Neurogenetic analysis of value-based decision making

项目摘要 失灵的决策可能会对个人和社会产生毁灭性的影响。多种类型 因此，正在对决策进行严格的调查。这一建议强调以价值为基础的决策。 期权，其中选择者根据他对选项价值的主观评估来选择选项。一个 需要对这种行为有更深入的理解，以便为决策制定出可能的最佳治疗方法。 障碍，包括多种形式的成瘾和伴随精神疾病而来的认知缺陷，大脑 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。研究表明，我们的 经济人物有重要的遗传基础，但很难追踪基因之间的因果联系 以及人类的行为。作为回应，遗传学家经常转向更简单的无脊椎动物，如NEMA- 线虫的基因功能与人类几乎相同的线虫可以被研究- 更快、更彻底，而且成本只有它的一小部分。到目前为止，有证据表明线虫确实是- 基于价值的决策制定的观点只是提示性的。然而，经济学家已经发展出 数学上严格的测试程序，用于确定决策是否基于主观价值。 PI的实验室已经开发出微流控设备，使这项测试能够在线虫身上进行，从而决定 在相对丰富的高质量食物和更稀缺的低质量食物之间。结果符合 所有以价值为基础的决策标准。 以前的工作已经确定了控制感觉神经元、中间神经元和运动神经元的回路 当蠕虫决定吃什么食物时，它的头就会移动。使用功能IM的组合- 老化(目标1)、神经元活动的光学操纵(目标2)和神经元消融(目标3)，建议 研究将确定每个神经元对基于价值的决策的贡献。一个中心问题是食物如何 价值和丰度在电路中表示，以及该表示如何在行为中读出。目标4 根据目标1的数据构建数学模型，并使用目标2和目标3的数据对其进行测试。 这项拟议研究的成功完成产生了一个生物上真实的计算模型 基于价值的决策的神经机制在紧凑的电路中，原则上可以低于- 完全站着。这项工作为在更复杂的情况下理解基于价值的决策奠定了基础 电路。这项工作也为单神经元分辨率的遗传分析奠定了基石 在与决策相关的关联研究中确定的人类基因。这项研究具有广泛的意义。 因为它建立了一种新的生物系统，在其中以单神经元分辨率分析相互作用 以前与人类决策相关的基因，并在- 在这种行为中游刃有余。

Project Summary 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 deci- sions, in which the chooser selects among options based on his subjective assessment of their value. A deeper understanding of this behavior is needed 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. Studies reveal that our economic personalities have a significant genetic basis, but it is difficult to trace causal links between genes and behavior in humans. In response, geneticists often turn to simpler invertebrate organisms like the nema- tode worm C. elegans in which the functions of genes nearly identical to their human equivalents can be inves- tigated more rapidly, completely, and at a fraction of the cost. Until now, evidence that nematodes are truly ca- pable of value-based decision making has merely been suggestive. However, economists have developed mathematically rigorous testing procedures for determining whether decisions are based on subjective value. The PI's laboratory has developed microfluidic devices that enable this test to be done on nematodes deciding between high-quality food that is relatively abundant and low-quality food that is more scarce. The results meet all the criteria of value-based decision making. Previous work has identified a circuit of sensory neurons, interneurons, and motor neurons that controls head movements as the worm makes decisions about which food to eat. Using a combination of functional im- aging (Aim 1), optical manipulation of neuronal activity (Aim 2), and neuronal ablations (Aim 3), the proposed research will identify contribution each neuron makes to value-based decisions. A central question is how food value and abundance are represented in the circuit and how this representation is read-out in behavior. Aim 4 constructs a mathematical model based on data from Aim 1 and tests it using data from Aims 2 and 3. Successful completion of the proposed research yields a biologically realistic computational model of the neuronal mechanism of value-based decision making in a compact circuit than can, in principle, be under- stood completely. This work provides a foundation for understanding value-based decisions in more complex circuits. The work also lays the cornerstone for genetic analyses, at single-neuron resolution, of orthologs of human genes identified in association studies related to decision making. The research is broadly significant because it establishes a new biological system in which to analyze at single-neuron resolution the interaction of genes previously associated with decision making in humans, and to discover novel genetic pathways in- volved in this behavior.