Repetitive and compulsive-like behaviors lead to cognitive dysfunction in Disc1Δ2-3/Δ2-3 mice
Repetitive and compulsive-like behaviors lead to cognitive dysfunction in Disc1Δ2-3/Δ2-3 mice
复制标题
重复性和强迫性行为导致 Disc1Δ2-3/Δ2-3 小鼠认知功能障碍
DOI：
10.1111/gbb.12478
复制
发表时间：
2018
影响因子：
2.5
通讯作者：
Yamada K
中科院分区：
文献类型：
--
作者：
Wulaer B;Nagai T;Sobue A;Itoh N;Kuroda K;Kaibuchi K;Nabeshima T;Yamada K
紊乱精神分裂症1 （Disc1）是精神疾病生物学的关键分子驱动因子。为了研究其在脑功能中的作用，我们之前在C57BL/6J遗传背景上培养了缺乏Disc1外显子2和3的小鼠（Disc1Δ2‐3/Δ2‐3小鼠），它们缺乏全长Disc1蛋白。在本研究中，我们通过基于触摸屏的视觉辨别（VD）任务来检验Disc1在认知功能中的作用。在这项任务中，小鼠必须同时辨别屏幕上显示的2个刺激中的1个，并获得液体奖励。Disc1Δ2‐3/Δ2‐3小鼠在VD任务中的表现受损，这主要归因于持久性反应明显强于野生型（WT）小鼠。此外，Disc1Δ2‐3/Δ2‐3小鼠在弹珠掩埋试验中掩埋的弹珠数量和在破巢试验中撕碎的雏鸟数量显著高于WT小鼠，这表明Disc1Δ2‐3/Δ2‐3小鼠具有持续性/强迫性行为。氯氮平治疗可改善VD和大理石掩埋任务中的行为缺陷。与WT小鼠相比，Disc1Δ2‐3/Δ2‐3小鼠第一次VD后，c‐Fos在背内侧纹状体（DMS）中的表达明显增强，而在背外侧纹状体（DLS）中的表达则不明显。用氯氮平-一氧化氮（CNO）治疗先前在DMS中表达hM3Dq的小鼠，会损害其在VD任务中的表现。这些结果表明，Disc1Δ2‐3/Δ2‐3小鼠中伴有持续性/强迫行为的认知障碍与DMS的过度活跃有关。
Disrupted‐in‐schizophrenia 1 (Disc1) is a key molecular driver for the biology of mental diseases. In order to investigate its role in brain function, we previously generated mice lacking exons 2 and 3 of Disc1 on a C57BL/6J genetic background (Disc1Δ2‐3/Δ2‐3mice), which have a deficiency of the full‐length Disc1 protein. In the present study, we examined the role of Disc1 in cognitive function using a touchscreen‐based visual discrimination (VD) task in which mice had to discriminate 1 of 2 stimuli simultaneously displayed on the screen and received a liquid reward. Disc1Δ2‐3/Δ2‐3mice showed impaired performance in the VD task, and this was mainly attributed to the perseverative response being significantly stronger than that in wild‐type (WT) mice. Furthermore, the numbers of marbles buried in the marble burying test and nestlets shredded in the nestlet shredding test by Disc1Δ2‐3/Δ2‐3mice were significantly higher than those by WT mice, suggesting perseverative/compulsive behaviors by Disc1Δ2‐3/Δ2‐3mice. A treatment with clozapine ameliorated behavioral deficits in the VD and marble burying tasks. c‐Fos expression was significantly stronger in the dorsomedial striatum (DMS), but not the dorsolateral striatum (DLS) after the first VD session in Disc1Δ2‐3/Δ2‐3mice than in WT mice. The treatment of mice that had previously expressed hM3Dq in the DMS with clozapine‐N‐oxide (CNO) impaired performance in the VD task. These results suggest that cognitive impairments accompanied by perseverative/compulsive behaviors in Disc1Δ2‐3/Δ2‐3mice are associated with hyperactivity of the DMS.