Mechanisms of Economic Decisions in Mice

小鼠经济决策机制

基本信息

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
项目类别：
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

项目摘要

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疾病中尤其受到干扰，包括从而更好地了解额颞叶痴呆、重度抑郁症和毒瘾的起源。疾病并为治疗铺平道路，了解这种疾病的神经基础至关重要来自非人类灵长类动物神经生理学、人类功能成像和损伤的证据。多个物种在经济选择和眶额皮质（OFC）之间建立了联系。 PI 实验室之前的研究检查了猴子 OFC 中单个神经元的活动这项工作确定了三组编码身份和主观的细胞。 OFC 中编码的变量捕获了提供和选择的商品的输入和输出。选择过程，表明在该领域确定的细胞群体构成了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，但我们对该电路的许多方面知之甚少，例如，我们不知道不同的细胞是否存在。 OFC 中识别的群体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中层，以及它们如何相互连接以及与其他大脑区域连接以解决这些问题和相关问题。在第一项研究中，我们将研究对象转向了一种基因上易于驯服的物种——小鼠。开发了经济选择行为的小鼠模型，我们证明了光遗传学失活外侧轨道区域 (LO) 会扰乱选择（Kuwabara 等人，eLife，2020）。 We 开发了一种用于执行选择的小鼠 LO 区域双光子 (2P) 钙 (Ca2+) 成像的协议。因此确定了与之前在灵长类动物中发现的神经元类似的三组神经元。该提案的目的是将 LO 中识别的功能细胞群与解剖学定义的细胞类型联系起来。我们将把 2P Ca2+ 成像与遗传标记和病毒追踪结合起来，在一系列实验中，我们将。评估（目标 1）与行为相关的不同细胞群是否优先居住在不同的细胞群中层，（目标 2）不同的细胞群是否与感觉和/或运动区域有不同的连接，（目标 3）功能细胞群和抑制性中间神经元之间的关系此外，（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，小鼠嗅觉和光学成像方面的专家，我们的合作已经持续了好几年。已经发表了第一份报告，这里提出的实验将开辟新的领域并扩展之前的研究。如果成功的话，我们的研究将揭示一个基本的大脑。它还将为追求每个问题的许多其他初步结果奠定基础。具体目标表明成功的可能性很高。 1