MPTP-induced executive dysfunction is associated with altered prefrontal serotonergic function.
MPTP-induced executive dysfunction is associated with altered prefrontal serotonergic function.
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DOI：
10.1016/j.bbr.2015.09.014
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发表时间：
2016-02-01
影响因子：
2.7
通讯作者：
McDonald MP
中科院分区：
文献类型：
--
作者：
Maiti P;Gregg LC;McDonald MP
在帕金森病中，认知缺陷表现为额纹状体介导的执行功能障碍，注意力、计划、判断和冲动控制受损。我们使用 3 项选择的连续反应时间 (SRT) 任务（包括持续注意力和冲动控制的测量）检查了亚慢性 1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP) 损伤的小鼠执行功能的变化。基线 SRT 任务的每次试验都包含一个 3 到 8 秒的伪随机预提示期，然后是 1 秒的提示持续时间。 MPTP 严重损害了所有冲动行为的测量，但通过额外的训练，他们的表现正常化到盐水控制水平。当受到较短提示持续时间的挑战时，MPTP 损伤的小鼠的反应时间明显慢于野生型小鼠。当受到更长的预提示时间的挑战时，MPTP 损伤的小鼠在较长的持续时间内表现出冲动控制的丧失。在受损小鼠中，纹状体多巴胺减少了 54%，黑质致密部酪氨酸羟化酶阳性神经元的数量减少了 75%。纹状体和前额叶皮层 (PFC) 中的血清素 (5-HT) 没有变化，但 MPTP 组 PFC 中 5-羟基吲哚乙酸 (5-HIAA) 与 5-HT 的比例显着降低。在受损小鼠中，前额叶 5-HIAA/5-HT 与执行障碍显着相关，纹状体去甲肾上腺素与反应时间减慢相关。没有任何神经化学指标与盐水处理对照组的行为显着相关。综上所述，这些结果表明前额叶 5-HT 转换可能在 MPTP 诱导的执行功能障碍中发挥关键作用。
In Parkinson's disease, cognitive deficits manifest as fronto-striatally-mediated executive dysfunction, with impaired attention, planning, judgment, and impulse control. We examined changes in executive function in mice lesioned with subchronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) using a 3-choice serial reaction-time (SRT) task, which included measures of sustained attention and impulse control. Each trial of the baseline SRT task comprised a pseudo-random pre-cue period ranging from 3 to 8 s, followed by a 1-s cue duration. MPTP impaired all measures of impulsive behavior acutely, but with additional training their performance normalized to saline control levels. When challenged with shorter cue durations, MPTP-lesioned mice had significantly slower reaction times than wild-type mice. When challenged with longer pre-cue times, the MPTP-lesioned mice exhibited a loss of impulse control at the longer durations. In lesioned mice, striatal dopamine was depleted by 54% and the number of tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta was reduced by 75%. Serotonin (5-HT) was unchanged in the striatum and prefrontal cortex (PFC), but the ratio of 5-hydroxyindolacetic acid (5-HIAA) to 5-HT was significantly reduced in the MPTP group in the PFC. In lesioned mice, prefrontal 5-HIAA/5-HT was significantly correlated with the executive impairments and striatal norepinephrine was associated with slower reaction times. None of the neurochemical measures was significantly associated with behavior in saline-treated controls. Taken together, these results show that prefrontal 5-HT turnover may play a pivotal role in MPTP-induced executive dysfunction.