Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.
Prostaglandin E2-mediated attenuation of mesocortical dopaminergic pathway is critical for susceptibility to repeated social defeat stress in mice.
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DOI：
10.1523/jneurosci.5952-11.2012
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发表时间：
2012-03-21
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影响因子：
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通讯作者：
Narumiya S
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文献类型：
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作者：
Tanaka K;Furuyashiki T;Kitaoka S;Senzai Y;Imoto Y;Segi-Nishida E;Deguchi Y;Breyer RM;Breyer MD;Narumiya S
各种各样的压力被认为会导致精神疾病，比如重度抑郁症。尽管对啮齿动物的研究表明内侧前额叶皮层（mPFC）在应激易感性中起关键作用，但mPFC如何决定应激易感性的机制尚不清楚。在这里，我们展示了前列腺素E2 (PGE2)，一种从花生四烯酸中提取的生物活性脂质，在小鼠反复的社会失败应激中的关键作用。反复的社交失败增加了大脑皮层下区域的PGE2水平，缺乏COX-1（一种前列腺素合成酶）或EP1（一种PGE2受体）的小鼠在反复的社交失败诱导的社交回避中受损。考虑到EP1增加gaba能输入到中脑多巴胺神经元的作用，我们分析了社交失败时的多巴胺能反应。对野生型小鼠mPFC内VTA多巴胺神经元c-Fos表达和多巴胺周转的分析表明，中脑皮层多巴胺能通路在社交失败时被激活，并随着社交失败的重复而减弱。EP1缺乏消除了这种反复应激诱导的中皮层多巴胺能通路的衰减。在社交失败过程中，多巴胺d1样受体的阻断恢复了ep1缺陷小鼠的社交回避，表明社交失败过程中多巴胺能的去抑制反应阻断了社交回避的诱导。此外，通过局部注射6-羟多巴胺，mPFC多巴胺能损伤，模仿EP1在重复应激中的作用，促进了社交失败后社交回避的诱导。综上所述，我们的数据表明，PGE2-EP1信号通路通过中脑皮层多巴胺能通路的衰减，对小鼠重复社会失败应激的易感性至关重要。
Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E2 (PGE2), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE2 level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE2-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway.