Inflammation plays a causal role in fatigue-like behavior induced by pelvic irradiation in mice.

Fatigue is a persistent and debilitating symptom following radiation therapy for prostate cancer. However, it is not well-understood how radiation targeted to a small region of the body can lead to broad changes in behavior. In this study, we used targeted pelvic irradiation of healthy male mice to test whether inflammatory signaling mediates changes in voluntary physical activity levels. First, we tested the relationship between radiation dose, blood cell counts, and fatigue-like behavior measured as voluntary wheel-running activity. Next, we used oral minocycline treatments to reduce inflammation and found that minocycline reduces, but does not eliminate, the fatigue-like behavioral changes induced by radiation. We also used a strain of mice lacking the MyD88 adaptor protein and found that these mice also showed less fatigue-like behavior than the wild-type controls. Finally, using serum and brain tissue samples, we determined changes in inflammatory signaling induced by irradiation in wild-type, minocycline treated, and MyD88 knockout mice. We found that irradiation increased serum levels of IL-6, a change that was partially reversed in mice treated with minocycline or lacking MyD88. Overall, our results suggest that inflammation plays a causal role in radiation-induced fatigue and that IL-6 may be an important mediator.

Extracellular matrix influences astrocytic extracellular vesicle function in wound repair.

Astrocytic injury responses are known to be influenced by the extracellular matrix (ECM). Astrocytes are also recognized as a source of extracellular vesicles (EVs) that can impact the activity and function of other astrocytes and cell types. Whether the ECM influences the function of astrocytic EVs in the context of wound recovery has not been previously studied. We report EVs from astrocytes cultured on varied ECM substrates are sufficient to elicit distinct injury responses in naive astrocytes that recapitulate the effects of the ECM of origin. When compared with wound recovery on control substrates, EVs from ECM-exposed astrocytes elicited accelerated rates of wound recovery that varied based on each ECM. When EVs were collected from IL-1ß treated and ECM-exposed astrocyte cultures, we found that IL-1ß arrested wound recovery in naive astrocytes treated with EVs from astrocytes cultured on ECM but adding EVs from IL-1ß treated Tenascin-c-cultured astrocytes increased wound recovery. To confirm that ECM was a primary influence on these astrocytic EV functions, we tested the contribution of ß1-integrin, a major integrin receptor for the ECM molecules tested in this study. We found that the ß1-integrin inhibitor Ha2/5, resulted in EVs that significantly attenuated the wound recovery of naive astrocytes. This provides new information on the importance of culture substrates on astrocytic responses, EV functions and injury responses that may impact the understanding of astroglial responses related to ECM compositional differences in diverse physiological states.

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

Fatigue and cognitive deficits are often co-occurring symptoms reported by patients after radiation therapy for prostate cancer. In this study, we induced fatigue-like behavior in mice using targeted pelvic irradiation to mimic the clinical treatment regimen and assess cognitive behavioral changes. We observed that pelvic irradiation produced a robust fatigue phenotype, a reduced rate of spontaneous alternation in a Y-maze test, and no behavioral change in an open field test. We found that reversal learning for fatigued mice was slower with respect to time, but not with respect to effort put into the test, suggesting that fatigue may impact the ability or motivation to work at a cognitive task without impairing cognitive capabilities. In addition, we found that mice undergoing pelvic irradiation show lower whole-brain levels of mature BDNF, and that whole-brain proBDNF levels also correlate with spontaneous alternation in a Y-maze test. These results suggest that changes in BDNF levels could be both a cause and an effect of fatigue-related changes in behavior.