRP injection into crus I showed a trend to impair timing.

Perspectives

How does this study impact clinical practice?

  • Cerebellar CGRP, especially in the fastigial nucleus, may contribute to some migraine-like behaviors such as light aversion, anxiety, and decreased locomotion.
  • While further studies are needed to determine the contributions of cerebellar CGRP to light aversion, there are connections between the fastigial nucleus and the posterior thalamic area, which are implicated in photophobia.

Perspectives

How does this study impact clinical practice?

  • Cerebellar CGRP, especially in the fastigial nucleus, may contribute to some migraine-like behaviors such as light aversion, anxiety, and decreased locomotion.
  • While further studies are needed to determine the contributions of cerebellar CGRP to light aversion, there are connections between the fastigial nucleus and the posterior thalamic area, which are implicated in photophobia.

This is a highlights summary of an oral session given at the AHSAM 2020 Virtual Annual Scientific Meeting and presented by:

Mengya Wang, Master
Graduate student and research assistant
Department of Neuroscience and Pharmacology, University of Iowa
Iowa City, Iowa

The content is produced by Infomedica, the official reporting partner of ASHAM 2020 Virtual Annual Scientific Meeting. The summary text was drafted by Goldcrest Medical Writing, reviewed by Marco Vercellino, MD, an independent external expert, and approved by Jessica Ailani, MD, FAHS and Mark J. Burish, MD, PhD, the scientific editors of the program.

The presenting authors of the original session had no part in the creation of this conference highlights summary.

In addition, an expert commentary on the topic has been provided by:

Amynah Pradhan, PhD
University of Illinois at Chicago, Chicago, USA

Amynah Pradhan, PhD
University of Illinois at Chicago, Chicago, USA

Dr. Amynah Pradhan PhD is an Associate Professor of Psychiatry at the University of Illinois at Chicago. She is interested in the investigation of novel therapies for migraine, and identified the delta opioid receptor as a promising target for this disorder. Ongoing work in her lab is focused on the differential role of mu and delta opioid receptors in headache. Additionally, Dr. Pradhan’s work focuses on identifying the molecular mechanisms that contribute to migraine chronicity, as well as overlapping mechanisms between migraine and neuropsychiatric conditions.

1. Moulton EA, Schmahmann JD, Becerra L, Borsook D. The cerebellum and pain: passive integrator or active participator?. Brain Res Rev. 2010;65(1):14-27.



Headache
Migraine


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