Neurogenetic analysis of value-based decision making

项目摘要/摘要 失灵的决策可能会对个人和社会产生毁灭性的影响。因此，许多类型的决策都受到了严格的调查。该提案强调基于价值的决策，在 选择者基于其对选项价值的主观评估在选项中进行选择。对这种行为的深入了解将有助于开发可能的最佳决策障碍治疗方法，包括多种形式的成瘾和伴随精神疾病、脑损伤和 神经退行性疾病。 消费者选择是基于价值的决策中研究最多的形式之一。经济学家与遗传学家合作，发现我们的经济基础我们的个性有一个重要的遗传基础，但它是 很难追踪人类基因和行为之间的因果联系。为了解决这个问题，许多遗传学家转向更简单的无脊椎动物有机体，如线虫线虫，它有许多相同的 基因与人类一样，在其中基因功能的研究要容易得多，成本更低，速度更快。但有证据表明 从科学意义上讲，线虫能够做出基于价值的决策一直是缺乏的。 经济学家已经制定了严格的测试程序，以确定主观价值是否是生物体决策的决定因素。在对这一提议的初步研究中，PI的实验室开发了 能够根据食物选择对线虫进行这项测试的微流控设备。测试表明， 线虫对食物的质量和价格非常敏感，这与基于价值的决定完全一致 制作。这项拟议的研究为定义神经的多阶段R01级项目奠定了基础 用于线虫基于价值的决策的回路，并利用这一知识来研究 已知的与经济决策相关的人类基因的相互作用。 这项研究首先开发了一种新的、高通量的检测方法，用于测量 觅食线虫种群的食物选择。提出的分析方法利用一种创新的方法来制造微型径向臂迷宫。迷宫的每一条手臂都将被定义为独特的食物选项 可食用细菌的浓度和病原菌分泌的自然产生的驱避剂的浓度。我们将使用这种方法来确定有关食物和驱虫剂的信息是如何由神经元活动表示的，以及这些表示是如何组合起来控制行为的。接下来，我们将开始使用遗传方法识别决策电路的过程，以创建线虫菌株，在这些菌株中 在五个探测食物的感觉神经元中，只有一个是有功能的。足以驱动决策的感觉神经元 Making将被认为是电路的输入神经元。这一知识将加速对 其余的神经元在未来的R01水平的电路研究。

PROJECT SUMMARY / ABSTRACT Dysfunctional decision making can have devastating impacts on individuals and on society. Many types of decision making are therefore under vigorous investigation. This proposal emphasizes value-based decisions, in which the chooser selects among options based on his subjective assessment of their value. A deeper understanding of this behavior will help to develop the best possible treatments for decision making disorders, including the many forms of addiction and the cognitive deficits that accompany mental illness, brain injury, and neurodegenerative disease. Consumer choice is one of the best studied forms of value-based decisions. Economists, in collaboration with geneticists, have found that our economic our personalities have a significant genetic basis, but it is difficult to trace causal links between genes and behavior in humans. To overcome this problem, many geneticists turn to simpler invertebrate organisms like the nematode worm C. elegans which has many of the same genes as humans and in which gene function is much easier, cheaper, and faster to study. But evidence that nematodes are capable of value-based decision making, in a scientifically meaningful sense, has been lacking. Economists have developed rigorous testing procedures for determining whether subjective value is the deciding factor in an organism's decisions. In preliminary research for this proposal, the PI's laboratory developed microfluidic devices that enable this test to be done on nematodes based on food choices. The tests show that nematodes are sensitive to the quality and price of food in a manner fully consistent with value-based decision making. The proposed research lays the cornerstone for a multiphase R01-level project that defines the neural circuit for value-based decision making in nematodes and exploits this knowledge to investigate the functional interactions of human genes known to be associated with economic decisions. The research begins by developing a new, high-throughput assay for measuring the subjective value of food options in populations of foraging nematodes. The proposed assay utilizes an innovative method for fabricating miniature radial arm mazes. Each arm of the maze will be baited with a unique food option defined in terms of the concentration of edible bacteria and a naturally occurring repellent secreted by pathogenic bacteria. We will use this approach to determine how information about food and repellents is represented by neuronal activity, and how these representations are combined to control behavior. Next, we will begin the processes of identifying the decision making circuit using a genetic approach to create nematode strains in which only one of the five food-detecting sensory neurons is functional. Sensory neurons sufficient to drive decision making will be considered to be the input neurons of the circuit. This knowledge will accelerate the search for the rest of the neurons in the circuit in future R01-level research.