TDP-43 敲入型 ALS-FTD 小鼠模型中存在持续状态和冷漠。
Coexistence of perseveration and apathy in the TDP-43 knock-in mouse model of ALS-FTD.
机构信息
Department of Psychiatry, Institute of Behavioral Science in Medicine, Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Psychology and MRC/Wellcome Trust Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge, UK.
出版信息
Transl Psychiatry. 2020 Nov 4;10(1):377. doi: 10.1038/s41398-020-01078-9.
Perseveration and apathy are two of the most common behavioural and psychological symptoms of dementia (BPSDs) in amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD). Availability of a validated and behaviourally characterised animal model is crucial for translational research into BPSD in the FTD context. We behaviourally evaluated the male TDP-43 mouse, an ALS-FTD model with a human-equivalent mutation (TDP-43) knocked into the endogenous Tardbp gene. We utilised a panel of behavioural tasks delivered using the rodent touchscreen apparatus, including progressive ratio (PR), extinction and visual discrimination/reversal learning (VDR) assays to examine motivation, response inhibition and cognitive flexibility, respectively. Relative to WT littermates, TDP-43 mice exhibited increased responding under a PR schedule. While elevated PR responding is typically an indication of increased motivation for reward, a trial-by-trial response rate analysis revealed that TDP-43 mice exhibited decreased maximal response rate and slower response decay rate, suggestive of reduced motivation and a perseverative behavioural phenotype, respectively. In the extinction assay, TDP-43 mice displayed increased omissions during the early phase of each session, consistent with a deficit in activational motivation. Finally, the VDR task revealed cognitive inflexibility, manifesting as stimulus-bound perseveration. Together, our data indicate that male TDP-43 mice exhibit a perseverative phenotype with some evidence of apathy-like behaviour, similar to BPSDs observed in human ALS-FTD patients. The TDP-43 knock-in mouse therefore has features that recommend it as a useful platform to facilitate translational research into behavioural symptoms in the context of ALS-FTD.
刻板和冷漠是肌萎缩侧索硬化-额颞叶痴呆(ALS-FTD)中最常见的行为和心理症状之一。在额颞叶痴呆背景下,行为特征明确的、经验证的动物模型的可用性对于 BPSD 的转化研究至关重要。我们对 TDP-43 雄性小鼠进行了行为评估,这是一种具有人类等效突变(TDP-43)的 ALS-FTD 模型,该突变被敲入内源性 Tardbp 基因。我们使用啮齿动物触摸屏设备提供的一系列行为任务,包括递增比率(PR)、消退和视觉辨别/反转学习(VDR)测试,分别检查动机、反应抑制和认知灵活性。与 WT 同窝仔相比,TDP-43 小鼠在 PR 方案下表现出更高的反应性。虽然升高的 PR 反应通常表明对奖励的动机增加,但逐次反应率分析表明,TDP-43 小鼠表现出最大反应率降低和反应衰减率减慢,分别提示动机降低和刻板行为表型。在消退测试中,TDP-43 小鼠在每个测试阶段的早期表现出更多的遗漏,这与激活动机缺陷一致。最后,VDR 任务显示出认知灵活性受损,表现为刺激束缚的刻板性。总之,我们的数据表明,雄性 TDP-43 小鼠表现出刻板行为表型,并且存在类似于人类 ALS-FTD 患者中观察到的类冷漠行为的一些证据。因此,TDP-43 敲入小鼠具有一些特征,推荐其作为促进 ALS-FTD 背景下行为症状转化研究的有用平台。