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，关于信息的代表，存储的理论，已经取得了巨大的进步 并在神经元和研究神经元组之间相互作用的方法中检索。 啮齿动物衰老的动物模型表明，连通性和可塑性机制改变了 海马有助于与空间认知变化相关的网络功能改变。此外 临时叶子依赖性情节内存的变化，记忆中检测到的一些最早的变化 整个寿命都发生在额叶依赖的任务中，包括工作记忆和注意力。每个 当然，这些认知功能对于与我们的环境有效互动至关重要。在人类中 从各种原因出发，全美71岁以上的人比例为14％。这表明它 对于理解正常的认知衰老过程至关重要，因为这反映了86％的老年人 71岁以上的个人。了解造成毁灭性的机制也至关重要 神经退行性疾病，例如阿尔茨海默氏病。该提案的两个目标使用两个不同 动物模型 - 一种代表正常衰老模型的动物模型，另一个模型模型 阿尔茨海默氏病的病理特征。目的是了解脑电路的相互作用 正常衰老和神经退行性疾病中的记忆至关重要。该提案重点是 关于海马和介质前额叶皮层（MPFC）之间的相互作用。这两个结构都是 已知对认知至关重要，并且在衰老和神经退行性疾病中很容易受到伤害。 AIM 1考试空间工作记忆和年龄对网络交互动力学的影响 在表演连续的同时，在年轻大鼠和年龄大鼠的海马和前额叶皮层之间 W-Track设备上的交替任务。此目标中解决的问题包括如何正常老化 大脑适应每个结构内的内在网络动态的变化 腹侧海马到MPFC，以及这些结构在衰老期间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。 AIM 2使用相对新建立的AD的大鼠遗传模型，即 带有突变的人类应用和PS1基因的TGF344-AD大鼠，但赞助的表现出Tau 病理学，海马细胞丧失和认知功能障碍，年龄15个月。我们已经开发了更多 以W-Track建立模型的约束空间序列内存任务，我们称为风扇迷宫。较小 设备使我们能够使大量高密度记录技术（神经质子探针）适应 长期植入自由植入的大鼠。从细胞合奏中记录跨整个细胞的能力 海马和MPFC而大鼠执行任务取决于这些大脑之间的相互作用 结构，将使我们能够从研究正常动物模型中学到的原则之间弥合差距 衰老和阿尔茨海默氏病，是那些基于人类认知衰老和疾病的神经基础的人。