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.

抽象的 近年来，信息如何表示、存储的理论取得了巨大的进步 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。 啮齿类动物衰老模型表明，大脑中的连接性和可塑性机制 除了空间认知的变化之外，海马体还有助于改变与空间认知相关的网络功能。 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 整个生命周期中发生的额叶依赖任务，包括工作记忆和注意力。 当然，这些认知功能对于与我们的环境进行有效互动至关重要。 美国 71 岁以上的人因各种原因而患有痴呆症的比例为 14%。 对于理解正常的认知衰老过程本身至关重要，因为这反映了 86% 的老年人 71 岁以上的人。了解造成破坏性的机制也很重要 该提案的两个目标使用两种不同的神经退行性疾病。 动物模型——一个代表正常人类衰老的模型，另一个模型模拟许多 阿尔茨海默病的病理特征的目标是了解大脑回路如何相互作用。 在正常衰老和神经退行性疾病中，对记忆至关重要的物质都会发生改变。 关于海马体和内侧前额皮质（mPFC）之间的相互作用。 已知对认知至关重要，并且在衰老和神经退行性疾病中很脆弱。 目标 1 检查空间工作记忆以及年龄对网络交互动态的影响 在年轻和老年大鼠的海马体和前额皮质之间进行连续的 本目标解决的问题包括如何规范老化。 大脑适应每个结构内内在网络动态的变化，在直接投影之间 腹侧海马体到 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 这个空间工作记忆问题使用了一种相对较新建立的 AD 大鼠遗传模型，即 TgF344-AD 大鼠，携带突变型人类 APP 和 PS1 基因，但自发表现出 tau 蛋白 病理学、海马细胞损失和认知功能障碍在 15 个月时我们已经发展了更多。 受限空间序列记忆任务，以 W 轨道为模型，我们称之为扇形迷宫。 设备使我们能够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老鼠具有记录整个细胞群的能力。 海马体和 mPFC，而大鼠执行任务时依赖于这些大脑之间的相互作用 结构，将使我们能够弥合从研究规范性动物模型中学到的原则之间的差距 衰老和阿尔茨海默病，以及人类认知衰老和疾病的神经基础。