A MOUSE MODEL OF ECONOMIC DECISIONS.

经济决策的老鼠模型。

• 批准号: 9222286
• 负责人: Camillo Padoa-Schioppa
• 金额: $ 19.06万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222286
• 关键词: Address; Affect; Animal Model; Animals; Area; Behavior; Cells; Clinical; Clinical Data; Collaborations; Decision Making; Decision Modeling; Disease; Drug Addiction; Economic Models; Economics; Frontotemporal Dementia; Functional Imaging; Funding Mechanisms; Genetic; Goals; Homologous Gene; Human; Impairment; Individual; Interneurons; Investigation; Juice; Label; Lateral; Left; Lesion; Light; Link; Liquid substance; Mental disorders; Modeling; Monkeys; Morphology; Mus; Neurons; Neurotransmitters; Obsessive-Compulsive Disorder; Odors; Output; Patients; Physiological; Primates; Process; Psyche structure; Pyramidal Cells; Research; Research Proposals; Restaurants; Rewards; Schizophrenia; Series; Smell Perception; Training; Work; base; cell type; experimental study; genetic approach; high reward; high risk; mouse model; multi-electrode arrays; nervous system disorder; neural circuit; neurophysiology; nonhuman primate; optogenetics; preference; quantum; relating to nervous system; tool

Many mental and neurological disorders – including frontotemporal dementia, schizophrenia and drug addiction – can be broadly characterized as patients making “poor choices.” While these disorders disrupt choices in a variety of domains, deficits can be unitarily described as affecting decisions based on subjective preferences. This behavior is referred to as “economic choice”. Thus to better understand the origins of these disorders, and to pave the way for treatments, it is critical to understand the neural underpinnings of this behavior. Evidence from neurophysiology in non-human primates, functional imaging in humans and lesions studies in multiple species establishes a link between economic decisions and the orbitofrontal cortex (OFC). In particular, previous research in the PI's lab examined the activity of single neurons in the OFC of monkeys choosing between different liquid rewards. This work identified three groups of cells encoding the identity and subjective values of offered and chosen goods. The three groups of cells identified in the primate OFC capture both the input and the output of the choice process, suggesting that decisions are formed in a circuit composed by these neurons. Recent results support this hypothesis. However, most aspects of this neural circuit remain poorly understood. For example, it is unclear whether the three groups of cells correspond to different morphologically identified cell types, whether they reside in different cortical layers, whether they use different neuro-transmitters and/or whether they can be manipulated genetically. Also, a causal link between neurons in the OFC and the decision made by the animal has not yet been established. Addressing these questions using traditional neurophysiology is technically difficult. However, all of these questions can in principle be addressed using genetic approaches developed in recent years. The overarching goal of this proposal is to take this field of investigation to a genetically tractable model ‒ the mouse. Specific aims are (1) to develop such animal model, (2) to recapitulate in mice the main physiological findings from the monkey work, and (3) to exploit this model to address some of the outstanding questions. Specifically, we will combine optogenetics and neuronal recordings to assess whether different groups of cells identified in relation to behavior are inhibitory or excitatory, and whether they are located in different cortical layers. If successful, this research will provide the opportunity for a quantum leap and open new avenues to address numerous fundamental questions. This is a collaboration between Dr Padoa-Schioppa (PI), an expert of economic decisions in primates, and Dr Holy (co-I), an expert of olfaction in mice. The experiments will break new ground and extend previous work in a new and promising direction. While preliminary results argue for feasibility, it remains unclear whether the critical experiments will provide interpretable results. Thus this research is high-risk high-reward. Finally, our ultimate goal is to establish a new model that will significantly impact future research on decision making. For all these reasons, the proposal is closely aligned with the purposes of the R21 funding mechanism. 1

许多精神和神经障碍--包括额颞叶痴呆、精神分裂症和毒品 上瘾--可以广泛地描述为患者做出了“糟糕的选择”。当这些紊乱扰乱 在各种领域的选择，赤字可以统一地描述为影响基于主观的决策 偏好。这种行为被称为“经济选择”。因此，为了更好地了解这些 障碍，并为治疗铺平道路，了解其神经基础是至关重要的 行为。来自非人灵长类动物神经生理学、人类功能成像和损伤的证据 对多个物种的研究建立了经济决策和眼眶额叶皮质(OFC)之间的联系。 特别是，PI实验室之前的研究检查了猴子OFC中单个神经元的活动 在不同的液体奖励中做出选择。这项工作鉴定了三组编码身份和 所提供和选择的商品的主观价值。在灵长类OFC捕获中识别的三组细胞 选择过程的输入和输出，表明决策是在一个由 通过这些神经元。最近的研究结果支持这一假设。然而，这种神经回路的大部分方面仍然存在 人们对此知之甚少。例如，目前还不清楚这三组细胞是否对应于不同的 形态识别的细胞类型，无论它们是否位于不同的皮质层，无论它们使用的是不同的 神经递质和/或它们是否可以被遗传操纵。此外，神经元之间的因果联系 OFC和动物所做的决定还没有确定。使用以下工具解决这些问题 传统的神经生理学在技术上是困难的。然而，所有这些问题原则上都是可以解决的 使用最近几年发展起来的遗传方法。这项提议的首要目标是夺取这一领域 对一种基因易驯化的模型--老鼠的研究。具体目标是(1)培育这种动物 模型，(2)在小鼠中总结猴子工作的主要生理发现，以及(3)利用这一点 模型来解决一些悬而未决的问题。具体地说，我们将结合光遗传学和神经元 用于评估与行为相关的不同细胞组是否具有抑制性或 兴奋性，以及它们是否位于不同的皮质层。如果成功，这项研究将提供 这是一次巨大飞跃的机会，并开辟了解决众多根本问题的新途径。 这是灵长类经济决策专家帕多阿-斯基奥帕博士和帕多阿-斯基奥帕博士的合作成果。 圣神(co-i)，老鼠嗅觉专家。这些实验将开辟新的天地，并扩展先前在 一个新的、有希望的方向。虽然初步结果证明了可行性，但目前仍不清楚 关键实验将提供可解释的结果。因此，这项研究是高风险、高回报的。最后，我们的 最终目标是建立一种新的模型，它将对未来的决策研究产生重大影响。为 所有这些原因，该提案与R21筹资机制的目的密切一致。 1