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，化学信息素（在生物体之间传递信息的化学感觉刺激;例如，信息素或社会线索）可以促进交配或攻击行为，或者可以有助于个体小鼠之间食物偏好的传递。然而，嗅觉介导的社会互动的分子，细胞和神经机制仍然知之甚少。这项建议将研究一个独特的嗅觉子系统内的主要嗅觉系统，GC-D+神经元/项链肾小球子系统，在检测化学信息素和调解社会互动相关的食物偏好的作用。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，受体鸟苷酸环化酶GC-D）和它们的嗅觉前脑靶点（后主嗅球的项链状肾小球）。GC-D+神经元似乎起着多模态化学传感器的作用，表现出对一小组化学刺激的反应，包括尿、尿钠肽激素尿鸟苷素和鸟苷素以及对CO2的反应。解剖学研究表明，项链肾小球也接受不同的化学感觉输入通过异质性传入神经支配和广泛的球内连接与其他嗅球。因此，GC-D/项链子系统可以理想地适合于整合化学信息素和一般气味信息，并且可以充当用于多种化学感觉刺激的符合检测器。我们提出了一个多学科的合作研究，以调查的GC- D/项链子系统中的作用，检测化学信息素，因为它们涉及到社会互动。本研究拟（1）采用分子生物学、电生理学和Ca ~（2+）显像等方法研究GC-D ~+神经元对多种信息素的反应，（2）采用神经解剖学示踪、免疫组织化学和电镜等方法研究向项链状肾小球提供感觉输入的神经元以及项链状投射神经元的中枢靶点;（3）研究GC-D+神经元在重要社会行为、食物偏好社会转移（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系统疾病的标志。正因为如此，社会互动的测定，如STFP已被用于自闭症小鼠模型的研究。因此，在这里获得的结果不仅将阐明嗅觉介导的社会沟通的关键机制，但应该提供重要的见解，这些疾病，如自闭症，在正常的社会交往中表现出赤字。

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.