Genes and Neural Circuits Mediating Avoidance Behavior

描述（由申请人提供）：特定的感觉刺激如何引起特定的行为是神经生物学的一个基本问题。大多数气味会引起吸引或回避，这取决于它们的浓度和特性，以及它们激活的神经回路的性质。此外，这种气味剂通常会激活嗅觉感觉神经元（OSNs）的组合，使将气味识别转化为行为的电路的解剖复杂化。相比之下，二氧化碳（CO2）在果蝇黑腹果蝇（Drosophila melanogaster）中引起了大范围浓度的回避，并且在灵敏的体内钙成像技术检测时仅激活了两个OSNs种群。先前的研究表明，最先发现的表达GR63a和GR21a受体的嗅觉神经元是避免低浓度二氧化碳的关键，但其他被二氧化碳激活的神经元的功能尚不清楚。在这里，我们建议确定假定的第二CO2 OSNs及其同源受体，属于最近发现的嗜离子性谷氨酸受体（IRs）家族的成员，对于检测和避免高浓度CO2和类似气味（如酸）是必要和充分的。为了解决这些问题，我们将进行体内钙成像和行为分析。确定第二种二氧化碳受体的亚细胞定位将预测该受体是否直接与气味剂相互作用。为了更好地理解中央电路介导的逃避行为，我们将追踪其投射到更高的大脑中心，并将它们与第一个二氧化碳途径进行比较，这两个途径是否会聚在更高的大脑中心（如侧角）的同一个目标神经元上。由于温血宿主释放的二氧化碳和酸是蚊子必不可少的嗅觉线索，并且蚊子天线中表达了第二种二氧化碳受体的同源物，因此我们计划研究表达同源物的蚊子OSNs是否被二氧化碳和酸激活。

DESCRIPTION (provided by applicant): How specific sensory stimuli evoke specific behaviors is a fundamental problem in neurobiology. Most odorants elicit attraction or avoidance depending on their concentrations and identity, as well as the nature of the neural circuits they activate. Such odorants, moreover, typically activate combinations of olfactory sensory neurons (OSNs), complicating the dissection of the circuits translating odor recognition into behavior. Carbon dioxide (CO2), in contrast, elicits avoidance over a wide range of concentrations in the fly, Drosophila melanogaster, and activates only two populations of OSNs when examined by a sensitive, in vivo calcium imaging technique. Previous studies showed that OSNs expressing GR63a & GR21a receptors, the first CO2 olfactory neurons identified, is essential for avoidance to low concentrations of CO2, but it remained unclear the function of the other neurons activated by CO2. Here, we propose to determine that the putative 2nd CO2 OSNs and its cognate receptor that belongs to a member of the recently identified Ionotropic Glutamate Receptors (IRs) family are necessary and sufficient for detection of and avoidance to high CO2 concentrations and similar odorants such as acids. To address these questions, we will perform in vivo calcium imaging and behavioral assays. Determining subcellular localization of the 2nd CO2 receptor will predict whether or not the receptor directly interacts with odorants. To better understand central circuits mediating avoidance behavior, we will trace its projections into higher brain centers and compare them to the 1st CO2 pathway whether these two pathways converge upon a same target neuron in a higher brain center such as the lateral horn. Because CO2 and acids released by warm-blooded hosts are essential olfactory cues for the mosquito, and a homolog of the 2nd CO2 receptor is expressed in the mosquito antenna, we plan to examine whether the mosquito OSNs expressing the homolog are activated by CO2 and acids. PUBLIC HEALTH RELEVANCE: Relevance Insects transmit diseases to humans and animals including livestock, and cause serious threats to health and enormous losses to agricultural output. Many insects respond to their human and animal hosts primarily through carbon dioxide (CO2) and lactic acid, key olfactory cues emanating from mammals. These olfactory cues activate defined populations of olfactory sensory neurons in the mosquito that express the same odorant receptors as in Drosophila. Understanding how the Drosophila sensory receptors are activated by CO2 and acids, and the mechanism by which their neural circuits trigger behavioral responses to these stimuli would help us develop better strategies to prevent transmission of insect-born diseases by mosquitoes, tsetse flies, and other pathogenic insects.