The objective of this proposal is to understand how the first elements of olfactory circuitry are correctly wired together during embryonic development. Odorant sensing neurons project axons from the olfactory epithelium to the olfactory bulb in the brain. Remarkably, axons extending from neurons that are scattered in the epithelium but choose to express the same odorant receptor from a large repertoire of receptors, converge together in specific reproducible locations within the bulb. This research proposal addresses how olfactory sensory axons locate their correct targets in the brain. The project takes advantage of the relative simplicity, rapid development, and experimental accessibility of the embryonic zebrafish to study the guidance of sensory neurons. In the first aim we will relate odorant receptor expression to target location within the bulb. Odorant receptors participate in the guidance of olfactory sensory axons and the second aim examines whether their contribution is important during the initial stages of target acquisition or later as sensory axons coalesce into distinct neuropilar structures called glomeruli.
The third aim addresses the role of a large and important class of axonal guidance cues, the semaphorins, in olfactory axon targeting. This work will explore how guidance receptors and olfactory receptor expression is coordinated, and how guidance cues determine the target locations of sensory axons in the bulb. Olfactory sensory neurons are constantly being born and making new connections within the mature olfactory bulb. Understanding how these connections form during development will be essential in understanding how this process fails in neurodegenerative diseases.
Age-related neural degeneration is often signaled by a loss of olfactory sensitivity. In contrast to every other known neural circuit in higher vertebrates, both peripheral and central olfactory neurons are continuously replaced in mature individuals. These new neurons must grow axons that interconnect with a high degree of specificity to preserve functional circuitry. The objective of this project is to identify the signals that direct this proess during embryonic development. This basic knowledge will be essential for understanding the pathology of anosmia and to develop regenerative therapies for it reversal.