Identification of the ligands and sensory neurons that mediate pheromone behavior

描述(由申请人提供)：神经信息处理利用了数量难以捉摸的离散电路，这些电路由看似相似的神经元组成，专门用于特定和不同的任务。阐明神经元之间的时间活动、空间组织或分子差异导致不同的感知、神经内分泌或行为结果，对于设计有效的治疗干预至关重要。化学感觉调节行为研究的分子遗传学革命为识别、操纵和揭示构成单个神经回路的机制提供了可能性。虽然在识别参与化学感觉信息编码的受体和神经元方面已经取得了很大的进展，但我们还不知道在哺乳动物模型中调节任何特定行为的特定配体和神经回路。这项研究的目的是确定信息素配体、反应感觉神经元和必要的神经元回路，以调节小鼠的特定社会行为。1)我们将使用一种新的化学捕获方法来对任何物理化学类别的小分子进行化学标记、浓缩和分析，以识别编码单一定义行为的特定信息素。2)我们认为个体的行为是由一组专门的化学感觉神经元来调节的。我们将使用钙成像结合分子和组织化学方法来定义促进行为的感觉神经元。3)啮齿动物的社会行为是可塑性的；接受动物的年龄和性别决定了它是否会做出反应。我们预测，在有反应的动物中活跃的神经通路是不活跃的，不存在，或者在空间上与在无反应的动物中激活的不同。我们将分析表达CFOS激活的一种新的遗传报告的小鼠，以定义和操纵单一行为背后的神经回路。我们预计，在完成这些目标后，我们将迈出重要的第一步，使我们能够可预测地激活小鼠的社会行为，从而在细胞和分子水平上确定神经功能和功能障碍的潜在机制。与公共健康相关在小鼠中，对信息素做出反应的感觉神经元激活杏仁内侧核和下丘脑的核。这些相同的核被认为与调节人类的社会行为有关。然而，由于缺乏对杏仁核和下丘脑神经元亚群相应功能的了解，这些中心的组织、功能意义和具体作用机制的阐明受到了阻碍。我们正在定义引发和规范已知行为的信号的组成部分。这一重要的第一步将使我们能够可预测地激活小鼠的社会反应，从而在细胞和分子水平上定义神经功能和功能障碍的潜在机制。

DESCRIPTION (provided by applicant): Neural information processing utilizes an unfathomable number of discrete circuits composed of seemingly similar neurons dedicated to specific and diverse tasks. Elucidation of the temporal activity, spatial organization, or molecular differences among neurons that lead to distinct perceptual, neuroendocrine, or behavioral outcomes is critical to the design of effective therapeutic intervention. The molecular-genetics revolution of the investigation of chemosensory-mediated behavior has provided the potential to identify, manipulate, and reveal the mechanisms that underlie individual neural circuits. Though great progress has been made in identifying groups of receptors and neurons that participate in chemosensory information coding we do not know the specific ligands and neural circuits that mediate any defined behavior in a mammalian model. The objective of this research is to identify the pheromone ligands, responding sensory neurons, and necessary neuronal circuits that mediate a specific social behavior in the mouse. 1) We will use a novel chemical capture method to chemically tag, enrich, and profile small molecules of any physicochemical class to identify the specific pheromones that encode a single defined behavior. 2) We expect that an individual behavior is mediated by a dedicated subset of chemosensory neurons. We will use calcium imaging combined with molecular and histochemical methods to define the sensory neurons that promote the behavior. 3) Social behavior in rodents is plastic; the age and gender of the receiving animal determines whether it will respond. We predict that neuronal pathways that are active in responding animals are inactive, not present, or spatially distinct from those activated in non-responding animals. We will analyze mice expressing a novel genetic reporter of cFos activation to define and manipulate the neural circuit underlying a single behavior. We expect that at the completion of these aims we will have made an important first step that will allow us to predictably activate social behavior in mice and therefore define at the cellular and molecular level underlying mechanisms of neural function and dysfunction. PUBLIC HEALTH RELEVANCE In the mouse, sensory neurons that respond to pheromones activate nuclei in the medial amygdala and hypothalamus. These same nuclei have been implicated in regulating social behavior in humans. However, elucidation of the organization, functional significance, and specific mechanism of action of these centers is impeded by the lack of knowledge of the corresponding function of subsets of amygdala and hypothalamic neurons. We are defining components of the signals that elicit and regulate a known behavior. This important first step will allow us to predictably activate social responses in mice, and therefore define at the cellular and molecular level, the underlying mechanisms of neural function and dysfunction.