Specific retinal circuits for behavioral responses to threat

项目摘要 了解不同细胞类型的功能和行为之间的关系是一个主要的挑战， 现代神经科学，并正在各种模型系统中进行广泛研究。的概念 在早期视觉系统中，功能不同的细胞类型已经被相对较好地定义，特别是在 哺乳动物视网膜然而，我们对不同视网膜神经元的贡献的理解， 对特定行为反应的初始视觉处理仍然相当有限。在这里，我们建议确定 隐约可见的刺激敏感的视网膜电路使用特定的行为作为读数。威胁性的视觉输入，例如 当物体靠近时，会引发动物和人类的普遍防御行为。最近，几个脑 已经使用光遗传学技术鉴定了对隐约出现的刺激作出响应的电路。然而，尽管如此， 我们对防御行为的重要视网膜回路的了解仍然非常有限， 他们对这种行为输出的潜在贡献。为了识别隐现触发行为的回路，我们 将集中在视网膜神经节细胞（RGC），从中间神经元接收视觉输入，并发送轴突， 大脑每种类型的研究资助拨款委员会都应该对特定的视觉特征作出反应，有人建议， 小鼠视网膜中有~46种不同的RGC类型。包括我们自己在内的几项研究 多个转基因小鼠品系标记特定的RGC类型，并使用形态学和 生理学方法在这些转基因中，特定的RGC类型通过以下两种基因的表达来标记： 荧光蛋白或DNA修饰重组酶（例如，Cre）允许进一步的基因操作。到 定义哪些类型的RGC专门用于检测接近的物体，我们将有选择地表达一个 基因编码的毒素或特定RGC类型中的光遗传调节剂，并检查行为 这种操纵的后果。根据之前的研究结果， 范例和我们的初步数据，我们将开始我们的分析集中在候选研资局类型（即，W3 和OFF α RGC）之后延伸到其它RGC。我们的研究将确定不同的RGC类型， 对接近物体的防御行为的必要性和充分性。鉴定和表征 调节视觉威胁相关行为的特定视网膜神经元应该可以让我们解构 参与对恐惧刺激的检测和解释。它还将帮助我们了解整体结构， 恐惧相关回路的功能特性。此外，本提案中使用的遗传方法可以 进一步扩展，以研究多种细胞类型在多种行为结果中的作用。

Project Summary Understanding the relationship between function of distinct cell types and behavior is a major challenge of modern neuroscience and is being extensively investigated in various model systems. The concept of functionally distinct cell types has been relatively well defined in the early visual system, especially in the mammalian retina. However, our understanding of the contribution of different retinal neurons responsible for the initial visual processing to specific behavioral responses remains rather limited. Here we propose to identify looming stimulus-sensitive retinal circuits using specific behaviors as readouts. Threatening visual inputs, such as approaching objects, trigger universal defensive behaviors in animals and humans. Recently, several brain circuits that respond to the looming stimulus have been identified using optogenetic techniques. Nevertheless, we still have a very limited knowledge about specific retinal circuits important for defensive behaviors and on their potential contribution to such behavioral outputs. To identify circuits for looming-triggered behaviors, we will focus on the retinal ganglion cells (RGCs) that receive visual inputs from interneurons and send axons to the brain. Each RGC type is supposed to respond to specific visual features, and it has been suggested that there are ~46 distinct RGC types in the mouse retina. Several studies, including our own, have generated multiple transgenic mouse lines that label specific RGC types and characterized them using morphological and physiological methods. Specific RGC types in those transgenics were marked by expression of either fluorescent proteins or DNA-modifying recombinase (e.g., Cre) allowing further genetic manipulations. To define which types of RGCs specialize in detecting approaching objects, we will selectively express a genetically encoded toxin or optogenetic regulators in specific RGC types and examine behavioral consequences of such manipulations. Based on previous findings from the looming-trigged behavioral paradigms and our preliminary data, we will start our analysis focusing on the candidate RGC types (i.e., W3 and OFF alpha RGCs) later extending to other RGCs. Our study will identify distinct RGC types that are necessary and sufficient for the defensive behaviors to approaching objects. Identification and characterization of specific retinal neurons regulating visual-threat related behaviors should allow us to deconstruct the circuitry involved in detection and interpretation of fearful stimuli. It will also help us understand an overall structure and functional properties of fear-related circuits. Moreover, the genetic methods utilized in this proposal could be expanded further to investigate the roles of a wide range of cell types in multiple behavioral outcomes.