Genetic Mapping of Functional Vomeronasal Circuit

描述（由申请人提供）：本提案的主要目标是了解涉及感官信息处理的机制和一般原则。感觉系统的正常功能对我们的健康和幸福至关重要。许多神经和精神疾病，如精神分裂症、自闭症、注意力缺陷多动障碍（ADHD）和抑郁症，都表现出感觉反应的缺陷。感觉缺陷也是帕金森氏症和阿尔茨海默氏症的最早征兆。对感觉系统的研究将使我们能够了解大脑的功能，并帮助我们将这些知识用于诊断和治疗。为了实现这一目标，我们必须研究检测和整合感觉输入并引出不同行为输出的神经回路。在脊椎动物中，交配仪式和领土侵略等先天行为在很大程度上是通过犁鼻器探测信息素线索引起的。这些行为是稳健和刻板的，它们的表达严重依赖于信息素的正确识别。参与信息素检测的神经回路在很大程度上是由基因决定的。在犁鼻系统中，感觉输入和行为反应之间存在内在联系，使其成为理解感觉处理的一个有吸引力且易于处理的电路。在本研究中，我们验证了感觉信息在感觉细胞中以不同信息素激活模式编码的假设。这些信息通过这些神经元的地形投影在大脑中进一步表现出来，从而使动物能够区分性别、菌株以及其他个体的社会和生殖状况。我们将首先开发在感觉神经元中表达钙指示剂的转基因动物，以鉴定对特定信息素有反应的细胞。结合荧光成像、小鼠遗传学和分子生物学，我们将鉴定这些细胞表达的信息素受体基因。第三，我们将通过基因标记实验绘制犁鼻通路来追踪信息流。最后，我们将基因灭活犁鼻通路中的神经元亚群，以阐明它们对信息素感知的功能贡献。这种犁鼻回路的功能映射将为了解感觉系统如何检测、解析和整合信息以引发特定行为提供洞见。

DESCRIPTION (provided by applicant): The major goal of this proposal is to understand the mechanisms and the general principles involved in sensory information processing. The proper function of the sensory systems is crucial to our health and well being. Numerous neurological and psychiatric disorders, such as schizophrenia, autism, attention deficit hyperactivity disorder (ADHD) and depression, all manifest defects in sensory responses. Sensory deficit is also the earliest sign of Parkinson's and Alzheimer's diseases. The study of the sensory systems will enable us to understand how the brain functions and help us to use this knowledge for diagnostic and therapeutic applications. To achieve this goal, one must study the neural circuitry that detects and integrates sensory input and elicits distinct behavioral output. In vertebrates, innate behaviors such as mating rituals and territorial aggression are largely elicited by the detection of pheromone cues through the vomeronasal organ. These behaviors are robust and stereotyped and their expression critically depends on the correct identification of pheromones. The neural circuits involved in pheromone detection are largely genetically determined. There is an intrinsic link between sensory input and behavior responses in the vomeronasal system, making it an attractive and tractable circuitry to understand sensory processing. In this study, we test the hypothesis that sensory information is encoded in the pattern of activation by different pheromones in the sensory cells. This information is further represented in the brain by the topographic projection from these neurons to allow an animal to discriminate gender, strain and the social and reproductive status of other individuals. We will first develop transgenic animals expressing calcium indicators in the sensory neurons to identify cells that respond to specific pheromones. Combining fluorescent imaging, mouse genetics and molecular biology, we will then identify the pheromone receptor gene these cells express. Third, we will trace the information flow by mapping the vomeronasal pathway with genetic labeling experiments. Finally, we will genetically inactivate subpopulations of neurons in the vomeronasal pathway to elucidate their functional contribution to pheromone perception. This functional mapping of the vomeronasal circuit will provide insight into how the sensory system detects, parses and integrates information to elicit specific behaviors.