Transduction mechanisms and CNS targets of GC-D neurons

描述（由申请人提供）：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，符号化学物质（在生物体之间传递信息的化学感觉刺激，如信息素或社会线索）可以促进交配或攻击行为，或者有助于在单个小鼠之间传递食物偏好。然而，嗅觉介导的社会互动背后的分子、细胞和神经机制仍然知之甚少。本提案将研究主要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，在检测与食物偏好相关的符号化学物质和社会互动中介中的作用。GC-D+神经元与典型嗅觉感觉神经元的不同之处在于它们表达的转导相关蛋白（例如，受体鸟酰环化酶GC-D）和它们的嗅觉前脑靶点（后主嗅球的项链肾小球）。GC-D+神经元似乎具有多模态化学传感器的功能，表现出对一小组化学刺激的反应，包括尿、尿观音和观音利钠肽激素，以及二氧化碳。解剖学研究表明，项链肾小球也通过异质传入神经支配和与其他嗅觉肾小球的广泛的球内连接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集成符号化学和一般气味信息，并可能作为多种化学感觉刺激的巧合检测器。我们提出了一项多学科合作研究，以调查GC- D/项链子系统在检测与社会互动相关的符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、电生理学和Ca2+成像方法来表征GC-D+神经元对几种半化学物质的反应；(2)利用神经解剖示踪、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目标；(3)研究GC-D+神经元对重要社会行为、食物偏好的社会转移（STFP）和食物来源偏好的贡献。正常社会交往的缺陷是自闭症和许多其他神经系统疾病的标志。正因为如此，诸如STFP之类的社会互动分析已被用于自闭症小鼠模型的研究。因此，这里获得的结果不仅将阐明嗅觉介导的社会交流的关键机制，而且应该为那些表现出正常社会互动缺陷的疾病，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.