Thursday, May 1, 2025
5/1/2025
Olfactory Combinatorial Coding in C. elegans - Our sense of smell (olfaction) affects appetite, the taste of food, many important physiological processes, and overall quality of life. Olfaction is an important and active area of study. A long-term goal of my laboratory is to understand how olfactory information is encoded and utilized to influence behavior and other physiological responses. The human genome encodes <400 olfactory receptor molecules, yet we are capable of discriminating millions of different odorants through combinatorial coding, where individual olfactory receptor neurons (ORNs) can respond to many different odorants (despite expressing just 1-2 receptors), and odorants can activate broad populations of ORNs; it is the combination of activated ORNs that determines an odorant's perceptual qualities and valence. A major gap in our knowledge is how these ORN combinations are decoded and translated into downstream responses. A significant obstacle is the size and complexity of higher brain structures that perform olfactory processing (eg. the piriform cortex in mammals, and mushroom bodies in Drosophila). A simple, experimentally-accessible model is needed in which odorant detection is transformed into behavioral responses through just a handful of neurons. Basic principles of end-to-end olfactory processing gleaned from such a system will provide fundamental insights into olfactory processing in more complex organisms. Caenorhabditis elegans provides an experimental system which has many potential advantages for studying olfactory combinatorial coding. Its nervous system is small (302 neurons), and recent advances in technology have enabled us to perform optical recordings of neuronal activity at a whole-brain scale. Using this approach, we have shown that olfaction in C. elegans, like in humans, follows the principles of combinatorial coding. C. elegans shows extensive conservation with mammals at the level of general molecular and cellular organization, but also in terms of specific olfactory coding strategies, ensuring that insights from C. elegans will be relevant to human health. Our goals are to use the powerful approaches available for study of C. elegans to uncover the fundamental mechanisms at play in olfactory combinatorial coding. We hypothesize that a single odorant is encoded both as an attractant and a repellant, and that the final behavioral outcome will reflect a balance between the two pathways. Interestingly, this balance can be modulated by environmental conditions, which provides a mechanism for behavioral plasticity. We will test these ideas using whole-brain recording and high- resolution quantitative measurements of sensory-driven behavior. Importantly, this proposal was designed to maximize the involvement of undergraduate students in the research. They will be encouraged to pursue discrete objectives of the proposal, trained in all of the necessary experimental techniques and laboratory safety, and given ample opportunity and guidance to generate the data. They will be trained in rigorous statistical analysis of the data, and contribute to the decision-making process for the next experiments. This authentic research experience will prepare students well for a future career in the biomedical sciences.
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