This proposal aims to understand the functional organization of sensory neural circuits, and lies at the interface of neurobiology and parasitology. A fundamental question in neuroscience is how sensory input is transformed into behavioral output. We are addressing this question using nematode olfaction as a model system. Over a hundred species of nematodes are parasites of humans, and over a quarter of the world's population is infected with parasitic nematodes, making parasitic nematodes a major health problem worldwide. Many parasitic nematodes actively search for hosts by responding to host-emitted sensory cues, and one possible control strategy is to interfere with their ability to locate hosts. However, the sensory behaviors of parasitic nematodes remain largely unexplored. We propose to undertake an in-depth analysis of olfactory behaviors and olfactory neural circuit function in free-living and parasitic nematodes, with particular emphasis on the odor-driven host-seeking behaviors of the skin-penetrating human threadworm Strongyloides stercoralis. We will use calcium imaging and quantitative behavioral analysis in combination with single-cell ablation and targeted gene disruption to identify genes, circuits, and behaviors required for successful human parasitism. We will also compare the functional properties of olfactory neural circuits in S. stercoralis, the closely related rat-parasitic nematode Strongyloids ratti, and the free-living nematode Caenorhabditis elegans. We will leverage the conserved neuroanatomy but diverse behavioral repertoires of nematodes to gain fundamental insights into how the specific features of a neural circuit shape its behavioral output. These experiments will lead to important discoveries about the functional organization of sensory neural circuits, and will provide a foundation for understanding how sensory circuits can be modified as a result of learning and memory, aging, and disease. At the same time, these experiments will provide insight into how human parasites use sensory cues to target humans, thereby paving the way for the development of novel strategies for preventing harmful parasitic infections.
Parasitic nematodes infect over a quarter of the world's population and are responsible for some of the most common neglected tropical diseases. A better understanding of their sensory behaviors will enable the development of new approaches for preventing nematode infections. In addition, a better understanding of how sensory neural circuits specify behaviors will have broad implications for human neurological disorders, many of which involve abnormal sensory processing.