Specific retinal circuits for behavioral responses to threat

对威胁做出行为反应的特定视网膜回路

• 批准号: 10303253
• 负责人: In-Jung Kim
• 金额: $ 22.07万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10303253
• 关键词: Ablation; Animals; Anxiety Disorders; Axon; Behavior; Behavioral; Behavioral Paradigm; Biological Models; Blindness; Brain; Cells; Circadian Rhythms; DNA; Data; Defense Mechanisms; Detection; Diphtheria Toxin; Enterobacteria phage P1 Cre recombinase; Eye Movements; Freezing; Fright; Functional disorder; Future; Genetic; Goals; Human; Impairment; Interneurons; Knowledge; Label; Light; Mediating; Methods; Modeling; Modernization; Morphology; Mus; Mutant Strains Mice; Neurons; Neurosciences; Output; Photoreceptors; Photosensitivity; Physiological; Property; Proteins; Reflex action; Retina; Retinal Ganglion Cells; Rodent; Role; Stimulus; Structure; Techniques; Testing; Toxin; Transgenic Mice; Transgenic Organisms; Visual; Visual system structure; Wild Type Mouse; anxiety-related disorders; base; behavioral outcome; behavioral response; brain circuitry; cell behavior; cell type; computer generated; experimental study; genetic manipulation; improved; novel strategies; optogenetics; receptive field; recombinase; response; retinal neuron; selective expression; tool; visual processing; visual stimulus

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.

项目摘要 理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，并在各种模型系统中被广泛研究。这一概念 在早期的视觉系统中，功能上不同的细胞类型已经被相对很好地定义，特别是在 哺乳动物的视网膜。然而，我们对不同视网膜神经元负责的贡献的理解 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 使用特定行为作为读数的隐约可见的对刺激敏感的视网膜回路。有威胁的视觉输入，如 当接近物体时，会在动物和人类中引发普遍的防御行为。最近，几个大脑 利用光遗传学技术已经识别出对隐约可见的刺激做出反应的电路。不过， 我们对特定的视网膜回路的了解仍然非常有限，这些回路对防御行为和其他 它们对这种行为输出的潜在贡献。为了识别隐约触发行为的电路，我们 将重点放在视网膜神经节细胞(RGC)上，这些细胞从中间神经元接收视觉输入，并将轴突发送到 大脑。每一种RGC类型都应该对特定的视觉特征做出反应，因此有人建议 小鼠视网膜有46种不同的RGC类型。几项研究，包括我们自己的，已经产生了 多个转基因小鼠系，标记特定的RGC类型并使用形态学和 生理学方法。这些转基因基因中特定的RGC类型通过表达以下任一项来标记 荧光蛋白或DNA修饰重组酶(例如，Cre)，允许进一步的遗传操作。至 定义哪些类型的RGC专门用于检测接近的对象，我们将选择性地表示 基因编码的毒素或特定RGC类型的光遗传调节器，并检查行为 这种操纵的后果。基于之前从隐约可见触发的行为中的发现 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RGC类型(即，W3 和非阿尔法RGC)，随后扩展到其他RGC。我们的研究将确定不同的研资局类型 对接近的物体实施防御行为的充要条件。鉴定和表征 对调节视觉威胁相关行为的特定视网膜神经元的研究应该允许我们解构电路 参与检测和解释可怕的刺激。它还将帮助我们了解总体结构和 恐惧相关回路的功能特性。此外，该提案中使用的遗传方法可能是 进一步扩展以调查广泛的细胞类型在多种行为结果中的作用。