Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity.
Forniceal deep brain stimulation induces gene expression and splicing changes that promote neurogenesis and plasticity.
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DOI：
10.7554/elife.34031
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发表时间：
2018-03-23
期刊：
影响因子：
7.7
通讯作者：
Zoghbi HY
中科院分区：
文献类型：
--
作者：
Pohodich AE;Yalamanchili H;Raman AT;Wan YW;Gundry M;Hao S;Jin H;Tang J;Liu Z;Zoghbi HY
目前正在进行临床试验，以评估穹窿深部脑刺激（DBS）改善阿尔茨海默氏症患者记忆的疗效，穹窿DBS已被证明可以改善Rett综合征（RTT）小鼠模型的学习和记忆，这是一种由MECP 2功能丧失突变引起的智力残疾障碍。然而，DBS益处的机制一直难以捉摸，因此我们评估了野生型小鼠和缺乏Mecp 2的小鼠急性穹窿DBS后基因表达、剪接异构体、DNA甲基化和蛋白质组的变化。我们发现DBS上调了参与突触功能、细胞存活和神经发生的基因，并且在Mecp 2缺失小鼠中改变了约25%的基因的正常表达。此外，DBS在其他智力残疾小鼠模型和重度抑郁症患者的死后人脑组织中诱导了17-24%的基因表达下调，这表明穹窿DBS可以使患有各种神经精神疾病的个体受益。许多脑部疾病导致学习和记忆障碍。这些包括发育障碍，如雷特综合征，其中儿童学习困难，以及老年疾病，如阿尔茨海默氏病。患有这些疾病的人通常会在大脑中一个叫做海马体的区域出现变化。海马体因其形状而得名，它在形成新记忆方面起着关键作用。因此，恢复海马体的正常活动有助于减少学习和记忆障碍。增加海马体活动的一种方法是通过一种称为深部脑刺激（DBS）的技术。顾名思义，DBS涉及将电极深入大脑以刺激脑组织的特定区域。将DBS应用于穹窿，一束神经纤维，将信息带入和传出海马体，改善了Rett综合征小鼠模型的记忆力。但DBS究竟是如何产生这种改善的尚不清楚。Pohodich等人现在表明穹窿的DBS改变了小鼠海马中的基因活性。为了激活基因，细胞首先使用基因的DNA作为模板来产生RNA分子。然后，他们使用RNA作为模板来产生蛋白质。Rett综合征等疾病破坏了大量基因的这一过程的效率。Pohodich等人表明，刺激雷特综合征小鼠的穹窿可以逆转大约四分之一受该疾病影响的基因的这些变化。DBS还在健康小鼠中诱导了数千个RNA分子的变化。其中许多来自支持神经细胞之间通信或促进新神经细胞形成的基因。DBS也可能对其他疾病产生有益的影响。Pohodich等人表明，DBS还增加了在其他两种智力残疾疾病中减少的基因水平，以及在抑郁症中改变的基因。为了使DBS成为一种可行的治疗方法，临床试验必须确定其安全性和有效性。这种试验已经在阿尔茨海默病患者中进行。未来的试验可能包括有学习障碍的患者，或者对其他治疗没有反应的抑郁症患者。
Clinical trials are currently underway to assess the efficacy of forniceal deep brain stimulation (DBS) for improvement of memory in Alzheimer’s patients, and forniceal DBS has been shown to improve learning and memory in a mouse model of Rett syndrome (RTT), an intellectual disability disorder caused by loss-of-function mutations in MECP2. The mechanism of DBS benefits has been elusive, however, so we assessed changes in gene expression, splice isoforms, DNA methylation, and proteome following acute forniceal DBS in wild-type mice and mice lacking Mecp2. We found that DBS upregulates genes involved in synaptic function, cell survival, and neurogenesis and normalized expression of ~25% of the genes altered in Mecp2-null mice. Moreover, DBS induced expression of 17–24% of the genes downregulated in other intellectual disability mouse models and in post-mortem human brain tissue from patients with Major Depressive Disorder, suggesting forniceal DBS could benefit individuals with a variety of neuropsychiatric disorders. Many brain disorders cause impairments in learning and memory. These include developmental disorders such as Rett syndrome, in which children struggle with learning, as well as diseases of old age such as Alzheimer’s disease. People with these disorders often show changes in a region of the brain called the hippocampus. Named after the Greek word for ‘seahorse’ because of its shape, the hippocampus has a key role in forming new memories. Restoring normal activity in the hippocampus could thus help reduce learning and memory impairments. One way to increase activity in the hippocampus is through a technique called deep brain stimulation (DBS). As the name suggests, DBS involves lowering electrodes deep into the brain to stimulate specific areas of brain tissue. Applying DBS to the fornix, a bundle of nerve fibers that carries information into and out of the hippocampus, improved memory in a mouse model of Rett syndrome. But exactly how DBS produced this improvement is unclear. Pohodich et al. now showed that DBS of the fornix alters gene activity in the mouse hippocampus. To activate a gene, cells first used the gene’s DNA as a template to produce a molecule of RNA. They then used the RNA as a template to produce a protein. Disorders such as Rett syndrome disrupt the efficiency of this process for large numbers of genes. Pohodich et al. showed that stimulating the fornix of mice with Rett syndrome reversed these changes for about a quarter of genes affected in the disorder. DBS also induced changes in thousands of RNA molecules in healthy mice. Many of these come from genes that support communication between nerve cells or that promote the formation of new nerve cells. DBS may have beneficial effects in other disorders too. Pohodich et al. showed that DBS also increases the levels of genes that are decreased in two other intellectual disability disorders, as well as genes that are altered in depression. For DBS to become a viable treatment, clinical trials must establish its safety and efficacy. Such trials are already underway in patients with Alzheimer’s disease. Future trials could include patients with learning impairments, or with depression that has not responded to other treatments.