Comparing passive measures of fatigue-like behavior in mice

Abstract

Fatigue is a very common and costly symptom associated with various diseases and disorders. Nonetheless, understanding the pathobiology and developing of therapies for fatigue have been difficult, partly because of a lack of consensus on the measures to phenotype this behavior, both in clinical settings and in animal studies. Here, we describe a fatigue-like behavior induced in mice by abdominal irradiation and compare three different methods of measuring changes in physical activity over time: running wheels, video home cage monitoring, and telemetry. These methods collect data passively and continuously, requiring no disruption of animals’ normal home cage behavior. In our experiments, all three methods reported a fatigue-like behavior, exhibited by a reduction in physical activity following abdominal irradiation. Video tracking showed the largest fatigue effect size (Cohen’s D = 1.78) over four days of monitoring, and was the only method showing a significant decrease in activity during the light period. Telemetry and running wheels showed a similar effect size (D = 1.68 and 1.65, respectively), but running wheels showed different circadian patterns of physical activity. In addition, we conducted rotarod and inverted grid suspension tests, which suggested that fatigue-like behavior was not the result of gross motor abnormalities.

Induction of fatigue-like behavior by pelvic irradiation of male mice alters cognitive behaviors and BDNF expression

“…Similar to previously published work [21], we found a large decrease in voluntary wheelrunning activity (VWRA) in Irrad mice compared to Sham (Fig 2A). The decrease was large and statistically significant (Fig 2B, d = 1.78, t = 15.64, p < 10 −22 , n = 67).…”

“…The mechanism by which irradiation constrained to a pelvic region affects both cognitive and fatigue behaviors is unknown. In a previous study we established that weight loss is also a result of this irradiation procedure [21], so a possibility that immediately occurred to us is that reduced food consumption, as shown in Fig 3C, induces these changes. However, this may be…”

“…In previous studies [21], we have used a mouse model of radiation therapy for treatment of prostate cancer to show that pelvic irradiation alone is sufficient to induce a profound fatiguelike behavior that can be measured as a decline in VWRA or home cage locomotor activity. In this study, we found that this pelvic irradiation also induces a change in cognitive behavior, most notably as a decrease in spontaneous alternation in a Y-maze.…”

“…Once per day for three days, mice were anesthetized with a mixture of 100 mg/kg ketamine (MWI Animal Health, Boise, ID, USA) and 10 mg/kg xylazine (Akorn Animal Health, Lake Forest, IL, USA) and placed inside a lead shielding device within a GammaCell 40 Exactor irradiator (Best Theratronics, Ottowa Ontario, Canada), where they then received 8 Gy irradiation targeted to a pelvic region. This dose causes no overt changes in physical appearance nor signs of tissue damage in the mice [20], though it does induce a decrease in bodyweight [21]. Mice in the Sham group underwent the same procedure as those in the Irrad group, except that they were left outside of the irradiator.…”

Cancer‑related fatigue during combined treatment of androgen deprivation therapy and radiotherapy is associated with mitochondrial dysfunction

“…A total of two weeks after initiating AdT, mice received three days of irradiation targeted to the pelvic region. Previous studies indicate that lower-abdominal irradiation causes fatigue-like behavior that lasts about six days (29,42), so the present study measured average VWRA across six days post-irradiation (Fig. 3c).…”