Dissertation
The role of the cerebellum in migraine-like symptoms
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2022
DOI: 10.17077/etd.006379
Abstract
Migraine is characterized by moderate or severe headaches accompanied by sensory abnormalities, e.g., photophobia and allodynia, affecting 15% of the population globally. The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. However, the sites of CGRP action are unclear. Previous studies demonstrated that intracerebroventricular administration of CGRP caused migraine-like light-aversive behavior in mice. My early studies helped demonstrate that stimulation of the posterior thalamic nuclei via CGRP injection or optogenetic stimulation elicited migraine-like light aversion in mice. Additionally, we identified the presence of CGRP-positive fibers and CGRP binding sites that are widely dispersed in the posterior thalamic nuclei. In contrast to the thalamus, optical stimulation or CGRP injection into the dorsal hippocampus did not affect light-aversive or anxiety-like responses, suggesting light aversion could not be induced by the stimulation of any brain region. However, other than the posterior thalamic nuclei, the other brain sites where CGRP action might cause migraine-like behaviors were not known.
The cerebellum has the highest binding density to CGRP receptor ligands in the central nervous system and is increasingly recognized as both a sensory and motor integration center. Thus, it is hypothesized that CGRP can act in the cerebellum, particularly the medial cerebellar nuclei (MN), to induce migraine-like behaviors in mice. To test this hypothesis, we injected CGRP directly into the right MN of C57BL/6J mice via a cannula or optically stimulated CGRP-expressing neurons in the MN (MNCGRP). A battery of behavioral tests (light/dark for light aversion, open field for anxiety, plantar von Frey test for tactile hypersensitivity, automated squint assay for spontaneous pain, gait dynamic assay using DigiGait) was conducted to assess migraine-like behaviors and motor function. CGRP injection into the MN caused light aversion with dim light, along with increased time resting in the dark zone without gait alterations. Moreover, significant responses of anxiety, contralateral tactile hypersensitivity and spontaneous pain were seen. Interestingly, CGRP injection caused significant anxiety-like and spontaneous pain responses only in female mice, and a more robust tactile hypersensitivity in female mice. Optical stimulation of MNCGRP neurons induced light aversion only in female mice along with increased time resting in the dark. Plantar tactile sensitivity was increased in the ipsilateral paws of both sexes upon stimulation of MNCGRP neurons. No detectable effect on gait and spontaneous pain was observed in either sex. Moreover, MNCGRP neurons send fibers to the posterior thalamic nuclei, suggesting that the MN may be at least one source of CGRP in the posterior thalamic nuclei.
Altogether, these studies show that CGRP can act in the MN locally and CGRP-expressing neurons in the MN play a role in inducing migraine-like behaviors. These results reveal the cerebellum as a new site of CGRP actions that may contribute to migraine-like hypersensitivity and may provide a new potential avenue for the development of migraine therapeutics.
Details
- Title: Subtitle
- The role of the cerebellum in migraine-like symptoms
- Creators
- Mengya Wang
- Contributors
- Andrew F Russo (Advisor)Krystal L Parker (Committee Member)Yuriy M Usachev (Committee Member)Stefan Strack (Committee Member)Huxing Cui (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Pharmacology
- Date degree season
- Spring 2022
- DOI
- 10.17077/etd.006379
- Publisher
- University of Iowa
- Number of pages
- xvii, 176 pages
- Copyright
- Copyright 2022 Mengya Wang
- Language
- English
- Description illustrations
- illustrations (chiefly color), tables, graphs
- Description bibliographic
- Includes bibliographical references.
- Public Abstract (ETD)
- Migraine is characterized by moderate or severe headaches accompanied by sensory abnormalities, e.g., photophobia and allodynia, affecting 15% of the population globally. However, the mechanisms underlying migraine are not yet elucidated. The neuropeptide calcitonin gene-related peptide (CGRP) is a major player in migraine pathophysiology. Previous studies demonstrated that central (intracerebroventricular) CGRP administration and stimulation of a brain region, the posterior thalamic nuclei, via direct CGRP injection or optogenetics (a technology to control neuronal activity using light-activated ion channels) elicited light aversion. However, other possible sites of CGRP action in the brain remain unidentified. The cerebellum has the highest binding density to CGRP receptor ligands in human and rhesus brains and is increasingly recognized as a sensory and motor integration center. The objective of this study is to investigate whether the cerebellum, particularly the medial cerebellar nuclei (MN), might be a site of CGRP action. We injected CGRP directly into the MN or optically stimulated CGRP neurons in the MN (MNCGRP) in mice. A battery of behavioral tests was conducted to assess migraine-like behaviors and motor function. CGRP injection caused light aversion, anxiety, tactile hypersensitivity and spontaneous pain. Optical stimulation of MNCGRP neurons induced light aversion and tactile hypersensitivity. Moreover, MNCGRP neurons project to the posterior thalamic nuclei, an important region involved in migraine pathophysiology. Together, these results reveal that the cerebellum is a new site for CGRP action in the central nervous system that may contribute to migraine pathophysiology. This work improves our understanding in CGRP action in migraine and provides insight into a new potential avenue for migraine therapeutics.
- Academic Unit
- Craniofacial Anomalies Research Center; Neuroscience and Pharmacology
- Record Identifier
- 9984271450802771
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