Paclitaxel Chemotherapy Disrupts Circadian Gene Transcription and Function of the Suprachiasmatic Nuclei in Female Mice.

Abstract

Cancer patients experience circadian rhythm disruptions during and after chemotherapy that can contribute to debilitating side effects. It is unknown how chemotherapy mediates circadian disruptions and specifically the extent to which these disruptions occur at the level of the principal clock, the suprachiasmatic nuclei (SCN) of the hypothalamus. In the present study, we assessed how the commonly used chemotherapeutic, paclitaxel, impacts the SCN molecular clock and SCN-dependent behavioral adaptations to circadian challenges in female mice. Following a repeated chemotherapy regimen, we measured rhythmic SCN expression of molecular clock and circadian-associated transcripts. Paclitaxel chemotherapy disrupted the SCN molecular clock through abolished rhythmicity (Bmal1, Nr1d2) and damped rhythmic transcription (Ciart, Dbp, Nr1d1, Per2) of key molecular clock genes. We further determined chemotherapy-induced changes to SCN function by measuring circadian wheel running adaptations to a jet lag phase-delay or phase-advance paradigm and by generating a phase response curve (PRC). Chemotherapy did not alter re-entrainment to a 6 h phase-advance, but after a 6 h phase-delay, chemotherapy-treated mice had a more stable and robust circadian rhythm than vehicle-treated mice, possibly indicative of a weakened or decoupled SCN. In the PRC, chemotherapy blunted light-induced phase-shift delays during subjective night compared with vehicle controls, also indicative of disrupted SCN-dependent entrainment. Together, this work demonstrates that paclitaxel chemotherapy disrupts both the molecular clock and functional re-entrainment of the SCN that could cause or contribute to observed circadian rhythm disruptions after treatment. This research could help guide application of circadian-mediated therapies to mitigate side effects of chemotherapy.