The neural basis of odor-driven behavior in skin-penetrating parasitic nematodes.

描述(申请人提供)：本提案旨在了解感觉神经回路的功能组织，位于神经生物学和寄生虫学的交界处。神经科学中的一个基本问题是感觉输入如何转化为行为输出。我们正在使用线虫嗅觉作为一个模型系统来解决这个问题。100多种线虫是人类的寄生虫，世界上超过四分之一的人口感染了寄生线虫，使寄生线虫成为世界范围内的一大健康问题。许多寄生线虫通过对寄主发出的感官信号做出反应来主动寻找寄主，一种可能的控制策略是干扰它们定位寄主的能力。然而，寄生线虫的感觉行为在很大程度上仍未被探索。我们打算对自由生活和寄生线虫的嗅觉行为和嗅觉神经回路功能进行深入的分析，特别是对穿透皮肤的人类粗线虫的气味驱动的寻找宿主行为进行研究。我们将使用钙成像和定量行为分析，结合单细胞消融和定向基因干扰来确定成功的人类寄生所需的基因、电路和行为。我们还将比较与鼠类寄生线虫Strongyloids Ratti和自由生活线虫Canowhabditis elegans的嗅觉神经回路的功能特性。我们将利用保守的神经解剖学但不同的线虫行为谱系来获得关于神经回路的特定特征如何塑造其行为输出的基本见解。这些实验将导致对感觉神经回路的功能组织的重要发现，并将为理解感觉回路如何因学习和记忆、衰老和疾病而改变提供基础。与此同时，这些实验将为人类寄生虫如何利用感官线索瞄准人类提供洞察力，从而为开发预防有害寄生虫感染的新策略铺平道路。

DESCRIPTION (provided by applicant): 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.