Cancer and cancer survival modulates brain and behavior in a time-of-day-dependent manner in mice

Improvements in breast cancer therapy/diagnosis have substantially increased the cancer survivor population, although many survivors report persistent mental health issues including fatigue, mood and anxiety disorders, and cognitive impairments. These behavioral symptoms impair quality-of-life and are often associated with increased inflammation. Nocturnal rodent models of cancer are critical to the identification of the neurobiological mechanisms underlying these behavioral changes. Although both behavior and immunity display distinct diurnal patterns, most rodent research in this field is performed during the rodents’ inactive (light) period, which could potentially undermine the conclusions and clinical relevance. Therefore, here we tested the extent to which mammary tumors or tumor resection (“survivors”) in mice affects behavior and neuroinflammation in a nyctohemeral (day versus night)-dependent manner. Indeed, only the dark (active) phase unmasked fatigue-like behavior and altered novel object investigation for both tumor-bearing and -resected mice relative to surgical controls. Several inflammatory markers were expressed in a time-of-day-dependent manner (lower in the dark phase) in the blood and brains of surgical control mice, whereas this temporal pattern was absent (IL-1β, CXCL1, Myd88, Cd4) or reversed (C3) in the respective tissues of tumor-bearing and -resected mice. Taken together, these data indicate that the time of day of assessment significantly modulates various persistent and transient tumor-induced behavioral and immune changes.