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

描述（由申请人提供）：该提案旨在了解感觉神经回路的功能组织，并位于神经生物学和寄生虫学的界面。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。我们正在解决这个问题，使用线虫嗅觉作为模型系统。超过100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，使寄生线虫成为全球主要的健康问题。许多寄生线虫通过响应宿主发出的感觉线索来主动寻找宿主，一种可能的控制策略是干扰它们定位宿主的能力。然而，寄生线虫的感觉行为仍然在很大程度上未被探索。我们建议进行深入分析的嗅觉行为和嗅觉神经回路功能的自由生活和寄生线虫，特别强调气味驱动的主机寻求行为的皮肤穿透人类线虫粪类圆线虫。我们将使用钙成像和定量行为分析，结合单细胞消融和靶向基因破坏来识别成功人类寄生所需的基因、电路和行为。我们还将比较S. stercoralis，密切相关的大鼠寄生线虫Strongyloids ratti，和自由生活的线虫秀丽隐杆线虫。我们将利用保守的神经解剖学，但不同的行为库线虫获得基本的见解如何神经回路的具体功能形状的行为输出。这些实验将导致关于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由于学习和记忆、衰老和疾病而被修改提供基础。与此同时，这些实验将深入了解人类寄生虫如何利用感官线索来瞄准人类，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.