Neurogenetic analysis of value-based decision making

项目摘要 功能失调的决策可能对个人和社会产生破坏性影响。许多类型 因此，决策过程受到了严格的调查。该提案强调基于价值的决策- 选择权，在这种情况下，选择者根据他对选项价值的主观评估在选项中进行选择。一 需要对这种行为有更深入的了解，以便为决策制定开发最好的治疗方法 疾病，包括多种形式的成瘾和伴随精神疾病的认知缺陷， 损伤和神经变性疾病。 消费者选择是基于价值的决策的最佳研究形式之一。研究表明，我们的 经济人格具有重要的遗传基础，但很难追踪基因之间的因果联系 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生物，如线虫- 托迪蠕虫C.与人类基因功能几乎相同的基因可以被研究， 更快、更彻底地解决问题，而且成本很低。到目前为止，有证据表明线虫真的是- 基于价值的决策仅仅是一种暗示。然而，经济学家们已经开发出 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体设备，使这项测试能够在线虫上进行， 相对丰富的高质量食物和相对稀缺的低质量食物之间的差异。结果符合 所有基于价值的决策标准。 以前的工作已经确定了一个感觉神经元，中间神经元和运动神经元的回路， 当蠕虫决定吃哪种食物时，头部会运动。使用功能性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），提出了 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， 值和丰度在电路中被表示，以及该表示如何在行为中被读出。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。 成功完成拟议的研究产生了一个生物现实的计算模型， 在一个紧凑的电路中，基于价值的决策的神经元机制，原则上， 完全站着。这项工作为理解更复杂的基于价值的决策提供了基础。 电路.这项工作也奠定了遗传分析的基石，在单神经元的分辨率，直系同源物， 在与决策相关的关联研究中发现的人类基因。这项研究具有广泛的意义 因为它建立了一个新的生物系统，在这个系统中， 研究人类以前与决策有关的基因，并发现新的遗传途径， 卷入了这种行为。

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.