Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175.
Increased temporal discounting after chronic stress in CHL1-deficient mice is reversed by 5-HT2C agonist Ro 60-0175.
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DOI：
10.1016/j.neuroscience.2017.05.047
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发表时间：
2017-08-15
期刊：
影响因子：
3.3
通讯作者：
Buhusi CV
中科院分区：
文献类型：
--
作者：
Buhusi M;Olsen K;Buhusi CV
精神分裂症是一种神经发育障碍，其中决策和目标导向行为受损是核心特征。与精神分裂症相关的基因之一是L1（CHL 1）的密切同源物; CHL 1缺陷小鼠被认为是精神分裂症样缺陷的模型，包括感觉运动门控，间隔计时和空间记忆障碍。在这里，我们研究了CHL 1缺陷（KO）小鼠及其野生型同窝仔的时间折扣。虽然在基线条件下没有发现折扣差异，但CHL 1-KO小鼠在慢性不可预测的压力后表现出增加的冲动选择（更大的选择百分比更少，折扣曲线下面积减少）。应激CHL 1-KO小鼠在前边缘皮层和背侧纹状体的贴现任务中也显示出神经元活化（cFos阳性神经元的数量）减少，这些区域被认为是执行和时间处理回路的一部分。5-HT 2C激动剂Ro 60-0175逆转了冲动选择的改变。我们的研究结果提供了证据的基因×环境，双重打击模型的压力相关的决策障碍，并确定CHL 1基因缺陷小鼠作为这些缺陷的小鼠模型在精神分裂症样表型。
Schizophrenia is a neurodevelopmental disorder in which impaired decision-making and goal-directed behaviors are core features. One of the genes associated with schizophrenia is the Close Homolog of L1 (CHL1); CHL1-deficient mice are considered a model of schizophrenia-like deficits, including sensorimotor gating, interval timing and spatial memory impairments. Here we investigated temporal discounting in CHL1-deficient (KO) mice and their wild-type littermates. Although no discounting differences were found under baseline conditions, CHL1-KO mice showed increased impulsive choice following chronic unpredictable stress (fewer % larger-later choices, and reduced area under the discounting curve). Stressed CHL1-KO mice also showed decreased neuronal activation (number of cFos positive neurons) in the discounting task in the prelimbic cortex and dorsal striatum, areas thought to be part of executive and temporal processing circuits. Impulsive choice alterations were reversed by the 5-HT2C agonist Ro 60-0175. Our results provide evidence for a gene×environment, double-hit model of stress-related decision-making impairments, and identify CHL1-deficient mice as a mouse model for these deficits in regard to schizophrenia-like phenotypes.
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