Frontal and Temporal Lobe Interactions in Rat Models of Normative Aging and Alzheimer's Disease

正常衰老和阿尔茨海默病大鼠模型中额叶和颞叶的相互作用

• 批准号: 10639909
• 负责人: CAROL A. BARNES
• 金额: $ 216.64万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639909
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Animal Model; Animals; Area; Attention; Behavioral; Brain; Brain Diseases; Brain region; Cells; Characteristics; Chronic; Cognition; Cognition Disorders; Cognitive; Cognitive aging; Communication; Compensation; Consensus; Elderly; Electrophysiology (science); Environment; Episodic memory; Event; Executive Dysfunction; Female; Genes; Genetic Models; Goals; Hippocampus; Human; Impaired cognition; Implant; Inbred F344 Rats; Individual; Information Theory; Learning; Longevity; Medial; Memory; Memory impairment; Methodological Studies; Methods; Modeling; Neurodegenerative Disorders; Neurons; Pathologic; Pathology; Performance; Persons; Prefrontal Cortex; Process; Rattus; Rodent; Rodent Model; Short-Term Memory; Sleep; Structure; System; Technology; Temporal Lobe; Testing; Training; Transgenes; age effect; age related; aged; aging brain; awake; cell assembly; cell cortex; cognitive function; demented; density; design; familial Alzheimer disease; frontal lobe; insight; male; millisecond; mutant; neural; neural network; normal aging; novel; processing speed; response; tau Proteins; tau mutation

ABSTRACT Dramatic advances have been made in recent years in the theory of how information is represented, stored and retrieved in neural networks and in the methodology for studying interactions among groups of neurons. Animal models of aging in rodents suggest that altered connectivity and plasticity mechanisms within the hippocampus contribute to altered network function associated with changes in spatial cognition. In addition to changes in temporal lobe-dependent episodic memory, some of the earliest alterations detected in memory across the lifespan occur in frontal lobe-dependent tasks, including working memory and attention. Each of these cognitive functions, of course, is essential for effective interaction with our environment. In humans, the proportion of people across the USA over 71 who are demented, from all causes, is 14%. This suggests that it is critical to understand normal cognitive aging processes in their own right, as this reflects 86% of aged individuals over 71. It is also critical to understand the mechanisms that underly devastating neurodegenerative disorders such as Alzheimer's disease. The two Aims of this proposal use two different animal models – one that represents a model of normative human aging and another that models many of the pathological characteristics of Alzheimer's disease. The goal is to understand how brain circuit interactions critical for memory are altered in both normal aging and in neurodegenerative disease. This proposal focuses on the interactions between the hippocampus and the medial prefrontal cortex (mPFC). Both structures are known to be critical for cognition and are vulnerable in aging and in neurodegenerative disease. Aim 1 examines spatial working memory and the effect of age on the dynamics of network interactions between the hippocampus and prefrontal cortex in young and aged rats while performing a continuous alternation task on a W-track apparatus. The questions addressed in this Aim include how the normative aging brain adapts to changes in intrinsic network dynamics within each structure, between the direct projection from ventral hippocampus to mPFC, and how these structures interact or compete during aging to find solutions to this spatial working memory problem. Aim 2 uses a relatively newly established rat genetic model of AD, the TgF344-AD rat, that carries the mutant human APP and PS1 genes, but spontaneously manifests tau pathology, hippocampus cell loss and cognitive dysfunction by 15 mo of age. We have developed a more constrained spatial sequence memory task, modeled after the W-track, that we call the Fan Maze. The smaller apparatus allows us to adapt a massively high-density recording technology (the Neuropixels probe) to chronically implanted freely behaving rats. The ability to record from ensembles of cells across the hippocampus and mPFC while rats perform tasks dependent on the interactions between these brain structures, will allow us to bridge the gap between principles learned from studying animal models of normative aging and Alzheimer's disease, to those that underlie the neural basis of human cognitive aging and disease.

摘要 近年来，关于信息如何被表示、存储和传播的理论已经取得了巨大的进展。 并在神经网络和研究神经元组之间相互作用的方法中检索。 啮齿类动物衰老的动物模型表明，大脑皮层内改变的连接和可塑性机制， 海马有助于改变与空间认知变化相关的网络功能。除了 颞叶依赖性情景记忆的变化，记忆中检测到的一些最早的改变， 在整个生命周期中，额叶依赖性任务，包括工作记忆和注意力。中的每 当然，这些认知功能对于我们与环境的有效互动至关重要。人类的 在美国，71岁以上的人中，有14%的人因各种原因而患上痴呆症。这表明它 对于理解正常的认知老化过程至关重要，因为这反映了86%的老年人 71岁以上的人。同样重要的是要了解破坏性的潜在机制， 神经退行性疾病，如阿尔茨海默病。本建议的两个目的是使用两个不同的 动物模型-一个代表正常人类衰老的模型，另一个模拟许多 阿尔茨海默病的病理特征。我们的目标是了解大脑回路的相互作用 在正常衰老和神经退行性疾病中，对记忆至关重要的是改变了。该提案重点 海马体和内侧前额叶皮质（mPFC）之间的相互作用。两种结构都 已知对认知至关重要，并且在衰老和神经退行性疾病中是脆弱的。 目的1考察空间工作记忆和年龄对网络互动动力学的影响 在年轻和老年大鼠海马和前额叶皮层之间进行连续的 在W轨道设备上的交替任务。在这个目标中解决的问题包括如何规范老龄化 大脑适应每个结构内内在网络动力学的变化，从直接投射到 腹侧海马到mPFC，以及这些结构在衰老过程中如何相互作用或竞争，以找到解决方案， 这个空间工作记忆的问题目的2使用相对新建立的AD大鼠遗传模型， TgF 344-AD大鼠，携带突变的人APP和PS1基因，但自发表现出tau蛋白 病理学、海马细胞丢失和15个月龄时的认知功能障碍。我们开发了一个更 受限空间序列记忆任务，仿照W轨迹，我们称之为扇形迷宫。越小 仪器允许我们采用大规模高密度记录技术（神经像素探针）， 长期植入自由行为的大鼠。从细胞集合中记录整个 而大鼠执行任务依赖于这些大脑之间的相互作用 结构，将使我们能够弥合差距之间的原则，从研究动物模型的规范 衰老和阿尔茨海默氏病，那些人类认知衰老和疾病的神经基础。