Institute of Cellular and Integrative Neuroscience, National Centre for Scientific Research, Strasbourg; University of Strasbourg, Strasbourg.
Institute of Pharmacology and Toxicology, University of Freiburg, and BIOSS Centre for Biological Signalling Studies, Freiburg, Germany.
Biol Psychiatry. 2017 Sep 1;82(5):370-379. doi: 10.1016/j.biopsych.2017.01.019. Epub 2017 Feb 14.
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.
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.
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.
These data point to ACC MKP-1 as a key factor in the pathophysiology of depression and a potential target for treatment development.
抑郁常与慢性疼痛或慢性应激相关。在皮质区域中，前扣带皮层（ACC，区域 24a 和 24b）似乎对情绪障碍很重要，并且构成了研究潜在分子机制的神经解剖学基础。目前的工作旨在确定与抑郁相关的 ACC 分子因素。
通过神经病理性疼痛、不可预测的慢性轻度应激和光遗传学 ACC 刺激，在 C57BL/6J 雄性小鼠中诱导焦虑抑郁样行为，并通过新奇抑制喂养、飞溅和强迫游泳试验进行评估。通过全基因组表达分析揭示慢性疼痛诱导的抑郁中 ACC 的分子变化。通过染色质免疫沉淀、Western blot 和免疫染色提供进一步的机制见解。使用基因敲除、药理学拮抗和局部病毒介导的基因敲低研究分子变化与抑郁之间的因果关系。
在慢性疼痛诱导的抑郁中，ACC 中的基因表达变化突出了丝裂原激活蛋白激酶途径的调节剂，丝裂原激活蛋白激酶磷酸酶-1（MKP-1）的过表达。这种上调与近端启动子区域转录活性染色质标记（乙酰化）的存在以及环磷酸腺苷反应元件介导的转录活性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增加有关。不可预测的慢性轻度应激和重复 ACC 光遗传学刺激也观察到 MKP-1 的过表达，并且被氟西汀逆转。MKP-1 的基因敲除、拮抗剂或局部沉默可减轻抑郁样行为，表明该磷酸酶在抑郁中具有重要作用。
这些数据表明 ACC 的 MKP-1 是抑郁病理生理学中的关键因素，也是治疗开发的潜在靶点。
