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

摘要 近年来，在信息如何表示、存储的理论方面取得了重大进展 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。 啮齿动物衰老的动物模型表明，脑内连接和可塑性机制的改变 海马体有助于改变与空间认知相关的网络功能。除了……之外 颞叶依赖情节记忆的变化，记忆中最早检测到的一些变化 整个生命周期都发生在额叶依赖的任务中，包括工作记忆和注意力。每一个 当然，这些认知功能对于有效地与我们的环境互动是必不可少的。在人类中， 全美71岁以上的人中，因各种原因患有精神错乱的比例为14%。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岁以上的个人。同样重要的是要了解那些不足以造成毁灭性破坏的机制 神经退行性疾病，如阿尔茨海默病。这项提议的两个目的使用了两个不同的 动物模型-一个代表了标准人类衰老的模型，另一个代表了许多 阿尔茨海默病的病理特点。我们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，对记忆至关重要的基因都会改变。这项提案将重点放在 关于海马和内侧前额叶皮质(MPFC)之间的相互作用。这两个结构都是 已知对认知至关重要，在衰老和神经退行性疾病中很容易受到影响。 目标1考察空间工作记忆和年龄对网络互动动力学的影响 青年和老年大鼠在进行连续运动时海马区和前额叶皮质之间的关系 W-Track设备上的交替任务。在这一目标中涉及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，在来自 腹侧海马区到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 这种空间工作记忆的问题。Aim 2使用了一种相对较新建立的AD大鼠遗传模型 TgF344-AD大鼠，携带突变的人类APP和PS1基因，但自发表现为tau 病理，15mo龄时海马区细胞丢失和认知功能障碍。我们开发了一种更多的 受限空间序列记忆任务，仿照W型轨迹，我们称之为扇形迷宫。越小 该设备允许我们采用大规模高密度记录技术(神经像素探头)来 长期植入自由行为的老鼠体内。能够从跨区域的细胞群中进行记录 当大鼠执行依赖于这些大脑之间的相互作用的任务时，海马体和mPFC 结构，将使我们能够弥合从研究标准化动物模型中学到的原理之间的差距 衰老和阿尔茨海默氏症，指那些构成人类认知老化和疾病的神经基础的疾病。

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.