Insulin-dependent maturation of newly generated olfactory sensory neurons after injury

Abstract Loss of olfactory sensory neurons (OSNs) after injury to the olfactory epithelium (OE) triggers the generation of OSNs that are incorporated into olfactory circuits to restore olfactory sensory perception. This study addresses how insulin receptor-mediated signaling affects the functional recovery of OSNs after OE injury. Insulin levels were reduced in mice by ablating the pancreatic beta cells via streptozotocin injections. These streptozotocin-induced diabetic and control mice were then intraperitoneally injected with the olfactotoxic drug methimazole to selectively ablate OSNs. The OE of diabetic and control mice regenerated similarly until day 14 after injury. Thereafter, the OE of diabetic mice contained fewer mature and more apoptotic OSNs than control mice. Functionally, diabetic mice showed reduced electro-olfactogram responses and their olfactory bulbs had fewer c-Fos-active cells following odor stimulation, as well as performed worse in an odor-guided task compared to control mice. Insulin administered intranasally during day 8 to 13 after injury was sufficient to rescue recovery of OSNs in diabetic mice compared to control levels, while insulin administration between days 1 – 6 did not. During this critical time window on day 8 – 13 after injury, insulin receptors are highly expressed and intranasal application of insulin receptor antagonist inhibits regeneration. Furthermore, an insulin-enriched environment could facilitate regeneration even in non-diabetic mice. These results indicate that insulin facilitates the regeneration of OSNs after injury and suggest a critical stage during recovery (8 – 13 days after injury) during which the maturation of newly generated OSNs is highly dependent on and promoted by insulin. Significance Statement Although insulin receptor signaling is known to influence on cellular processes such as proliferation and apoptosis, it is poorly understood whether the insulin influences the regeneration of olfactory sensory neurons (OSNs) after injury. We compared the maturation processes of new OSNs after the methimazole-induced loss of pre-existing OSNs between diabetic and control mice. The results show that the regeneration of new OSNs depend on sufficient insulin levels during a specific temporal window, when insulin receptor expression is highly upregulated. Furthermore, an insulin-enriched environment via nasal insulin application during the critical period facilitates OSNs regeneration even in non-diabetic mice. The present results have implications for intranasal application of insulin as potential clinical therapeutics to facilitate OSNs regeneration after the injury.