Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression
Chronic unpredictable mild stress-induced behavioral changes are coupled with dopaminergic hyperfunction and serotonergic hypofunction in mouse models of depression
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DOI：
10.1016/j.bbr.2019.112053
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发表时间：
2019-10-17
影响因子：
2.7
通讯作者：
Saito, Kuniaki
中科院分区：
文献类型：
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作者：
Lu, Qiaohui;Mouri, Akihiro;Saito, Kuniaki
越来越多的证据表明，应激事件会引起大脑中的分子变化，这被认为是严重抑郁障碍(MDD)的一种病理。然而，慢性应激对脑内神经传递和细胞内信号通路的影响还没有得到充分的研究。我们研究了慢性不可预测的轻度应激(CUMS)对大鼠伏隔核、海马和前额叶皮质的情绪行为、多巴胺能和5-羟色胺能功能以及细胞内信号的影响。雄性C57BL/6J小鼠暴露于CUMS 4周。结果表明，在新的环境中，CUMS能诱导多动，在社会互动实验中减少交互时间，在新奇抑制摄食实验中延长摄食潜伏期，在强迫游泳实验中增强不动能力。CUMS可增加伏隔核(NAC)多巴胺及其代谢产物和代谢产物、酪氨酸羟化酶(TH)蛋白水平。CUMS可降低大鼠海马区(HPC)和前额叶皮质(PFC)5-羟色胺水平及色氨酸羟化酶(TPH)和TH蛋白水平。随着多巴胺能功能的增强，胞外信号调节蛋白(ERK)、蛋白激酶B(Akt)和cAMP反应元件结合蛋白(CREB)的磷酸化水平也随之升高。氟西汀(选择性5-羟色胺再摄取抑制剂：20 mg/kg ip)阿立哌唑(多巴胺D-2受体部分激动剂：0.1 mg/kg ip)。在CUMS期间，阻止了行为改变和NAC中多巴胺水平的增加。这些数据表明，CUMS诱导的抑郁样行为与NAC的多巴胺能功能亢进和HPC和PFC的5-羟色胺能功能低下相关联。
Accumulating evidence shows that stressful events evoke molecular alterations in the brain, considered a pathology in major depressive disorder (MDD). However, the abnormalities of neurotransmissions as well as intracellular signaling pathways affected by chronic stress in brain have not been fully explored. We investigated the effect of chronic unpredictable mild stress (CUMS) on the emotional behaviors, dopaminergic and serotoninergic function, and intracellular signaling in the nucleus accumbens, hippocampus and prefrontal cortex. Male C57BL/6J mice were exposed to CUMS for 4 weeks. CUMS was shown to induce hyperactivity in a novel environment, decrease interaction time in the social interaction test, prolong feeding latency in the novelty suppressed feeding test and enhance immobility in the forced swimming test. The levels of dopamine, its metabolites and turnover, and protein level of tyrosine hydroxylase (TH) were increased by CUMS in the nucleus accumbens (NAc). The level of serotonin and protein levels of tryptophan hydroxylase (TPH) and TH were decreased by CUMS in the hippocampus (HPC) and prefrontal cortex (PFC). Accompanying the increase in dopaminergic function, phosphorylation levels of extracellular signal-regulated kinases (ERK), protein kinase B (Akt) and cAMP response element-binding protein (CREB) were increased by CUMS in the NAc. Administration of fluoxetine (selective serotonin re-uptake inhibitor: 20 mg/kg i.p.) and aripiprazole (dopamine D-2 receptor partial agonist: 0.1 mg/kg i.p.) during CUMS, prevented behavioral changes and increase of dopamine level in the NAc. These data suggest that CUMS-induced depression-like behaviors are coupled with dopaminergic hyperfunction in the NAc and serotonergic hypofunction in the HPC and PFC.