Elucidating the Neural Computations Underlying Spatial Learning, Decision-Making and Generalization in Virtually-Navigating Monkeys

阐明虚拟导航猴子空间学习、决策和泛化背后的神经计算

• 批准号: 10723874
• 负责人: Roberto Adamo Gulli
• 金额: $ 12.54万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 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 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10723874
• 关键词: Address; Affect; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Area; Award; Behavior; Biological Models; Brain; Brain region; Cells; Cognition; Cognitive; Coupled; Decision Making; Deep Brain Stimulation; Development; Disease; Dissociation; Electrophysiology (science); Environment; Etiology; Exhibits; Functional disorder; Geometry; Goals; Grant; Hippocampus; Institution; Intervention; Joystick; Knowledge; Laboratories; Laboratory Research; Learning; Link; Location; Maps; Medial; Mediating; Memory Disorders; Monkeys; Motor; Motor Cortex; Motor output; Neurons; Output; Pathway interactions; Population; Prefrontal Cortex; Process; Research Personnel; Role; Running; Scientist; Structure; Symptoms; Temporal Lobe; Testing; Time; Training; Visit; behavior prediction; career; cognitive capacity; effective therapy; experience; experimental study; frontal lobe; improved; innovation; insight; knowledge integration; medical schools; neural; neural circuit; neuromechanism; neurophysiology; novel; novel therapeutics; sensory input; translational neuroscience; virtual; virtual environment; virtual reality; virtual reality environment; way finding

Project Summary/Abstract Patients with Alzheimer’s disease and Alzheimer’s disease-related dementias exhibit symptoms that include deficits in spatial navigation, and in forming/using cognitive maps of space to guide decision-making, especially in new environmental situations. These deficits are linked to disease-related perturbation of medial temporal lobe and frontal lobe brain structures, but surprisingly little is known about the underlying computations that go awry. Spatial navigation is believed to be dependent on populations of neurons in the hippocampus with “place-cell” like representations. Decision-making in novel situations is dependent on representations of latent features that are shared across examples or experiences, as observed in prefrontal cortex. Finally, the output of these computations must reach the motor cortex where neural activity is coupled to immediate behavior. However, studies to determine whether/how neural computations across these brain regions contribute to decisions based on spatial location, especially in novel situations have not been conducted. Furthermore, whether symptoms of Alzheimer’s disease and related dementias can be treated by modulating these computations is not known. To address this gap, I created an innovative new virtual reality paradigm and trained monkeys to make decisions about which objects to collect based on learned spatial rules. I will combine this with high-channel- count electrophysiology in trained monkeys to determine if/how population-level representations in the HPC- PFC-PMd support decision-making based on spatial rules. Then, I will elucidate if and how population activity in the HPC-PFC-PMd circuit supports generalization in novel situations. In my independent laboratory, I will use this model system as a platform for elucidating the neural mechanism of an emerging treatment for Alzheimer’s disease and Alzheimer’s disease-related dementias. These contributions are significant because they will provide new insights into the neural mechanisms of some of our most adaptive cognitive capacities, while also creating a new platform for discovering and testing new treatments where I systematically test the effects of neural perturbations on neural circuit function and behavior. This project will facilitate my training as an independent researcher through new experience in high-channel count, multi-area recordings, training in the etiology and treatment of Alzheimer’s disease and related dementias, and in running a monkey electrophysiology lab at the intersection of basic and translational neuroscience. This project will result in direct interactions between experimental neurophysiologists, theoretical neuroscientists, and clinician-scientists. This award will help me achieve my long-term career goal to run an independent research laboratory at an academic institution with a medical school, where I will operate a monkey electrophysiology lab at the nexus of 1) elucidating neural mechanisms of learning and decision-making, and 2) developing/testing novel therapeutics for disorders of memory and decision-making, including Alzheimer’s disease and Alzheimer’s disease related dementias.

项目总结/摘要 阿尔茨海默病和阿尔茨海默病相关痴呆患者表现出的症状包括 空间导航的缺陷，以及形成/使用空间认知地图来指导决策的缺陷，特别是 在新的环境条件下。这些缺陷与疾病相关的内侧颞叶扰动有关 和额叶大脑结构，但令人惊讶的是，人们对出错的底层计算知之甚少。 空间导航被认为依赖于海马中具有“位置细胞”的神经元群体。 就像表象。新情况下的决策取决于潜在特征的表征， 正如在前额叶皮质中观察到的那样，在例子或经历中是共享的。最后，这些输出 计算必须到达运动皮层，在那里神经活动与即时行为相耦合。然而，在这方面， 研究以确定这些大脑区域的神经计算是否/如何有助于基于 空间位置，特别是在新的情况下，还没有进行。此外，如果症状 阿尔茨海默氏症和相关痴呆症可以通过调节这些计算来治疗还不知道。 为了解决这个问题，我创造了一个创新的虚拟现实模式，并训练猴子 基于学习的空间规则来决定要收集哪些对象。我会联合收割机把这个和高频道- 计算受过训练的猴子的电生理学，以确定HPC中的群体水平表示是否/如何- PFC-PMd支持基于空间规则的决策。然后，我将阐明人口活动是否以及如何在 HPC-PFC-PMD电路支持在新情况下的通用化。在我的独立实验室里， 该模型系统作为阐明阿尔茨海默氏症新兴治疗方法的神经机制的平台， 疾病和阿尔茨海默病相关的痴呆症。这些贡献是重要的，因为它们将 为我们一些最具适应性的认知能力的神经机制提供了新的见解， 创建一个新的平台，用于发现和测试新的治疗方法，在那里我系统地测试 对神经回路功能和行为的神经扰动。 这个项目将促进我的培训，作为一个独立的研究人员通过新的经验，在高通道 计数，多区域记录，阿尔茨海默病和相关痴呆症的病因学和治疗方面的培训， 以及在基础神经科学和转化神经科学的交叉点上运行一个猴子电生理学实验室。这 该项目将导致实验神经生理学家，理论神经科学家和 临床科学家这个奖项将帮助我实现我的长期职业目标，运行一个独立的研究 我将在一所医学院的学术机构的实验室，在那里我将操作一个猴子电生理实验室， 在1）阐明学习和决策的神经机制，2）开发/测试的关系 用于包括阿尔茨海默病和阿尔茨海默病的记忆和决策障碍的新疗法 疾病相关的痴呆症。