Convergent neural substrates of inattention in bipolar disorder patients and dopamine transporter-deficient mice using the 5-choice CPT
Convergent neural substrates of inattention in bipolar disorder patients and dopamine transporter-deficient mice using the 5-choice CPT
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DOI：
10.1111/bdi.12786
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发表时间：
2020-02-01
影响因子：
5.4
通讯作者：
Eyler, Lisa T.
中科院分区：
文献类型：
--
作者：
Young, Jared W.;Geyer, Mark A.;Eyler, Lisa T.
目的双相情感障碍(BD)是一种影响2%-5%人群的衰弱精神疾病。虽然躁狂症是BD的主要特征，但注意力不集中和相关的认知功能障碍在所有阶段都可以观察到。由于认知功能障碍导致患者的功能结果较差，了解相关的神经机制仍然是开发新的靶向治疗方法的关键。方法5选择连续操作测试(5C-CPT)是一种与小鼠和fMRI兼容的人类注意任务，要求对靶刺激做出反应，同时抑制对非靶刺激的反应，就像临床CPT一样。这项任务被用来描绘BD患者以及顶叶皮质(PC)病变或多巴胺转运体(DAT)表达降低的小鼠模型中导致BD患者注意力不集中的系统水平的神经缺陷。心境良好的BD患者5C-CPT轻度受损。与健康受试者相比，高冲动的BD受试者在靶反应和非靶反应中PC激活减少。在小鼠中，双侧PC损伤同时损害了靶和非靶反应。在BD躁狂症DAT基因敲除小鼠模型中，与野生型相比，基因敲除小鼠表现出严重的5C-CPT表现。结论这些数据支持PC在BD注意力不集中中的作用，特别是在识别对目标刺激和非目标刺激的适当反应方面。此外，研究结果表明，DAT功能严重下降/多巴胺过敏症重现了BD躁狂症患者的注意缺陷。确定PC中DAT对注意力的贡献可能为未来的治疗发展提供一个目标。
Objectives Bipolar disorder (BD) is a debilitating psychiatric illness affecting 2%-5% of the population. Although mania is the cardinal feature of BD, inattention and related cognitive dysfunction are observed across all stages. Since cognitive dysfunction confers poor functional outcome in patients, understanding the relevant neural mechanisms remains key to developing novel-targeted therapeutics.Methods The 5-choice continuous performance test (5C-CPT) is a mouse and fMRI-compatible human attentional task, requiring responding to target stimuli while inhibiting responding to nontarget stimuli, as in clinical CPTs. This task was used to delineate systems-level neural deficits in BD contributing to inattentive performance in human subjects with BD as well as mouse models with either parietal cortex (PC) lesions or reduced dopamine transporter (DAT) expression.Results Mania BD participants exhibited severe 5C-CPT impairment. Euthymic BD patients exhibited modestly impaired 5C-CPT. High impulsivity BD subjects exhibited reduced PC activation during target and nontarget responding compared with healthy participants. In mice, bilateral PC lesions impaired both target and nontarget responding. In the DAT knockdown mouse model of BD mania, knockdown mice exhibited severely impaired 5C-CPT performance versus wildtype littermates.Conclusions These data support the role of the PC in inattention in BD-specifically regarding identifying the appropriate response to target vs nontarget stimuli. Moreover, the findings indicate that severely reduced DAT function/hyperdopaminergia recreates the attentional deficits observed in BD mania patients. Determining the contribution of DAT in the PC to attention may provide a future target for treatment development.