Persistent Infection by HSV-1 Is Associated With Changes in Functional Architecture of iPSC-Derived Neurons and Brain Activation Patterns Underlying Working Memory Performance
Persistent Infection by HSV-1 Is Associated With Changes in Functional Architecture of iPSC-Derived Neurons and Brain Activation Patterns Underlying Working Memory Performance
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DOI：
10.1093/schbul/sbu032
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发表时间：
2015-01-01
影响因子：
6.6
通讯作者：
Nimgaonkar, Vishwajit L.
中科院分区：
文献类型：
--
作者：
D'Aiuto, Leonardo;Prasad, Konasale M.;Nimgaonkar, Vishwajit L.
1 型单纯疱疹病毒 (HSV-1) 通常会产生溶解性粘膜病变。它总是会引发感觉神经节的潜伏感染，从而实现持续的终生感染。急性 HSV-1 脑炎很少见，并且缺乏大脑潜伏感染的明确证据。然而，无法追踪的脑炎暴露多次与工作记忆和执行功能受损相关，特别是在精神分裂症患者中。在人类诱导多能干细胞 (iPSC) 衍生的神经元中检查了 HSV-1 感染模式和基因表达变化。另外，使用功能磁共振成像 (fMRI) 研究了精神分裂症病例/对照中使用字母 n-back 测试对工作记忆挑战的血氧水平依赖性 (BOLD) 反应的差异。HSV-1 诱导 iPSC 衍生的谷氨酸能神经元和神经祖细胞的裂解变化。在神经元中，HSV-1 在与抗病毒药物共孵育后也进入静止状态，与谷氨酸能信号传导等功能相关的基因表达发生明显变化。在 fMRI 研究中，观察到精神分裂症 (P = .001) 和 HSV-1 暴露（1-back，P = 1.76 x 10(-) (4)；2-back，P = 1.39 x 10(-) (5)）对 BOLD 反应的主要影响。我们还注意到，与未暴露的人相比，HSV-1暴露的精神分裂症病例和对照者的额顶叶、丘脑和中脑区域的BOLD反应增加。iPSC衍生的神经元的裂解/静止周期表明可能发生持续的神经元感染，从而改变细胞功能。功能磁共振成像研究证实了非脑炎性 HSV-1 感染与工作记忆障碍相关的大脑功能变化之间的关联。 fMRI 和 iPSC 研究共同提供了与 HSV-1 暴露相关的认知障碍的推定机制。
Herpes simplex virus, type 1 (HSV-1) commonly produces lytic mucosal lesions. It invariably initiates latent infection in sensory ganglia enabling persistent, lifelong infection. Acute HSV-1 encephalitis is rare and definitive evidence of latent infection in the brain is lacking. However, exposure untraceable to encephalitis has been repeatedly associated with impaired working memory and executive functions, particularly among schizophrenia patients.Patterns of HSV-1 infection and gene expression changes were examined in human induced pluripotent stem cell (iPSC)-derived neurons. Separately, differences in blood oxygenation level-dependent (BOLD) responses to working memory challenges using letter n-back tests were investigated using functional magnetic resonance imaging (fMRI) among schizophrenia cases/controls.HSV-1 induced lytic changes in iPSC-derived glutamatergic neurons and neuroprogenitor cells. In neurons, HSV-1 also entered a quiescent state following coincubation with antiviral drugs, with distinctive changes in gene expression related to functions such as glutamatergic signaling. In the fMRI studies, main effects of schizophrenia (P = .001) and HSV-1 exposure (1-back, P = 1.76 x 10(-) (4); 2-back, P = 1.39 x 10(-) (5)) on BOLD responses were observed. We also noted increased BOLD responses in the frontoparietal, thalamus, and midbrain regions among HSV-1 exposed schizophrenia cases and controls, compared with unexposed persons.The lytic/quiescent cycles in iPSC-derived neurons indicate that persistent neuronal infection can occur, altering cellular function. The fMRI studies affirm the associations between nonencephalitic HSV-1 infection and functional brain changes linked with working memory impairment. The fMRI and iPSC studies together provide putative mechanisms for the cognitive impairments linked to HSV-1 exposure.