Neurogenetic analysis of value-based decision making

基于价值的决策的神经遗传学分析

基本信息

批准号：
10205097
负责人：
SHAWN R LOCKERY
金额：
$ 44.81万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-23 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10205097
关键词：
Ablation Adherence Afferent Neurons Aging Animal Model Animals Bacteria Behavior Behavioral Biological Biological Models Brain Injuries Caenorhabditis elegans Cognitive deficits Complex Computer Models Data Decision Making Disease Drosophila genus Eating Economics Etiology Feeds Food Food Preferences Foundations Genes Genetic Genetic Epistasis Genetic Models Head Head Movements Health Human Individual Interneurons Invertebrates Investigation Laboratories Learning Link Locomotion Mathematics Measures Mental disorders Methods Microfluidic Microchips Modeling Motor Neurons Nematoda Neurodegenerative Disorders Neurons Numerical value Nutritional Optics Organism Orthologous Gene Partner in relationship Pathway interactions Pensions Personality Persons Phase Procedures Property Research Resolution Role Side Smell Perception Societies Source Specific qualifier value Suggestion Sum Synapses Testing Twin Studies Vertebrates Weight Work addiction base biological systems comorbidity cost fitness food quality gene function gene interaction genetic analysis genome wide association study interest man mathematical model neural circuit neurogenetics neurophysiology novel preference presynaptic neurons response trait welfare

项目摘要

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.

项目概要功能失调的决策可能会对个人和社会产生毁灭性影响。种类很多因此，正在对决策进行严格调查。该提案强调基于价值的决策选择者根据其对选项价值的主观评估来选择选项。一个需要更深入地了解这种行为，才能制定最佳的决策治疗方法疾病，包括多种形式的成瘾和伴随精神疾病、大脑的认知缺陷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充分的形式之一。研究表明我们的经济人格具有显着的遗传基础，但很难追踪基因之间的因果关系和人类的行为。作为回应，遗传学家经常转向更简单的无脊椎动物生物，如线虫线虫中的线虫的基因功能几乎与人类相同，可以对其进行研究更快速、更彻底且成本更低。到目前为止，有证据表明线虫确实可以基于价值的决策制定的表只是暗示性的。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 的实验室已开发出微流体装置，使该测试能够在线虫上进行，决定相对丰富的优质食品和较为稀缺的劣质食品之间。结果满足基于价值的决策的所有标准。先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电路当蠕虫决定吃什么食物时头部的运动。使用功能组合的组合衰老（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），研究将确定每个神经元对基于价值的决策的贡献。一个核心问题是食物如何价值和丰度在电路中表示，以及如何在行为中读出这种表示。目标 4 根据目标 1 的数据构建数学模型，并使用目标 2 和 3 的数据对其进行测试。成功完成拟议的研究产生了生物学上真实的计算模型紧凑电路中基于价值的决策的神经元机制原则上可以被理解为完全站了起来。这项工作为理解更复杂的基于价值的决策奠定了基础电路。这项工作还为单神经元分辨率的直系同源基因分析奠定了基石在与决策相关的关联研究中发现的人类基因。该研究具有广泛意义因为它建立了一个新的生物系统，可以在单神经元分辨率下分析相互作用以前与人类决策相关的基因，并发现新的遗传途径参与了这种行为。