The location discrimination reversal task in mice is sensitive to deficits in performance caused by aging, pharmacological and other challenges
The location discrimination reversal task in mice is sensitive to deficits in performance caused by aging, pharmacological and other challenges
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DOI：
10.1177/0269881118779383
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发表时间：
2018-09-01
影响因子：
4.1
通讯作者：
Hughes, Zoe A.
中科院分区：
文献类型：
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作者：
Graf, Radka;Longo, Jami L.;Hughes, Zoe A.
海马介导的模式分离缺陷是精神分裂症 (SZ) 或阿尔茨海默病 (AD) 认知功能受影响的一方面。为了开发新的疗法，在临床前探索认知的这一特定方面是有益的。位置辨别逆转（LDR）任务是一种依赖海马的操作范式，它使用触摸屏评估空间学习和认知灵活性。在这里，我们评估了小鼠的基线表现以及多模式疾病相关操作。小鼠被训练来区分两个图像的位置，其中分离程度影响性能。施用推定的促认知药物无法改善窄间距时的表现。此外，还对一系列与疾病相关的操作进行了表征，以评估表现是否会受到损害和恢复。与 AD 中的胆碱能丧失相关，东莨菪碱 (0.1 mg/kg) 会破坏 LDR，而多奈哌齐 (1 mg/kg) 可减弱这种作用。与 SZ 相关认知障碍中的 NMDA 功能减退一致，MK-801 (0.1 mg/kg) 也会扰乱表现；然而，咯利普兰并没有改变这一缺陷。与 SZ (22q11) 相关的基因的微缺失会导致表现受损，但通过咯利普兰 (0.032 mg/kg) 可以恢复。由于衰老和炎症影响认知并且是 AD 的危险因素，因此也对这些方面进行了评估。老年小鼠比年轻小鼠更慢地完成任务，并且没有达到相同的表现水平。全身炎症挑战（脂多糖（LPS），1 mg/kg）导致 LDR 任务长期（7 天）缺陷。这些数据表明，LDR 任务是评估模式分离中与疾病相关的缺陷的一个有价值的平台，并为识别新疗法提供了潜力。
Deficits in hippocampal-mediated pattern separation are one aspect of cognitive function affected in schizophrenia (SZ) or Alzheimer's disease (AD). To develop novel therapies, it is beneficial to explore this specific aspect of cognition preclinically. The location discrimination reversal (LDR) task is a hippocampal-dependent operant paradigm that evaluates spatial learning and cognitive flexibility using touchscreens. Here we assessed baseline performance as well as multimodal disease-relevant manipulations in mice. Mice were trained to discriminate between the locations of two images where the degree of separation impacted performance. Administration of putative pro-cognitive agents was unable to improve performance at narrow separation. Furthermore, a range of disease-relevant manipulations were characterized to assess whether performance could be impaired and restored. Pertinent to the cholinergic loss in AD, scopolamine (0.1 mg/kg) produced a disruption in LDR, which was attenuated by donepezil (1 mg/kg). Consistent with NMDA hypofunction in cognitive impairment associated with SZ, MK-801 (0.1 mg/kg) also disrupted performance; however, this deficit was not modified by rolipram. Microdeletion of genes associated with SZ (22q11) resulted in impaired performance, which was restored by rolipram (0.032 mg/kg). Since aging and inflammation affect cognition and are risk factors for AD, these aspects were also evaluated. Aged mice were slower to acquire the task than young mice and did not reach the same level of performance. A systemic inflammatory challenge (lipopolysaccharide (LPS), 1 mg/kg) produced prolonged (7 days) deficits in the LDR task. These data suggest that LDR task is a valuable platform for evaluating disease-relevant deficits in pattern separation and offers potential for identifying novel therapies.