Mechanisms of Economic Decisions in Mice

经济选择行为在各种精神和神经障碍中尤其受到干扰，包括 额颞性痴呆症、重度抑郁症和药物成瘾。因此，为了更好地了解这些 并为治疗铺平道路，了解其神经基础是至关重要的 行为。非人灵长类动物的神经生理学证据，人类的功能成像和 多种物种在经济选择和眼眶额叶皮质(OFC)之间建立了联系。特别是， PI实验室之前的研究检测了猴子选择OFC时单个神经元的活动 在不同的液体奖励之间。这项工作鉴定了三组编码身份和主观的细胞 所提供和选择的商品的价值。在OFC中编码的变量同时捕获输入和输出 选择过程，表明在该地区确定的细胞组构成了 在其中形成决策的回路。一系列的理论和实验结果支持这一假说， 但人们对这条赛道的许多方面知之甚少。例如，我们不知道不同的细胞 OFC中确定的群对应于不同的解剖细胞类型，无论它们位于不同的大脑皮层 以及它们是如何相互连接以及如何与其他大脑区域连接的。要解决这些问题和相关问题 问题，我们将我们的调查带到了一种遗传上容易驯服的物种--老鼠。在第一项研究中，我们 开发了一个经济选择行为的小鼠模型，我们证明了光遗传失活 侧眼眶面积(LO)破坏了选择(Kuwabara等人，eLife，2020)。在准备这项提案的过程中，我们 开发了一种用于对执行选择的小鼠的LO区进行双光子(2P)钙(Ca~(2+))成像的方案。我们 从而确定了三组神经元，与以前在灵长类动物中发现的神经元相似。首要目标是 这一建议的目的是将LO中确定的功能细胞组与解剖学上定义的细胞类型联系起来。要做到这一点， 我们将结合2P钙离子成像与遗传标记和病毒追踪。在一系列实验中，我们将 评估(目标1)根据行为定义的不同细胞组是否优先驻留在不同的 层，(目标2)不同的细胞组是否与感觉和/或运动区有不同的联系， 目的3)功能细胞群与抑制性中间神经元的关系。此外，(目标4)我们将 使用格兰杰因果分析来评估不同细胞群之间的有效连通性。 这是经济决策专家Padoa-Schioppa博士(PI)和克里斯蒂安博士(co-I)的合作， 鼠标嗅觉和光学成像方面的专家。我们的合作已经进行了几年，我们 已经发布了第一份报告。这里提出的实验将带来新的突破，并扩展以前的 朝着一个新的、有希望的方向努力。如果成功，我们的研究将揭示一个基本的大脑 功能。它还将为探索许多其他问题奠定基础。每种方法获得的初步结果 明确的目标表明成功的可能性很高。 1

Economic choice behavior is specifically disrupted in a variety of mental and neurological disorders including frontotemporal dementia, major depression and drug addiction. 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 in multiple species establishes a link between economic choice 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 variables encoded in OFC capture both the input and the output of the choice process, suggesting that the cell groups identified in this area constitute the building blocks of a circuit in which decisions are formed. A series of theoretical and experimental results support this hypothesis, but many aspects of this circuit are poorly understood. For example, we don’t know whether different cell groups identified in OFC correspond to different anatomical cell types, whether they populate different cortical layers, and how they are connected with each other and with other brain regions. To address these and related questions, we brought our investigation to a genetically tractable species – the mouse. In a first study, we developed a mouse model of economic choice behavior and we demonstrated that optogenetic inactivation of the lateral orbital area (LO) disrupts choices (Kuwabara et al, eLife, 2020). In preparation for this proposal, we developed a protocol for two-photon (2P) calcium (Ca2+) imaging of area LO in mice performing choices. We thus identified three groups of neurons analogous to those previously found in primates. The overarching goal of this proposal is to link the functional cell groups identified in LO to anatomically defined cell types. To do so, we will combine 2P Ca2+ imaging with genetic markers and viral tracing. In a series of experiments, we will assess (Aim 1) whether different cell groups defined in relation to behavior reside preferentially in different layers, (Aim 2) whether different cell groups are differentially connected with sensory and/or motor regions, and (Aim 3) the relation between functional cell groups and inhibitory interneurons. In addition, (Aim 4) we will use Granger causality analysis to assess the effective connectivity between different cell groups. This is a collaboration between Dr. Padoa-Schioppa (PI), an expert in economic decisions, and Dr. Holy (co-I), an expert in mouse olfaction and optical imaging. Our collaboration has been ongoing for several years and we already published a first report. The experiments proposed here will break new ground and extend previous work in a new and promising direction. If successful, our research will shed light on a fundamental brain function. It will also lay the ground to pursue numerous other questions. Preliminary results obtained for each specific aim demonstrate high likelihood of success. 1