Thermoregulatory Dynamics Reveal Sex-Specific Inflammatory Responses to Experimental Autoimmune Encephalomyelitis in Mice: Implications for Multiple Sclerosis-Induced Fatigue in Females

Abstract

The course of multiple sclerosis (MS) is characterized by striking sex differences in symptoms such as fatigue and impaired thermal regulation, which are associated with aggravated systemic pro-inflammatory processes. The purpose of this study was to replicate these symptoms in experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice in the quest to advance the preclinical study of non-motor symptoms of MS. Male and female C57BL/6 mice exposed to a mild form of EAE were evaluated for the progression of clinical, behavioural, thermal, and inflammatory processes. We show higher susceptibility in females to EAE than males based on greater clinical score and cumulative disease index (CDI), fatigue-like and anxiety-like behaviours. Accordingly, infrared (IR) thermography indicated higher cutaneous temperature in females from post-induction days 12 to 23. Females also responded to EAE with greater splenic and adrenal gland weights than males as well as sex-specific changes in pro- and anti-inflammatory cytokines. These findings provide the first evidence of a sex-specific thermal response to immune-mediated demyelination, thus proposing a non-invasive assessment approach of the psychophysiological dynamics in EAE mice. The results are discussed in relation to the thermoregulatory correlates of fatigue and how endogenously elevated body temperature without direct heat exposure may be linked to psychomotor inhibition in patients with MS.