Chemotherapy-induced circadian master clock disruptions and fatigue

Understanding the causes and mechanisms underlying circadian rhythm disruptions that are associated with fatigue during cancer treatment remains unclear. This current deficiency means that successful cancer treatment falls short of its potential and prior quality-of-life remains elusive for patients. Our long-term goal is to improve debilitating behavioral sequelae in cancer patients, thus improving quality-of-life, other comorbidities, and mortality. Thus, the overall objective here is to establish the potential role of circadian disruption as a fundamental pathway by which chemotherapy promotes cancer-associated fatigue. Indeed, robust circadian rhythmicity of virtually all physiology is extremely well-conserved; desynchrony of these rhythms leads to negative health and behavioral consequences. The central hypothesis is that chemotherapy-induced inflammation inhibits SCN function leading to fatigue. The rationale for this work is that circadian circuitry disruption is an understudied, relevant pathway in psycho-oncology research that could elucidate mechanisms and new, rhythm-focused interventions. Three specific aims are proposed to test the central hypothesis using our novel breast cancer “survivor” mouse model. Aim 1 will determine the ability of the master clock to entrain after chemotherapy. Behavioral SCN rhythm adaptations to environmental challenges will be assessed. Aim 2 will identify the role of central inflammation in master clock disruptions after chemotherapy. The role of chemotherapy-induced neuroinflammation on SCN molecular and behavioral rhythms will be quantified. The potential resolution of fatigue will also be assessed. Aim 3 will determine the role of circadian disruption in chemotherapy-induced fatigue. Genetic and pharmacological SCN timing manipulations will precede a battery of behavioral assessments of the physical, motivation, and cognitive components of fatigue. In vivo and ex vivo circadian timing approaches combined with systems-, cellular-, and molecular-level analyses will pinpoint the effects of two regimens of chemotherapy on master oscillator circadian circuitry relevant to cancer-related behavioral comorbidities. The proposed research is conceptually innovative because using circadian approaches is new to psychooncology. It is also technically innovative by way of the superior translational model and the circadian genetic and pharmacological techniques planned. This research will result in essential new knowledge about how common cancer treatments affect the pacemaker, which is crucial to extensive downstream physiology and behavior (i.e., beyond fatigue). Results will provide much needed evidence to make circadian-based approaches standard in clinical practice, as well as inform the design of novel circadian-directed pharmacological and nonpharmacological interventions. This research is applicable to other cancers and in non-oncological populations treated with chemotherapy (e.g., stem cell transplant, lupus).