Mammalian olfactory sensory neurons must "choose" to express a single chemoreceptor gene from among hundreds in the genome. In addition to determining the odors (or pheromones) to which a neuron responds, the chosen receptor plays several critical roles during the life cycle of the cell. Activity of the receptor participates in controlling the position within the brain to which the axon is guided, refining axonal projections, and controlling how long the neuron will live. Variable neuronal longevity among olfactory neurons is thought to facilitate refinement of neuronal connections, elimination of damaged neurons, and, possibly, sensitization of an animal to odors and pheromones. Preliminary studies have led to the discovery of a mouse histone variant gene whose expression is detected only in olfactory sensory neurons in a pattern that is inversely related to neuronal activity. Histones are basic proteins that make direct contact with DNA and play critical roles in regulating gene expression. Elimination of the olfactory-specific histone gene from the genome caused mice to exhibit abnormal weight gain and significant defects in olfactory receptor gene expression as they aged. Two possible explanations for the observed defects in receptor gene expression are: 1) that the histone participates in choosing and/or maintaining receptor gene expression, or 2) that the histone participates in controlling neuronal longevity. These hypotheses will be tested in Aims 1 and 2. A hypothesis that the olfactory histone gene plays a role in axon guidance or refinement was born from observations that its elimination from the genome caused defects in the expression of genes involved in axon guidance, higher rates of cell death among immature neurons, and axonal projection defects in adults. A possible role for the histone in activity-dependent axon guidance or refinement will be investigated in Aim 3. Molecular, histological, genetic, and high-resolution imaging techniques will be used to complete the proposed aims. The proposed studies are anticipated to provide new mechanistic perspectives on how neuronal activity and epigenetics affect the development, refinement, and plasticity of the peripheral olfactory system, and may have important implications for other parts of the nervous system as well. Mechanistic issues regarding the choice of receptor gene expression, the guidance and refinement of axonal projections, and the control of neuronal longevity are central to the development and function of the olfactory system and remain particularly challenging. Understanding these processes will have major implications for olfactory dysfunction and related health problems in humans. PUBLIC HEALTH RELEVANCE: The role of an olfactory-specific histone variant in the activity-dependent control of neuronal longevity and axon guidance in mammals The human olfactory system contains hundreds of different types of sensory neurons, whose relative abundance and functional connection to the brain are controlled by processes that are poorly understood, but are critical to normal olfactory function. We have discovered a gene in mouse that is expressed only in olfactory tissues and that we suspect may play an important role in these processes. The study of this gene may have important implications for olfactory dysfunction in humans, including age-related olfactory decline and olfactory-related eating disorders.