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

📖 Top 20% JournalSep 8, 2025eNeuro

Paclitaxel chemotherapy disrupts daily gene rhythms and the brain’s internal clock in female mice

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Abstract

Paclitaxel chemotherapy disrupted rhythmic expression of key molecular clock genes in the (SCN) of female mice.

Chemotherapy led to abolished rhythmicity and dampened rhythmic transcription of molecular clock genes in the SCN.
After a 6-hour phase-delay, chemotherapy-treated mice exhibited a more stable and robust compared to vehicle-treated mice.
Chemotherapy did not affect re-entrainment to a 6-hour phase-advance but blunted light-induced phase-shift delays during subjective night.
These findings suggest that chemotherapy may disrupt both the molecular clock and functional re-entrainment of the SCN.

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Cancer patients experience 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 (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 (,) and damped rhythmic transcription (,,,) 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. Bmal1Nr1d2Ciart Dbp Nr1d1Per2

Key numbers

Unique Rhythmically Expressed Genes

Unique genes rhythmically expressed in chemotherapy-treated mice

Unique Rhythmically Expressed Genes in

Unique genes rhythmically expressed in -treated mice

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