Genetic Mapping of Functional Vomeronasal Circuits

描述(申请人提供)：感官和内分泌系统的正常运作对人类的健康和福祉是必不可少的。感觉经验往往对内分泌系统有直接影响，许多经验诱导的内分泌反应是与生俱来的。然而，控制这些过程的神经回路还没有被很好地理解。在本项目中，我们将以小鼠犁鼻神经回路为模型系统，以阐明感觉信息处理的神经机制和感觉控制内分泌功能的机制。在脊椎动物中，交配仪式和领土攻击等先天行为是通过犁鼻器检测到信息素线索而引发的。这些行为是强健的和刻板的，但它们的表达关键取决于对信息素的适当反应。犁鼻回路直接连接到内分泌系统，并影响它们的输出。这些回路在很大程度上是由基因决定的，感觉输入与行为和内分泌反应之间存在内在联系，这使得它成为了解感觉加工和内分泌变化的感觉控制的一个有吸引力和易处理的回路。这项应用的目的是识别性信息素及其受体，并追踪处理信息的神经回路。我们假设，雄性和雌性信息素在VNO的不同细胞群中引发反应。这种信息在大脑中由感觉神经元投射的不同空间模式表示，并允许性别歧视和不同的内分泌反应变化。在目标1中，我们将使用在感觉神经元中表达钙指示剂的转基因动物来识别对尿液中特定信息素做出反应的细胞。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。我们将对尿液组分进行筛选，以化学方式识别信息素。在目标2中，我们将通过对表达性信息素受体的神经元进行基因标记来追踪信息流。在目标3中，我们将结合遗传实验和行为分析来分析信息素对内分泌反应的控制。动物已经进化出专门的神经回路，将感觉输入与内分泌反应联系起来。感觉体验的复杂性使得研究人类内分泌反应的感觉控制变得困难。犁鼻系统在大多数脊椎动物中高度进化，专门控制内分泌系统和情绪状态。类似的回路在人类中也存在，但在灵长类动物进化过程中可能被压缩，主要由主要的嗅觉组成，并包括其他感觉形式。本研究将有助于阐明内分泌系统和动机状态的调控机制，以及社会交往的过程。

DESCRIPTION (provided by applicant): The proper functioning of the sensory and endocrine systems is essential for the health and well being of human beings. Sensory experiences often have direct influence on endocrine systems and many experience- induced endocrine responses are innate. However, the neural circuitry that controls these processes is not well understood. In the proposed project, we will study the mouse vomeronasal circuitry as a model system to elucidate the neural mechanism of sensory information processing and mechanism of sensory control of endocrine function. In vertebrates, innate behaviors such as mating rituals and territorial aggression are elicited by the detection of pheromone cues through the vomeronasal organ. These behaviors are robust and stereotyped, but their expression critically depends on the proper response to pheromones. The vomeronasal circuit connects directly to the endocrine systems and influences their output. These circuits are largely genetically determined and there is an intrinsic link between sensory input and the behavior and endocrine responses, making it an attractive and tractable circuitry to understand sensory processing and sensory control of endocrine changes. The objective of this application is to identify the sex pheromones, their receptors and trace the neural circuitry processing the information. We hypothesize that male and female pheromones elicit responses from distinct populations of cells in the VNO. This information is represented in the brain by the distinct spatial patterns of the sensory neuron projection and allows sex discrimination and differential endocrine changes in response. In Aim 1, we will use transgenic animals expressing calcium indicators in the sensory neurons to identify cells that respond to specific pheromones in urine. Combining fluorescent imaging, mouse genetics and molecular biology, we will identify the pheromone receptor gene expressed by these cells. We will screen urine fractions to chemically identify the pheromones. In Aim 2, we will trace the information flow by genetically labeling the neurons expressing the sex pheromone receptors. In Aim 3, we will combine genetic experiments with behavioral assays to analyze pheromone control of endocrine responses. Animals have evolved specialized neural circuitry that links sensory input to endocrine responses. The complexity of sensory experiences makes it difficult to study sensory control of endocrine response in humans. The vomeronasal system is highly evolved in most vertebrate species and is specialized in controlling endocrine system and emotional states. Similar circuits exist in humans but may have been compacted during primate evolution to consist of mostly the main olfactory, and to include other sensory modalities. Insight gained from this study will help to elucidate control mechanism of endocrine systems and motivational states, as well as the processing of social communication.