Proper development and adaptation of the mammalian nervous system depend on sensory experience and learning, but the scope and mechanisms of these changes are only partially understood. The olfactory system exhibits a particularly high capacity for experience-dependent change. While research has focused largely on brain areas that process olfactory information, experience-dependent changes occur even at the level of the odor-sensing neurons. These neurons are born throughout life, a process presumed to function simply to replace damaged neurons. This Faculty Early Career Development (CAREER) project will explore the possibility that olfactory sensory neurogenesis also plays an important adaptive role. This concept was inspired by a recent discovery within the Principal Investigator’s lab that, in mice, odor stimulation selectively promotes the birth of neurons that display specific odorant receptors. To understand these results, the investigators will explore the possibility that neuron receptor fates begin to be determined much earlier during cell development than is currently assumed and are selectively amplified through cell division. Further, they will investigate the possibility that the amplification of specific stem cells is driven by signals from mature daughter neurons whose signaling is enabled by olfactory learning. The research objectives of this project will be complemented by educational objectives, including the development, use, and sharing of a virtual reality application for active learning of sensory biology. This project is expected to enhance our understanding of fundamental aspects of olfactory development and adaptation and may provide insights into the cause of age-related olfactory dysfunction in humans.
The persistence of olfactory sensory neurogenesis throughout life in mammals is thought to function solely to replace neurons that become damaged due to environmental exposure. The central hypothesis of this CAREER project is that olfactory sensory neurogenesis also has an important adaptive function. This hypothesis is based in part on recent findings from the PI's lab that, in mice, olfactory stimulation selectively promotes the neurogenesis of a fraction of olfactory neuron ‘subtypes,’ which are defined by the single odorant receptor gene that each neuron ‘chooses’ to express out of ~1000 possibilities. As a result, mature neurons of these subtypes are selectively increased in abundance in the presence of olfactory stimulation. These findings challenge the current model of olfactory sensory neurogenesis, which predicts that the relative birth rates of distinct neuron subtypes are determined by the fixed probabilities with which their receptor genes are stochastically chosen for expression. To explain these findings, the investigators will first employ a fate-mapping approach to test the hypothesis that receptor choice begins within stem cells, a much earlier stage than is currently thought, and that specific receptor fate-restricted stem cells are subject to selective proliferation. Second, the investigators will use olfactory conditioning to test the hypothesis that the neuron subtypes that undergo stimulation-dependent neurogenesis are specified by olfactory learning. Third, the investigators will use a single-cell sequencing approach to test the hypothesis that the selective birth of specific neuron subtypes is promoted by signals emitted exclusively from mature neurons with the same receptor identities.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
