A MOUSE MODEL OF ECONOMIC DECISIONS.

许多精神和神经系统疾病-包括额颞叶痴呆症，精神分裂症和药物 成瘾-可以广泛地描述为患者做出“糟糕的选择”。虽然这些疾病破坏了 在各种领域的选择，赤字可以被统一地描述为影响基于主观的决定， 喜好这种行为被称为“经济选择”。为了更好地了解这些的起源， 疾病，并为治疗铺平道路，关键是要了解这种神经基础 行为来自非人类灵长类动物神经生理学、人类功能成像和病变的证据 对多个物种的研究建立了经济决策和眶额皮质（OFC）之间的联系。 特别是，PI实验室以前的研究检查了猴子OFC中单个神经元的活动 在不同的液体奖励之间进行选择。这项工作确定了三组编码身份的细胞， 提供和选择商品的主观价值。在灵长类OFC捕获中鉴定的三组细胞 选择过程的输入和输出，表明决策是在一个电路中形成的， 这些神经元。最近的结果支持这一假设。然而，这种神经回路的大部分方面仍然存在， 不太了解。例如，目前还不清楚这三组细胞是否对应于不同的 形态学上识别的细胞类型，它们是否位于不同的皮质层，它们是否使用不同的 神经递质和/或它们是否可以被基因操纵。此外，神经元之间的因果联系， OFC和动物所做的决定尚未确定。解决这些问题，使用 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可以解决， 利用近年来发展起来的遗传学方法。该提案的总体目标是将这一领域 对一种遗传学上易处理的模型--老鼠--的研究。具体目标是：（1）开发这种动物 模型，（2）在小鼠中概括猴子工作的主要生理学发现，以及（3）利用这一点 解决一些悬而未决的问题。具体来说，我们将联合收割机结合光遗传学和神经元 记录，以评估与行为相关的不同细胞群是否具有抑制作用， 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 这是一个巨大飞跃的机会，为解决许多根本问题开辟了新的途径。 这是灵长类动物经济决策专家Padoa-Schioppa博士（PI）和 Holy（co-I），小鼠嗅觉专家。这些实验将开辟新的领域，并扩展以前的工作， 一个新的且有前途的方向。虽然初步结果证明了可行性，但仍不清楚 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 最终目标是建立一个新的模型，这将对未来的决策研究产生重大影响。为 鉴于所有这些原因，该提案与R21供资机制的宗旨密切一致。 1

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