Project Summary/Abstract The olfactory epithelium is one of three major regions within the mammalian nervous system where new neurons are added throughout life. In humans, a failure to maintain olfactory sensory neurogenesis is associated with olfactory dysfunction, which afflicts an estimated 12.4 percent of adults in the U.S. and can adversely affect health and quality of life. A key barrier to treating olfactory dysfunction is our incomplete understanding of how persistent olfactory sensory neurogenesis is regulated and maintained. A related deficiency lies in our understanding of why neurogenesis persists within the olfactory epithelium. Life-long olfactory sensory neurogenesis is presumed to function solely to replace damaged olfactory sensory neurons. However, work from our laboratory has demonstrated that the birthrates of neurons that express a fraction of odorant receptors are accelerated upon stimulation by specific odors, leading to the central hypothesis of this proposal: that persistent neurogenesis within the olfactory epithelium serves, in part, an adaptive function. Our results are not readily explained by the current model of olfactory sensory neurogenesis, which predicts that the relative birthrates of neurons expressing each of the hundreds of different receptor genes encoded in the genome are determined stochastically by a process in which each post-mitotic neural precursor randomly ‘chooses’ a single odorant receptor gene for expression. Accordingly, the relative birthrates of distinct olfactory sensory neuron ‘subtypes’ are expected to be impervious to olfactory experience. The overall objective of this proposal is to determine how odor stimulation selectively accelerates the birthrates of specific olfactory sensory neuron subtypes. Our working model is that a fraction of subtypes have a special capacity, upon stimulation by odors with potential salience, to amplify themselves by selectively promoting the proliferation of mitotic neural progenitors that are of the same lineage and predisposed toward the same subtype fate. This model will be tested through three specific aims. Aim 1 will test the hypothesis that olfactory stimuli that selectively promote the neurogenesis of specific neuron subtypes are discrete, salient odors that selectively stimulate those subtypes. This will be tested by identifying, via a selective single-cell sequencing-based approach, the scope of neuron subtypes whose birthrates are accelerated by sex-specific odors. Aim 2 will test the hypothesis that some mitotic neural progenitors are predisposed toward specific odorant receptor fates that can be selectively amplified via cell proliferation. This will be tested by mapping the subtype fates of individual progenitors using genetic barcoding and in situ sequencing strategies. Aim 3 will test the hypothesis that mature olfac- tory sensory neurons of specific subtypes have a special capacity to promote the proliferation of progenitors within the same lin...