Shipment Stress in Early Life Aggravates Disease Pathogenesis in Mice with Experimental Autoimmune Encephalomyelitis: Support for a Two-Hit Hypothesis of Multiple Sclerosis Etiology

Abstract Visual impairments are one of the earliest diagnosed symptoms of multiple sclerosis (MS). The onset and progression of vision loss in MS may be influenced by cumulative psychophysiological stress. Here, we used a two-hit model of stress in female mice to determine if early life stress (ELS) influences the clinical severity of experimental autoimmune encephalomyelitis (EAE) later in life. We hypothesized that ELS caused by animal transportation during early postnatal development represents a co-factor which can exacerbate the disease severity of EAE. Adult EAE mice with ELS displayed more severe clinical signs and delayed recovery compared to non-stressed EAE mice. ELS also diminished visual acuity measured by optokinetic responses, locomotion and exploratory behaviours in EAE mice. Notably, ELS caused earlier onset of visual impairments in EAE. Exacerbated functional impairments in stressed EAE mice were highly correlated with circulating corticosterone levels. The findings show that the progression of induced EAE (second hit) in adulthood can be significantly impacted by adverse early life experiences (first hit). The observations emphasize the importance of comprehensive behavioural testing, including non-motor functions, to enhance the translational value of preclinical animal models of MS. Moreover, shipment stress of laboratory animals should be considered a necessary variable in preclinical MS research. The consideration of cumulative lifetime stresses provides a new perspective of MS pathogenesis within a personalized medicine framework.