The olfactory system is unusual in retaining a high level of plasticity throughout life, enabling olfactory circuits to regenerate following damage. Ou long-term goal is to determine how adult olfactory circuits balance this high level of plasticity with functional stability. One major contributor to the regenerative capacity of the olfactory system is lifelong neurogenesis of olfactory sensory neurons (OSNs) from stem cells in the nose. OSNs transmit sensory input to neurons in the olfactory bulb, where odor information is processed before being sent to olfactory cortical areas. However, the process by which new OSNs functionally incorporate into adult olfactory bulb circuits has been unclear. Understanding this process will be crucial in designing effective stem cell-based therapeutic strategies to repai damaged neural circuits in conditions such as neurodegenerative disease, stroke and traumatic brain injury. We will use a transgenic strategy to label and manipulate the activity of immature OSNs, in order to determine their role in olfactory bulb function and plasticity. First, using optogenetic photoactivation and electrophysiological recording in olfactory bulb slices, we will identify the olfactory bulb neurons with which immature OSNs form synaptic connections. Next, using in vivo 2-photon calcium imaging in combination with odor stimulation and optogenetic activation and silencing, we will determine the contribution made by immature OSNs to olfactory bulb output via mitral and tufted cells. Finally, using in vivo 2-photon imaging of synapses, we will determine the rate of recovery of immature and mature OSN synapse turnover following restoration of odor input. Successful completion of the proposed research will reveal the functional impact of incorporation of an endogeneous population of stem cell-derived neurons into adult neural circuits.
The neurons in the nose that detect smells are unusual, because they are produced throughout life. In this project, we will determine how these new neurons form connections with neurons in the brain, and how this contributes to the sense of smell. Understanding this process will be important in designing treatments to replace damaged neurons in a number of diseases, such as Alzheimer's disease, Parkinson's disease and stroke.