Critical Period for Murine Olfactory Map Formation

Wu, Yunming (2017). Critical Period for Murine Olfactory Map Formation. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000cc24

Abstract

Formation of neural circuits in the brain is sensitive to deprivation of neural activity during the critical period. In the last few decades, the critical period has been studied extensively. These studies are primarily focused on the development of receptive fields in the cortex. Mechanisms regulating the connection between sensory neurons and their central targets during the critical period remain unknown.

In this study, together with other members of the Yu lab, I performed a series of experiments in mice to perturb the projection pattern of olfactory sensory neurons (OSNs) during postnatal development. I observed a critical period during the formation of the olfactory circuit. Neurons generated during and after the critical period adopted different mechanisms in axon targeting. The early-born neurons were able to form converging projection into single glomerulus de novo. They also possessed the ability to correct mis-targeted axons. The late born neurons relied on existing axon tracks to target the correct glomeruli. Through genetic chronicle tracing experiments, I was able to demonstrate that early born neurons had a shorter life span, a faster turnover rate, and an increased axon projection plasticity compared to the late born neurons. Because of these unique characteristics, I defined the early born OSNs as “settler neurons”. Genetic ablation of settler neurons resulted in a disrupted axon projection pattern. Transgenic expression of Bcl2, an anti-apoptotic gene, in the OSNs extended the life span of the settler neurons beyond the critical period. The existence of the settler neurons after the critical period promoted the axon exuberant growth. It also affected the OSNs’ axon projection pattern. Transcriptome analysis revealed a genetic switch during the critical period. Different sets of transcription regulators, axon guidance molecules, and signaling molecules were expressed between the settler neurons and the OSNs born afterwards. I identified a G protein coupled receptor, Frizzled 1 (Fzd1), as a critical regulator of the critical period in the olfactory system. Ectopic expression of Fzd1 after the closure of the critical period enabled OSN axons to grow exuberantly and caused mis-targeting phenotype. Removing Frizzled 1 postponed the closure of the critical period. Finally, I showed that Fzd1 was physically associated with olfactory receptors (ORs). This interaction provided a molecular basis for Fzd1 to influence OSN’s axon guidance.