Suppression of Locomotor Activity in Female C57Bl/6J Mice Treated with Interleukin-1β: Investigating a Method for the Study of Fatigue in Laboratory Animals

Abstract

Fatigue is a disabling symptom in patients with multiple sclerosis and Parkinson’s Disease, and is also common in patients with traumatic brain injury, cancer, and inflammatory disorders. Little is known about the neurobiology of fatigue, in part due to the lack of an approach to induce fatigue in laboratory animals. Fatigue is a common response to systemic challenge by pathogens, a response in part mediated through action of the pro-inflammatory cytokine interleukin-1 beta (IL-1β). We investigated the behavioral responses of mice to IL-1β. Female C57Bl/6J mice of 3 ages were administered IL-1β at various doses i.p. Interleukin-1β reduced locomotor activity, and sensitivity increased with age. Further experiments were conducted with middle-aged females. Centrally administered IL-1β dose-dependently reduced locomotor activity. Using doses of IL-1β that caused suppression of locomotor activity, we measured minimal signs of sickness, such as hyperthermia, pain or anhedonia (as measured with abdominal temperature probes, pre-treatment with the analgesic buprenorphine and through sucrose preference, respectively), all of which are responses commonly reported with higher doses. We found that middle-aged orexin-/- mice showed equivalent effects of IL-1β on locomotor activity as seen in wild-type controls, suggesting that orexins are not necessary for IL-1β -induced reductions in wheel-running. Given that the availability and success of therapeutic treatments for fatigue is currently limited, we examined the effectiveness of two potential clinical treatments, modafinil and methylphenidate. We found that these treatments were variably successful in restoring locomotor activity after IL-1β administration. This provides one step toward development of a satisfactory animal model of the multidimensional experience of fatigue, a model that could allow us to determine possible pathways through which inflammation induces fatigue, and could lead to novel treatments for reversal of fatigue.

Host and Environmental Factors Influencing Individual Human Cytokine Responses

“…One of the most interesting observations is the role of seasonality as a factor influencing cytokine production variability. This is biologically very relevant especially given the seasonality of many infectious diseases (Bonsall et al, 2015). A separate HFGP manuscript that assessed variation of cell counts in the 500FG cohort supports the importance of seasonality on immune parameters (Aguirre-Gamboa et al, 2016).…”

Inflammation Effects on Motivation and Motor Activity: Role of Dopamine

“…Similar to the effects of IFN-α, peripheral administration of IL-1β to rodents has been shown to decrease effortful responding for sucrose reward over freely available chow, in the absence of a decrease in preference for freely available sucrose over chow (Nunes et al, 2014); an effect that was reversed by lisdexamfetamine (Yohn et al, 2016). Interestingly, peripheral administration of IL-1β in mice at 24 h has been shown to decrease locomotor (wheel running) activity, which was improved by methylphenidate but not modafinil (Bonsall et al, 2015). Furthermore, similar to IL-1β administration, an overall decrease in responding for food reward has been reported in mice following peripheral administration of lipopolysaccharide (LPS; ie, endotoxin) with no decrease in reward sensitivity (preference for high value sucrose rewards) (Vichaya et al, 2014).…”

A novel mutation in Slc2a4 as a mouse model of fatigue

“…Moreover, wheel running is a robust behavior in rodents and is amenable to quantitative analysis . Some characteristics that may imply fatigue in mice include reduced daily amount of activity, changes in pattern or day‐night distribution, a lack of consolidated running with an increase in the number of distinct bouts, or a delayed onset or shortened duration of the daily active phase …”