Nat Med：揭示压力和抑郁导致大脑萎缩机制

严重抑郁症或慢性压力能够导致脑容量减少，从而导致情感障碍和认知障碍。如今，耶鲁大学科学家们领导的一个研究小组发现这为何会发生的一个原因：单个基因开关触发人大脑连接减少和模式动物产生抑郁。2012年8月12日，相关研究结果发表在Nature Medicine期刊上。

这些发现表明这种被称作转录因子的基因开关抑制几个在脑细胞之间突触连接的形成中发挥至关重要作用的基因的表达，从而能够导致前额皮质中脑容量减少。

论文通信作者Ronald Duman教授说，“我们想验证这种观点：压力导致人大脑突触减少。我们证实当这单个转录因子保被激活时，正常条件下参与情感和认知的神经环路受到破坏。”

研究人员分析了抑郁症病人和非抑郁症病人的大脑组织样品，研究了不同的基因激活模式。抑郁症病人的大脑表现出较低水平的基因表达，其中这些基因是大脑突触功能和结构所必需的。论文第一作者Hyo Jung Kang发现至少5个这样的基因能够受到被称作GATA1的单个转录因子的调控。当这个转录因子被激活时，啮齿动物表现出类似抑郁的症状，这就提示着GATA1在神经元之间连接的减少中发挥着作用，而且也在抑郁症状中发挥着作用。

Duman推测到，GATA1上的基因变异可能有朝一日有助于鉴定出哪些人有高风险患上严重抑郁症或对压力较为敏感。

本文编译自Study finds how stress, depression can shrink the brain

doi: 10.1038/nm.2886
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Decreased expression of synapse-related genes and loss of synapses in major depressive disorder

Hyo Jung Kang, Bhavya Voleti, Tibor Hajszan, Grazyna Rajkowska, Craig A Stockmeier, Pawel Licznerski, Ashley Lepack, Mahesh S Majik, Lak Shin Jeong, Mounira Banasr, Hyeon Son & Ronald S Duman

revious imaging and postmortem studies have reported a lower brain volume and a smaller size and density of neurons in the dorsolateral prefrontal cortex (dlPFC) of subjects with major depressive disorder (MDD)1, 2. These findings suggest that synapse number and function are decreased in the dlPFC of patients with MDD. However, there has been no direct evidence reported for synapse loss in MDD, and the gene expression alterations underlying these effects have not been identified. Here we use microarray gene profiling and electron microscopic stereology to reveal lower expression of synaptic-function–related genes (CALM2, SYN1, RAB3A, RAB4B and TUBB4) in the dlPFC of subjects with MDD and a corresponding lower number of synapses. We also identify a transcriptional repressor, GATA1, expression of which is higher in MDD and that, when expressed in PFC neurons, is sufficient to decrease the expression of synapse-related genes, cause loss of dendritic spines and dendrites, and produce depressive behavior in rat models of depression.