Age-related changes of the regeneration mode in the mouse peripheral olfactory system following olfactotoxic drug methimazole-induced damage.

We investigated age-related changes in the mode of regeneration in the mouse peripheral olfactory system after olfactotoxic drug-induced damage. Mice at postnatal ages of 10 days, 3 months, and 16 months were given an intraperitoneal injection of methimazole to produce damage in the olfactory neuroepithelium. The olfactory neuroepithelia were harvested and analyzed immunohistochemically at various postlesion timepoints, from 1 day through to 94 days, to investigate neuroepithelial cell proliferation, the time course of neuronal differentiation, the reconstitution of neuroepithelium, and the innervation of the olfactory bulb. Functional recovery was assessed using the vanillin avoidance behavioral test. The chronological pattern in the expression of Ki67, beta III tubulin, and olfactory marker protein, molecular markers for neuronal cell proliferation and differentiation, changed similarly among the different age groups. In contrast, the extent of neuroepithelial cell proliferation after injury decreased with age, and the final histological recovery of the olfactory neuroepithelium and the innervation of the olfactory bulb were significantly smaller in the 16-month-old group compared to the younger age groups. These results suggest that the age-related decline in the capacity of olfactory neuroepithelium to reconstitute neuroepithelium is associated with its age-related decrease in proliferative activity after the neuroepithelial injury rather than changes in the process of neuronal differentiation. In spite of these incomplete anatomical recoveries, 16-month-old mice regained the ability to avoid vanillin solution by 1 month postlesion, suggesting that the extent of anatomical epithelial damage is not necessarily proportional to the threshold of olfactory perception.