The intersection of pain, disease severity, and circadian disruption in experimental autoimmune encephalomyelitis

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Authors
Segal, Julia
Keyword
multiple sclerosis , pain , neuroinflammation , circadian rhythm , experimental autoimmune encephalomyelitis
Abstract
Multiple sclerosis (MS) is an autoimmune disease causing neuroinflammation and demyelination to the central nervous system. The overall goal of this thesis was to explore an emerging area of research in the MS field: circadian rhythms, the 24-hour biological rhythms governing a significant number of functions at the behavioural, systems, cellular, and molecular levels. Evidence suggests that people with MS experience disruption in their circadian rhythms, and that those who are exposed to environmental sources of circadian disruption have an increased susceptibility for MS. Furthermore, people with MS often report a rhythm to their pain intensity, peaking at night. I therefore sought to investigate circadian rhythms in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, with a focus on pain outcomes. However, limitations in this model led to the pursuit of novel methodology and tools in the EAE field. First, a mild induction protocol of EAE was characterized in order to improve the study of pain; the lack of hindlimb paralysis in mild EAE mice allowed for continuous assessment of pain behaviours with stimulus-evoked testing. Second, an observer-independent assay, advanced dynamic weight bearing (ADWB), was investigated as a tool for monitoring disease progression in EAE. ADWB was shown to accurately detect shifts in weight bearing as EAE mice developed locomotor dysfunction in the hindlimbs. Third, circadian rhythms were identified as disrupted in peripheral but not central clocks of EAE mice, as seen by altered rhythms of immune cell numbers and clock genes in the spinal cord, but not of locomotor activity. Mechanical hypersensitivity, on the other hand, was rhythmic in EAE mice, peaking during the rest phase. Finally, environmental circadian disruption through altered light cycles was shown to exacerbate EAE severity and underlying neuroinflammation and demyelination. Although significant work remains to fully understand these phenomena and to translate it to people with MS, this research provides a new perspective on the role of environmental and endogenous factors in MS.
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