Layer 2/3 pyramidal cells in the medial prefrontal cortex moderate stress induced depressive behaviors.
Layer 2/3 pyramidal cells in the medial prefrontal cortex moderate stress induced depressive behaviors.
复制标题
内侧前额叶皮层中等压力引起的抑郁行为的2/3层锥体细胞。
DOI：
10.7554/elife.08752
复制
发表时间：
2015-09-15
期刊：
影响因子：
7.7
通讯作者：
Heintz N
中科院分区：
文献类型：
--
作者：
Shrestha P;Mousa A;Heintz N
重度抑郁症（MDD）是一种流行病，可由急性或慢性压力引起。对Wolfram综合征患者和携带者的研究已经确定Wfs 1突变是MDD的病因。内侧前额叶皮层（mPFC）被认为与抑郁和行为恢复有关，尽管mPFC中调节抑郁行为的细胞类型和回路尚未确定。在这里，我们报告说，删除Wfs 1从第2/3层锥体细胞损害的mPFC的能力，以抑制应激诱导的抑郁行为，并导致下丘脑-垂体-肾上腺轴的过度激活和改变重要的生长和神经营养因子的积累。我们的数据确定浅层2/3锥体细胞作为关键的背景下，抑郁行为的压力缓和，并建议在这些细胞的功能障碍可能有助于压力和抑郁症之间的临床关系。DOI：http://dx.doi.org/10.7554/eLife.08752.001大约16%的人会在生活中的某个时候经历一段严重的抑郁症，症状包括失去动力，减少对以前愉快活动的享受，以及睡眠和食欲的干扰。多种基因和环境因素与抑郁症有关，而发展这种疾病的最大风险因素之一是暴露于压力。压力和抑郁会影响大脑的许多相同区域，最明显的是前额皮质一个与决策、解决问题和调节情绪有关的区域。因此，Shrestha等人推断，要深入了解压力和抑郁之间的关系，一个好方法是研究表达与抑郁有关的基因的前额叶皮层细胞。其中一个基因是Wfs 1。这种基因的突变会导致一种罕见的疾病，称为Wolfram综合征，其中受影响的个体会经历各种症状，通常包括严重的抑郁症。Shrestha等人在前额叶皮层中发现了表达Wfs 1的特定细胞群。当受到压力事件时，例如被限制，经过基因改造的小鼠在其前额叶皮层中缺乏这种基因，比未经改造的小鼠更有可能表现出抑郁样行为。这些转基因小鼠在受到约束时也会释放更多的应激激素，并产生不同数量的调节神经元生长和信号传导的蛋白质。Shrestha等人提出，这些蛋白质作用于控制小鼠如何应对压力的神经回路。此外，这些蛋白质的水平或分布的变化可能会增加压力事件引发与抑郁症相关的行为的可能性。需要进一步的实验来研究使用药物操纵表达Wfs 1的细胞可以防止压力的有害影响，甚至治疗现有的抑郁症发作的可能性。DOI：http://dx.doi.org/10.7554/eLife.08752.002网站
Major depressive disorder (MDD) is a prevalent illness that can be precipitated by acute or chronic stress. Studies of patients with Wolfram syndrome and carriers have identified Wfs1 mutations as causative for MDD. The medial prefrontal cortex (mPFC) is known to be involved in depression and behavioral resilience, although the cell types and circuits in the mPFC that moderate depressive behaviors in response to stress have not been determined. Here, we report that deletion of Wfs1 from layer 2/3 pyramidal cells impairs the ability of the mPFC to suppress stress-induced depressive behaviors, and results in hyperactivation of the hypothalamic–pituitary–adrenal axis and altered accumulation of important growth and neurotrophic factors. Our data identify superficial layer 2/3 pyramidal cells as critical for moderation of stress in the context of depressive behaviors and suggest that dysfunction in these cells may contribute to the clinical relationship between stress and depression. DOI: http://dx.doi.org/10.7554/eLife.08752.001 Around 16% of people will experience an episode of major depression at some point in their lives, with symptoms including a loss of motivation, a reduced enjoyment of previously pleasurable activities, and disturbances in sleep and appetite. Multiple genes and environmental factors have been implicated in depression, and one of the strongest risk factors for developing the disorder is exposure to stress. Stress and depression affect many of the same brain regions, most notably the prefrontal cortex—an area that is involved in decision making, problem solving and regulating emotions. Shrestha et al. therefore reasoned that a good way of obtaining insights into the relationship between stress and depression would be to study prefrontal cortex cells that express genes that have been linked to depression. One such gene is Wfs1. Mutations in this gene cause a rare disorder called Wolfram syndrome, in which affected individuals experience a wide range of symptoms that often include severe depression. Shrestha et al. identified a specific population of cells in the prefrontal cortex that express Wfs1. When subjected to a stressful event, such as being restrained, mice that had been genetically modified to lack this gene in their prefrontal cortex were more likely to exhibit depression-like behaviors than non-modified mice. The genetically modified mice also released more stress hormones when restrained and produced different amounts of a number of proteins that regulate the growth and signaling of neurons. Shrestha et al. propose that these proteins act on neural circuits that control how the mice respond to stress. Furthermore, changes in the levels or the distribution of these proteins may increase the likelihood that a stressful event will trigger behaviors associated with depression. Further experiments are required to investigate the possibility that using drugs to manipulate cells that express Wfs1 could protect against the harmful effects of stress, or even treat existing episodes of depression. DOI: http://dx.doi.org/10.7554/eLife.08752.002