Mechanisms of Economic Decisions in Mice

小鼠经济决策机制

• 批准号: 10587316
• 负责人: Camillo Padoa-Schioppa
• 金额: $ 44.3万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587316
• 关键词: Address; Anatomy; Animals; Anterior; Area; Behavior; Brain; Brain region; Calcium; Cells; Choice Behavior; Clinical; Clinical Data; Collaborations; Computer Models; Contralateral; Corpus striatum structure; Data; Decision Making; Disease; Dorsal; Drug Addiction; Economic Models; Economics; Etiology; Fluorescence; Frontotemporal Dementia; Functional Imaging; Genetic; Genetic Markers; Goals; Head; Human; Image; Impairment; Individual; Interneurons; Investigation; Juice; Lateral; Lesion; Link; Liquid substance; Major Depressive Disorder; Medial; Mental disorders; Monkeys; Motor; Mus; Neurons; Output; Parvalbumins; Play; Population; Preparation; Primates; Procedures; Process; Protocols documentation; Publishing; Pyramidal Cells; Reporting; Research; Restaurants; Rewards; Role; Schizophrenia; Sensory; Series; Serotonin; Side; Signal Transduction; Smell Perception; Somatostatin; Subcellular Anatomy; Synapses; Testing; Time; Viral; Virus; With laterality; Work; calcium indicator; cell type; experimental study; lens; mouse model; nervous system disorder; neural; neural circuit; neurophysiology; nonhuman primate; olfactory stimulus; optical imaging; optogenetics; piriform cortex; preference; sensory input; success; tool; two-photon

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

经济选择行为在各种精神和神经系统疾病中特别受到干扰，包括 额颞叶痴呆症、重度抑郁症和药物成瘾。为了更好地了解这些的起源， 为了给治疗铺平道路，了解这种疾病的神经基础至关重要。 行为来自非人类灵长类动物神经生理学、人类功能成像和 多个物种建立了经济选择和眶额皮质（OFC）之间的联系。特别是， PI实验室先前的研究检查了猴子OFC中单个神经元的活动， 不同的液体奖励之间的差异。这项工作确定了三组细胞编码的身份和主观 提供和选择的商品的价值。OFC中编码的变量捕获以下变量的输入和输出： 选择过程，表明在这一领域确定的细胞群构成了一个 形成决策的电路。一系列的理论和实验结果支持了这一假设， 但对该电路的许多方面了解甚少。例如，我们不知道不同的细胞 OFC中识别的组对应于不同的解剖细胞类型，无论它们是否分布在不同的皮质 层，以及它们如何相互连接以及与其他大脑区域连接。为了解决这些问题和相关问题， 问题，我们把我们的调查带到了一个遗传上易于控制的物种-老鼠。在第一项研究中，我们 我们开发了一个小鼠经济选择行为模型，我们证明了， 外侧眶区（LO）干扰选择（Kuwabara等人，eLife，2020）。为了准备这项提案，我们 开发了一种用于在进行选择的小鼠中进行LO区域的双光子（2 P）钙（Ca 2+）成像的方案。我们 从而确定了三组类似于先前在灵长类动物中发现的神经元。总体目标 这一建议的一个重要方面是将LO中鉴定的功能细胞群与解剖学上定义的细胞类型联系起来。要执行此操作， 我们将联合收割机2 PCa 2+成像与遗传标记和病毒追踪相结合。在一系列实验中，我们将 评估（目标1）与行为有关的不同细胞群是否优先存在于不同的细胞群中， 层，（目标2）不同的细胞群是否与感觉和/或运动区域有差异地连接， （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） 使用格兰杰因果关系分析来评估不同小区组之间的有效连接。 这是经济决策专家Padoa-Schioppa博士（PI）和Holy博士（co-I）之间的合作， 老鼠嗅觉和光学成像方面的专家我们的合作已经持续了几年，我们 已经发布了第一份报告。本文提出的实验将开拓新的领域， 朝着新的、有希望的方向努力。如果成功的话，我们的研究将揭示一个基本的大脑 功能它还将为探讨许多其他问题奠定基础。每项研究的初步结果 具体目标表明成功的可能性很大。 1