Judd Jessica M, Winslow Wendy, McDonough Ian, Mistry Faizan, Velazquez Ramon
Arizona State University-Banner Neurodegenerative Disease Research Center at the Biodesign Institute, Arizona State University, Tempe, AZ, United States.
School of Life Sciences, Arizona State University, Tempe, AZ, United States.
Front Aging Neurosci. 2024 Dec 18;16:1466415. doi: 10.3389/fnagi.2024.1466415. eCollection 2024.
The 3xTg-AD transgenic mouse model of Alzheimer's disease (AD) is an important tool to investigate the relationship between development of pathological amyloid-β (Aβ) and tau, neuroinflammation, and cognitive impairments. Traditional behavioral tasks assessing aspects of learning and memory, such as mazes requiring spatial navigation, unfortunately suffer from several shortcomings, including the stress of human handling and not probing species-typical behavior. The automated IntelliCage system was developed to circumvent such issues by testing mice in a social environment while measuring multiple aspects of cognition. Water consumption can serve as a primary motivator for task engagement. Once animals adapt to the cage and can access water, mice can be subjected to operant tasks. Each of the four corners of a cage contains doors to manipulate access to water, visual LED cues, and a valve allowing administration of an air puff. Previously, we detected significant impairments in 3xTg-AD mice in the IntelliCage, however a high failure rate and genotypical differences in water motivation were observed.
Here, we implemented an IntelliCage paradigm where mice underwent progressively more difficult reaction time tasks to assess attention and impulsivity, behaviors mediated by the prefrontal cortex. Mice were placed in the IntelliCage at 11.5 months of age, which corresponds with the presence of widespread pathology.
As the difficulty of the reaction time tasks increased, 3xTg-AD mice exhibited lower percent Correct Responses than NonTg. When implementing varying pre-cue durations, where animals are required to wait between the initiation of the trial and the LED turning on (which then requires a nose-poke to access water), 3xTg-AD mice prematurely nose-poked on trials requiring a longer delay before a second nose poke would allow water access, demonstrating heightened impulsivity. The presence of soluble and insoluble fractions of cortical Aβ40 and 42, and phosphorylated tau epitopes threonine 181 and serine 396 confirmed the presence of neuropathological hallmarks in 3xTg-AD mice.
Together, this study describes a novel protocol that overcomes motivational differences and detects attention and impulsivity deficits in 3xTg-AD mice utilizing the IntelliCage.
阿尔茨海默病（AD）的3xTg-AD转基因小鼠模型是研究病理性淀粉样β（Aβ）和tau蛋白的发展、神经炎症与认知障碍之间关系的重要工具。传统的评估学习和记忆方面的行为任务，如需要空间导航的迷宫，不幸存在几个缺点，包括人为处理带来的压力且未探究物种典型行为。自动化的智能笼系统旨在通过在社交环境中测试小鼠同时测量认知的多个方面来规避此类问题。水消耗可作为参与任务的主要动力。一旦动物适应笼子并能获取水，小鼠即可接受操作性任务。笼子的四个角每个都包含用于控制水获取的门、视觉LED提示以及允许施加吹气的阀门。此前，我们在智能笼中检测到3xTg-AD小鼠存在显著损伤，然而观察到较高的失败率以及水动机方面的基因类型差异。
在此，我们实施了一种智能笼范式，其中小鼠接受难度逐渐增加的反应时间任务以评估注意力和冲动性，这些行为由前额叶皮质介导。小鼠在11.5月龄时被置于智能笼中，这与广泛病理状态的存在相对应。
随着反应时间任务难度的增加，3xTg-AD小鼠的正确反应百分比低于非转基因小鼠。当实施不同的预提示持续时间时，即动物需要在试验开始与LED亮起之间等待（然后需要戳鼻子才能获取水），3xTg-AD小鼠在需要更长延迟才能通过第二次戳鼻子获取水的试验中过早地戳鼻子，表明冲动性增强。皮质Aβ40和42的可溶性和不可溶性部分以及磷酸化tau蛋白表位苏氨酸181和丝氨酸396的存在证实了3xTg-AD小鼠存在神经病理学特征。
总之，本研究描述了一种新颖的方案，该方案克服了动机差异，并利用智能笼检测3xTg-AD小鼠的注意力和冲动性缺陷。
