Gregory, J. D. | Search bioRxiv

bioRxiv2025

Immature olfactory sensory neurons provide complementary input in the healthy olfactory system

Adult neurogenesis of olfactory sensory neurons (OSNs) provides the unique opportunity to understand how new neurons functionally integrate into existing circuitry and contribute to behaviors. Previous studies have shown that immature OSNs express odorant receptors, form dendritic knobs with short cilia, and project their axons into the olfactory bulb (OB) to form functional synapses. Furthermore, a previous study found that immature OSNs respond selectively to odorants and exhibit graded responses in a higher odorant concentration range than mature OSNs. Finally, this study also showed that, in mice that lack mature OSNs, sensory input from immature OSNs can mediate odor detection and discrimination. What remains unknown is how these immature OSNs contribute to odor-guided behavior in the healthy, intact olfactory system. Here we show that chemogenetically silencing immature OSNs impairs odor detection ability in a buried food assay. Furthermore, immature OSN silencing reduces the amplitude of odor-evoked dendritic calcium responses in OB neurons in vivo. Together, these findings suggest that immature OSNs provide distinct odor input that complements mature OSN input to contribute to odor-guided behaviors in the healthy, intact olfactory system.

neuroscience↗

bioRxiv2024

Regional deficits in endogenous regeneration of mouse olfactory sensory neuron axons

Postnatal neurogenesis occurs in only a few regions of the mammalian nervous system. Hence, neurons that are lost due to neurodegenerative disease, stroke, traumatic brain injury or peripheral neuropathy cannot be replaced. Transplantation of stem cell-derived neurons provides a potential replacement strategy, but how these neurons can be encouraged to functionally integrate into circuits remains a significant challenge. In the mammalian olfactory epithelium (OE), olfactory sensory neurons (OSNs) continue to be generated throughout life from basal stem cells and can be repopulated even after complete ablation. However, the specialized population of navigator OSNs that ensures accurate olfactory receptor-specific targeting of OSN axons to glomeruli in the olfactory bulb (OB) is only present perinatally. Despite this, some studies have reported complete regeneration of specific glomeruli, while others have found various degrees of recovery, following OSN cell death. Variability in the extent of both initial OSN ablation and subsequent repopulation of the OE, and the focus on anatomical recovery, leave the extent to which newly generated OSNs can reinnervate the OB unclear. Here, we employed the olfactotoxic drug methimazole (MMZ) to selectively ablate OSNs without damaging the basal stem cells that generate them, enabling us to assess the extent of functional recovery of OSN input to the OB in the context of complete OSN repopulation. We found profound deficits in the recovery of odor-evoked responses in OSN axons in the glomerular layer of the dorsal OB five weeks after OSN ablation, a time point at which OSNs are known to have repopulated the OE. Histological analysis of mature OSN axons in the OB at 10 and 20 weeks post-methimazole showed persistent region-specific deficits in OSN axon reinnervation of the dorsal and medial OB, with the dorsomedial region being particularly adversely affected. In contrast, reinnervation of the glomerular layer in lateral and ventral regions of the OB was essentially complete by 10 weeks post-MMZ. Hence, we have identified a region-specific deficit in OSN reinnervation of the mouse OB, which sets the stage to identify the mechanisms that mediate successful vs. unsuccessful axonal regeneration in an endogenous population of stem cell-derived neurons.

neuroscience↗