Transduction mechanisms and CNS targets of GC-D neurons

描述(申请人提供)：人类和其他哺乳动物的社会互动受到嗅觉信号的显著影响。例如，信号化学物质(在有机体之间传递信息的化学感觉刺激；例如，信息素或社交线索)可以促进交配或攻击行为，或者有助于在个体小鼠之间传递食物偏好。然而，嗅觉介导的社会相互作用背后的分子、细胞和神经机制仍然知之甚少。这项建议将研究主嗅觉系统中一个独特的嗅觉子系统-GC-D+神经元/项链肾小球子系统在检测信号化学物质和调节与食物偏好有关的社会互动中的作用。GC-D+神经元不同于标准的嗅觉感觉神经元，其表达的信号转导相关蛋白(如受体鸟苷环化酶GC-D)和嗅觉前脑靶点(后主嗅球的项链小球)不同。GC-D+神经元似乎具有多模式化学感受器的功能，对一小群化学刺激包括尿液、利钠肽激素尿鸟苷和鸟苷，以及对二氧化碳有反应。解剖学研究表明，项链肾小球还通过异质传入神经和与其他嗅觉小球的广泛球内联系接受不同的化学感觉输入。因此，GC-D/项链子系统可能非常适合于整合信号化学和一般气味信息，并可以作为多种化学感觉刺激的符合检测器。我们提出了一项多学科的协作研究，以调查GC-D/项链子系统在检测与社会相互作用相关的信号化学物质中的作用。我们提出的研究将(1)使用分子生物学、电生理和钙成像方法来表征GC-D+神经元对几种信号化学物质的反应；(2)使用神经解剖示踪、免疫组织化学和电子显微镜来表征那些为项链肾小球提供感觉输入的神经元以及项链相关投射神经元的中心靶标；以及(3)研究GC-D+神经元在重要的社会行为、食物偏好的社会转移(STFP)和食物来源偏好中的作用。正常社会交往的缺陷是自闭症和许多其他神经疾病的标志。正因为如此，社会相互作用的分析，如STFP，已经被用于自闭症小鼠模型的研究。因此，这里的结果不仅将阐明嗅觉介导的社会交流的关键机制，而且应该为那些显示正常社会互动缺陷的疾病(如自闭症)提供重要的见解。 公共卫生相关性：正常社会交往的缺陷是自闭症和许多其他神经疾病的标志。人类和其他哺乳动物的社会互动受到嗅觉信号的显著影响。然而，嗅觉介导的社会相互作用背后的分子、细胞和神经机制仍然知之甚少。这里的结果不仅将阐明嗅觉介导的社交沟通的潜在机制，而且应该为那些显示正常社交互动缺陷的疾病(如自闭症)提供重要的见解。

DESCRIPTION (provided by applicant): Social interactions in humans and other mammals are significantly impacted by olfactory signals. For example, semiochemicals (chemosensory stimuli that communicate information between organisms; e.g., pheromones or social cues) can promote mating or aggression behaviors or can contribute to transmission of food preferences between individual mice. However, the molecular, cellular and neural mechanisms underlying olfactory-mediated social interactions remain poorly understood. This proposal will examine the role of a distinct olfactory subsystem within the main olfactory system, the GC-D+ neuron/necklace glomeruli subsystem, in the detection of semiochemicals and the mediation of social interactions related to food preference. GC-D+ neurons differ from canonical olfactory sensory neurons in the transduction-related proteins they express (e.g., the receptor guanylyl cyclase GC-D) and in their olfactory forebrain targets (the necklace glomeruli of the posterior main olfactory bulb). GC-D+ neurons appear to function as multimodal chemosensors, exhibiting responses to a small group of chemostimuli including urine, the natriuretic peptide hormones uroguanylin and guanylin, and to CO2. Anatomical studies suggest that necklace glomeruli also receive diverse chemosensory inputs through heterogeneous afferent innervation and extensive intrabulbar connections with other olfactory glomeruli. Thus, the GC-D/necklace subsystem may be ideally suited to integrate semiochemical and general odor information and may act as coincidence detectors for multiple chemosensory stimuli. We propose a multidisciplinary, collaborative study to investigate the role of the GC- D/necklace subsystem in the detection of semiochemicals as they relate to social interactions. Our proposed study will (1) use molecular biological, electrophysiological and Ca2+-imaging approaches to characterize the responses of GC-D+ neurons to several semiochemicals; (2) use neuroanatomical tracing, immunohistochemistry and electron microscopy to characterize those neurons that provide sensory input to the necklace glomeruli, as well as the central targets of necklace-associated projection neurons; and (3) examine contributions of GC-D+ neurons to important social behaviors, the social transfer of food preference (STFP) and food source preference. Deficits in normal social interactions are a hallmark of autism and many other neurological disorders. Because of this, assays of social interactions such as STFP have been utilized in the study of mouse models of autism. Thus, results obtained here will not only elucidate key mechanisms underlying olfactory-mediated social communication, but should provide important insights into those diseases, such as autism, that show deficits in normal social interactions. PUBLIC HEALTH RELEVANCE: Deficits in normal social interactions are a hallmark of autism and many other neurological disorders. Social interactions in humans and other mammals are significantly impacted by olfactory signals. However, the molecular, cellular and neural mechanisms underlying olfactory- mediated social interactions remain poorly understood. Results obtained here will not only elucidate the mechanisms underlying olfactory-mediated social communication, but should provide important insights into those diseases, such as autism, that show deficits in normal social interactions.