Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression
Cingulate Overexpression of Mitogen-Activated Protein Kinase Phosphatase-1 as a Key Factor for Depression
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DOI：
10.1016/j.biopsych.2017.01.019
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发表时间：
2017-09-01
影响因子：
10.6
通讯作者：
Yalcin, Ipek
中科院分区：
文献类型：
--
作者：
Barthas, Florent;Humo, Muris;Yalcin, Ipek
背景：抑郁症经常与慢性疼痛或慢性压力有关。在皮质区域中，前扣带皮质（ACC，区域24 a和24 b）似乎对情绪障碍很重要，并构成了研究潜在分子机制的神经解剖学基底。目前的工作旨在确定ACC分子因素subserving depression.METHODS：神经性疼痛，不可预测的慢性轻度应激，和光遗传学ACC刺激诱导C57 BL/6 J雄性小鼠的抑郁样行为，并进行了评估，采用新奇的抑制喂养，飞溅，和强迫游泳测试。通过全基因组表达分析揭示了慢性疼痛诱导的抑郁症中ACC分子的变化。染色质免疫沉淀、蛋白质印迹和免疫染色提供了进一步的机制见解。分子变化和抑郁症之间的因果关系进行了研究，使用基因敲除，药理学拮抗作用，和本地病毒介导的基因knockdown.Results：慢性疼痛诱导的抑郁症，基因表达的变化在ACC突出的过表达的调节丝裂原活化蛋白激酶途径，丝裂原活化蛋白激酶磷酸酶-1（MKP-1）。这种上调与其近端启动子区域存在转录活性染色质标记（乙酰化）以及环磷酸腺苷反应元件介导的转录活性增加和环磷酸腺苷反应元件结合蛋白和激活转录因子的磷酸化有关。在不可预测的慢性轻度应激和重复ACC光遗传学刺激下也观察到MKP-1过表达，并且通过氟西汀逆转。一个敲除，拮抗剂，或MKP-1的局部沉默减弱抑郁样行为，指向一个重要的作用，这种磷酸酶在depression.CONCLUSIONS：这些数据点ACC MKP-1作为一个关键因素，在抑郁症的病理生理和治疗发展的潜在目标。
BACKGROUND: Depression is frequently associated with chronic pain or chronic stress. Among cortical areas, the anterior cingulate cortex (ACC, areas 24a and 24b) appears to be important for mood disorders and constitutes a neuroanatomical substrate for investigating the underlying molecular mechanisms. The current work aimed at identifying ACC molecular factors subserving depression.METHODS: Anxiodepressive-like behaviors in C57BL/6J male mice were induced by neuropathic pain, unpredictable chronic mild stress, and optogenetic ACC stimulation and were evaluated using novelty suppressed feeding, splash, and forced swim tests. ACC molecular changes in chronic pain-induced depression were uncovered through whole-genome expression analysis. Further mechanistic insights were provided by chromatin immunoprecipitation, Western blot, and immunostaining. The causal link between molecular changes and depression was studied using knockout, pharmacological antagonism, and local viral-mediated gene knockdown.RESULTS: Under chronic pain-induced depression, gene expression changes in the ACC highlighted the overexpression of a regulator of the mitogen-activated protein kinase pathway, mitogen-activated protein kinase phosphatase-1 (MKP-1). This upregulation is associated with the presence of transcriptionally active chromatin marks (acetylation) at its proximal promoter region as well as increased cyclic adenosine monophosphate response element-mediated transcriptional activity and phosphorylation of cyclic adenosine monophosphate response element binding protein and activating transcription factor. MKP-1 overexpression is also observed with unpredictable chronic mild stress and repeated ACC optogenetic stimulation and is reversed by fluoxetine. A knockout, an antagonist, or a local silencing of MKP-1 attenuates depressive-like behaviors, pointing to an important role of this phosphatase in depression.CONCLUSIONS: These data point to ACC MKP-1 as a key factor in the pathophysiology of depression and a potential target for treatment development.