Establishment and characterization of a mouse model of cisplatin-induced olfactory aversion

Chemotherapy-induced sensory alterations, including changes in taste and smell, have been reported as adverse effects of anticancer treatments. However, olfactory aversion has received little attention, and its underlying mechanisms remain unclear, limiting effective preventive or therapeutic strategies. Therefore, chemotherapy-induced olfactory aversion was investigated using cisplatin, a widely used anticancer drug. Three odorants-vanillin, benzaldehyde, and isoamyl acetate-were presented to C57BL/6J mice as conditioned stimuli together with cisplatin-induced visceral malaise (30 μg, intraperitoneal) to induce olfactory aversion. Odor preference was assessed using a two-bottle test. Cisplatin-treated mice exhibited altered preferences for all odor solutions and reduced total fluid intake compared with saline-treated controls. Meanwhile, no olfactory aversion was observed in zinc sulfate-induced anosmic male mice. Notably, female mice showed weaker olfactory aversion than male mice, suggesting a possible sex difference. These results established a cisplatin-induced olfactory-aversion mouse model. No structural abnormalities were observed in the olfactory epithelium of olfactory-aversion model mice following cisplatin treatment. In contrast, c-Fos immunostaining revealed increased neuronal activity in the septal region, whereas c-Fos expression in the lateral septum showed a similar but non-significant trend following vanillin administration to mice with established vanillin aversion. These findings suggest that central neural mechanisms may be associated with cisplatin-induced olfactory aversion, although the involvement of peripheral olfactory processes cannot be excluded. This study provides new insights into the neural correlates of chemotherapy-induced olfactory aversion and may aid the development of future therapeutic strategies.