Kappa受体激活介导谷氨酸转运体表达异常在社交逃避抑郁样行为中的作用及机制研究

Accumulating evidence suggests that dynorphin and its cognate kappa opioid receptor (KOR) play an important role in regulating stress responsiveness including depression, however, the underlying mechanism is unclear. Exposure to stress can trigger debilitating psychiatric illness, in particular depressive disorders. Our preliminary data showed that social defeat stress induced social avoidance, with significantly increased endogenous dynorphin expression and decreased glutamate transporters (GLT-1, cystine/glutamate exchange) expression in the medial prefrontal cortex. Blocking KOR activation in the prelimbic, but not infralimbic subregion of the medial prefrontal cortex restored glutamate transporter expression and ameliorated depressive-like behaviors. Thus, we hypothesized that the activation of KOR in the prelimbic cortex induced by social defeat stress mediated depressive-like behavior by decreasing glutamate transporter expression and thereby increasing extracellular glutamate concentration and activating NMDA receptor. Pharmacological and genetic approaches will be used to reveal the role of dynorphin/KOR system in regulating depressive-like behaviors. The present study will give insights into the mechanism of depression and provide new strategies for treating depression.

强啡肽/kappa受体(KOR)系统参与情绪调控，激活KOR介导动物表现抑郁样行为，调控机制尚不清楚。应激是导致抑郁症发生的重要原因。社交失败应激可良好地建立与人类抑郁症相符的动物模型。我们前期研究发现社交失败应激介导动物表现明显的社交逃避抑郁样行为，伴随前额叶皮层KOR内源性配体强啡肽表达增加，谷氨酸转运体（GLT-1，Xc-系统）表达降低。阻断前额叶皮层prelimbic而非infralimbic区KOR激活可以逆转Xc-系统的下调，改善动物抑郁样表现。谷氨酸转运体表达降低可能会介导谷氨酸清除障碍致胞外谷氨酸浓度过高，过度激活突触后膜NMDA受体导致抑郁的发生。因此我们将从社交失败应激-KOR激活-谷氨酸转运体表达减少-谷氨酸递质系统异常的角度，结合药理学和基因学手段，阐述强啡肽/KOR系统调控抑郁样行为的分子机制。本项目有助深入理解抑郁发病机理和KOR功能，为临床抑郁治疗提供新靶点。

抑郁是一种严重的神经精神疾病，情绪低落是主要临床特征。研究表明强啡肽/kappa阿片受体（KOR）系统参与抑郁的发生，但涉及的分子机制尚不清楚。本研究发现社交失败应激引起的抑郁依赖前额叶皮层prelimbic区域内源性强啡肽表达增加引起的KOR激活。KOR 激活通过下游p38MAPK引起谷氨酸转运体xCT表达下调导致谷氨酸递质系统紊乱进而介导抑郁。Prelimbic区域定位注射xCT激动剂或者过表达xCT会抑制社交失败应激引起的抑郁行为。药理学手段抑制或者敲除prelimbic区域KOR也会抑制社交失败应激引起的抑郁，而恢复KOR敲除鼠prelimbic脑区的KOR受体后动物会恢复抑郁样行为。进一步研究发现敲除胶质细胞上KOR会明显降低社交失败应激引起的抑郁。综上，本研究揭示KOR受体依赖的xCT下调是社交失败应激介导抑郁的关键机制，证明强啡肽/KOR系统是重要的抑郁调节系统和靶标。