Sasahara, A. | Search bioRxiv

bioRxiv2026

Ramelteon facilitates hippocampal ripple occurrence and amplitude in mice

The hippocampus is essential for memory consolidation, a process mediated by high-frequency oscillations known as ripples during non-rapid eye movement (NREM) sleep. Ramelteon, a selective MT1/MT2 receptor agonist, has been reported to possess cognitive-enhancing properties; however, its impact on the fine-scale dynamics of hippocampal ripples remains unclear. We performed chronic local field potential recordings from the dorsal hippocampus and prefrontal cortex in mice. Following the intraperitoneal administration of either vehicle or ramelteon, we evaluated sleep architecture and characterized ripple properties, including occurrence rate, amplitude, instantaneous frequency, and duration during NREM sleep. Ramelteon administration significantly increased NREM sleep occupancy. Notably, we found that ramelteon significantly enhanced both the occurrence rate and amplitude of hippocampal ripples compared to the control group. While a slight increase in intra-ripple frequency was observed, other structural features, such as ripple duration and asymmetry index, remained unaffected. Our findings demonstrate that ramelteon facilitates hippocampal ripple dynamics by increasing their occurrence and synchrony during NREM sleep. Given the critical role of ripples in memory consolidation, these neurophysiological changes may underlie the procognitive effects of ramelteon. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=55 SRC="FIGDIR/small/723673v1_ufig1.gif" ALT="Figure 1"> View larger version (15K): org.highwire.dtl.DTLVardef@77b58org.highwire.dtl.DTLVardef@132dbc1org.highwire.dtl.DTLVardef@1f98dc1org.highwire.dtl.DTLVardef@c9a3f2_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2020

MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells

Cancer stem-like cells (CSCs) are responsible for the drug resistance of tumors and recurrence while they experience DNA replication stress. However, the underlying mechanisms that cause DNA replication stress in CSCs and how they compensate for this stress remain unclear. Here we provide evidence that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), which is a firing (activating) factor of the DNA replication origins, to compensate for the DNA replication stress. Expression levels of MCM10 are upregulated in CSCs and maintained by c-Myc. c-Myc-dependent collisions may take place between RNA transcription and DNA replication machinery in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to the collisions to ensure replication progression. Moreover, patient-derived breast CSCs were dependent on MCM10 for their maintenance even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. In addition, MCM10 depletion decreased the growth of cancer cells but not normal cells. Therefore, MCM10 is likely to robustly compensate for DNA replication stress and facilitate genome duplication in the S-phase in cancer cells, which is more pronounced in CSCs. We provide a preclinical rationale to target the c-Myc-MCM10 axis to prevent drug resistance and recurrence.

cancer biology↗