AppNL-G-F/NL-G-F mice overall do not show impaired motivation, but cored amyloid plaques in the striatum are inversely correlated with motivation
AppNL-G-F/NL-G-F mice overall do not show impaired motivation, but cored amyloid plaques in the striatum are inversely correlated with motivation
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DOI：
10.1016/j.neuint.2019.104470
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发表时间：
2019-10-01
影响因子：
4.2
通讯作者：
Tanaka, Kenji F.
中科院分区：
文献类型：
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作者：
Hamaguchi, Takuya;Tsutsui-Kimura, Iku;Tanaka, Kenji F.
冷漠在临床上被定义为缺乏动机。冷漠是阿尔茨海默病（AD）患者的常见症状。目前尚不清楚β - 淀粉样蛋白（Aβ）病理是否与冷漠相关。为了解决这个问题，我们使用了App（NL - G - F / NL - G - F）小鼠，这是一种在整个生命周期中无神经原纤维缠结和神经元细胞死亡且有Aβ沉积的小鼠，并使用累进比率（PR）任务来监测16至39周龄之间的工具性动机。在PR任务中，获得一次奖励所需的杠杆按压次数增加，小鼠完成的最后一次试验中主动杠杆按压次数代表一个断点，这是动机的一个指标。在观察期间，App（NL - G - F / NL - G - F）小鼠总体上未表现出动机受损。然而，App（NL - G - F / NL - G - F）小鼠在39周龄时组内断点出现离散情况。因此，我们研究了断点程度与Aβ病理之间的关联；纹状体中有核心的淀粉样斑块数量与动机程度呈负相关。此外，我们使用蛋白质印迹分析测量了包括纹状体在内的皮质下组织中的多巴胺转运体（DAT）水平，结果显示App（NL - G - F / NL - G - F）小鼠的DAT水平低于C57BL / 6J小鼠。尽管我们无法直接确定核心淀粉样斑块对DAT的影响，但这项研究的结果提示了一条核心淀粉样斑块损害DAT并导致动机受损的途径。这些结果将使人们关注核心淀粉样斑块，并有助于研究人员寻找对预防和治疗动机受损有效的新策略。
Apathy is clinically defined as lack of motivation. Apathy is a frequent symptom in patients with Alzheimer's disease (AD). It is unclear whether amyloid beta (A beta) pathology is associated with apathy. To address this question, we employed the App(NL-G-F/NL-G-F) mouse, an A beta deposition-bearing mouse without neurofibrillary tangles and neuronal cell death throughout the lifespan and used a progressive-ratio (PR) task to monitor instrumental motivation between the ages of 16 and 39 weeks. In the PR task, the number of lever presses to receive one reward increases and the number of active lever presses in the final trial a mouse completes represents a break point, which is an index of motivation. During the observation period, App(NL-G-F/NL-G-F) mice overall did not show impaired motivation. However, App(NL-G-F/NL-G-F) mice showed a dispersion of the break point at 39 weeks of age within the group. Therefore, we examined the association between the degree of the break point and A beta pathology; the number of cored amyloid plaques in the striatum was inversely correlated with the degree of motivation. Furthermore, we measured the dopamine transporter (DAT) levels in the subcortical tissues including the striatum using western blot analysis and showed that App(NL-G-F/NL-G-F) mice have lower DAT levels than do C57BL/6J mice. Although we could not directly determine the effect of core amyloid plaques on the DAT, the results of this study suggest a pathway through which cored amyloid plaques damage the DAT and cause impaired motivation. These results will draw attention to cored amyloid plaques and will aid researchers searching for new strategies that are effective for the prevention and treatment of impaired motivation.