Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada.
Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA.
Brain Behav Immun. 2019 Aug;80:25-34. doi: 10.1016/j.bbi.2019.02.013. Epub 2019 Feb 15.
Executive dysfunction and white matter inflammation continue to be relatively understudied in rodent models of Alzheimer's disease (AD). Behavioural inflexibility is an important component of executive dysfunction that can be further categorized as perseverative or regressive, which respectively specify whether maladaptive persistence occurs early or late during a behavioural change. Previous studies of the TgAPP21 rat model of AD (expressing pathogenic hAPP) suggested a potentially spontaneous increase of regressive behavioral inflexibility. In this study, 7-8-month-old male TgAPP21 rats were tested for behavioral flexibility, learning, and memory using an operant conditioning chamber and the Morris Water Maze (MWM). TgAPP21 rats demonstrated a regressive behavioral inflexibility during set shifting in an operant conditioning chamber (regressive errors η = 0.32 and number of errors after criterion η = 0.33). Regressive behavior was also demonstrated in the MWM probe test, wherein TgAPP21 rats significantly increased their swim time in the target quadrant during the last third of the probe test (43% vs 33% in the first 2 thirds of the probe test or the Wt rats' 29%-32%); this behavioral phenotype has not been previously described in the MWM. TgAPP21 demonstrated further impairment of behavioural inflexibility as they committed a greater number of reversal errors in the operant conditioning chamber (η = 0.30). Diffuse microglia activation was increased in the white matter tracts of TgAPP21 (corpus callosum, cingulum, and internal capsule; η = 0.59-0.62), which was found to correlate with the number of reversal errors in the operant conditioning chamber (R = 0.42). As TgAPP21 rats do not spontaneously develop amyloid plaques but have been shown in previous studies to be vulnerable to the development of plaques, these rats demonstrate an important onset of cognitive change and inflammation in the pre-plaque phase of AD. TgAPP21 rats are also an instrumental model for studying the role and mechanism of white matter microglial activation in executive functioning. This is pertinent to clinical research of prodromal AD which has suggested that white matter inflammation may underlie impairment of executive functions such as behavioral flexibility.
在阿尔茨海默病（AD）的啮齿动物模型中，执行功能障碍和白质炎症仍然相对研究不足。行为灵活性是执行功能的一个重要组成部分，可以进一步分为坚持性或退行性，分别指定在行为改变过程中，适应性持续存在是早期还是晚期发生。之前对表达致病性 hAPP 的 TgAPP21 大鼠 AD 模型的研究表明，退行性行为灵活性可能会自发增加。在这项研究中，7-8 月龄雄性 TgAPP21 大鼠在操作条件反射室和 Morris 水迷宫（MWM）中进行行为灵活性、学习和记忆测试。TgAPP21 大鼠在操作条件反射室中的转换任务中表现出退行性行为灵活性（退行性错误 η=0.32，标准后错误数 η=0.33）。退行性行为也在 MWM 探测测试中表现出来，其中 TgAPP21 大鼠在探测测试的最后三分之一时间内显著增加了它们在目标象限的游泳时间（与探测测试前 2/3 时间或 Wt 大鼠的 29%-32%相比增加了 43%；在 MWM 中尚未描述过这种行为表型）。TgAPP21 在操作条件反射室中犯了更多的反转错误，表现出进一步的行为灵活性障碍（η=0.30）。TgAPP21 的白质束中弥漫性小胶质细胞激活增加（胼胝体、扣带和内囊；η=0.59-0.62），这与操作条件反射室中的反转错误数相关（R=0.42）。由于 TgAPP21 大鼠不会自发产生淀粉样斑块，但之前的研究表明它们易患斑块形成，因此这些大鼠在 AD 的斑块前阶段表现出重要的认知变化和炎症。TgAPP21 大鼠也是研究白质小胶质细胞激活在执行功能中的作用和机制的工具模型。这与前驱 AD 的临床研究相关，该研究表明，白质炎症可能是执行功能障碍（如行为灵活性）的基础。
