The Stability of NR2B in the Nucleus Accumbens Controls Behavioral and Synaptic Adaptations to Chronic Stress

被引:46
作者
Jiang, Bo [1 ]
Wang, Wei [1 ]
Wang, Fang [1 ,2 ,3 ]
Hu, Zhuang-Li [1 ,2 ,3 ]
Xiao, Jun-Li [1 ]
Yang, Si [1 ]
Zhang, Jing [4 ]
Peng, Xiao-Zhong [4 ]
Wang, Jin-Hui [5 ]
Chen, Jian-Guo [1 ,2 ,3 ]
机构
[1] Tongji Med Coll, Dept Pharmacol, Wuhan, Peoples R China
[2] Huazhong Univ Sci & Technol, Key Lab Neurol Dis, Wuhan 430030, Peoples R China
[3] Key Lab Drug Target Res & Pharmacodynam Evaluat H, Wuhan, Peoples R China
[4] Natl Key Lab Med Mol Biol, Beijing, Peoples R China
[5] State Key Labs Macrobiomol & Brain & Cognit Sci, Beijing, Peoples R China
基金
对外科技合作项目(国际科技项目);
关键词
Chronic social defeat stress; depression; hippocampal neurogenesis; long-term depression; NMDA; NR2B; nucleus accumbens; NMDA GLUTAMATE RECEPTORS; SOCIAL DEFEAT STRESS; LONG-TERM DEPRESSION; MEDIUM SPINY NEURONS; D-ASPARTATE RECEPTOR; SURFACE EXPRESSION; MESSENGER-RNA; AMPA RECEPTOR; PLASTICITY; RAT;
D O I
10.1016/j.biopsych.2012.10.031
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
Background: The nucleus accumbens (NAc) is closely correlated with depression. It has been demonstrated that the glutamatergic system in NAc plays an important role in the reward pathway, dysfunction of which would cause anhedonia, a core symptom of depression. We therefore tested whether N-methyl-D-aspartate receptors and the synaptic plasticity in the NAc are regulated by chronic stress and the relevance to depression. Methods: We applied behavioral tests (n = 12, each group) of social interaction and sucrose preference tests to identify the susceptibility of mice to chronic social defeat stress. We then tested N-methyl-D-aspartate receptor-long-term depression at corticoaccumbal synapse to determine the relationship between the susceptibility and changes in synaptic plasticity (n = 8, each group). We further investigated whether restoration of these changes could produce antidepressant effects (n = 10). Results: We found that chronic stress induced selective downregulation of N-methyl-D-aspartate receptor NR2B subunits in the confined surface membrane pool of NAc neurons. Remarkably, the loss of synaptic NR2B was a long-lived event and further translated to the significant modulation of synaptic plasticity in the form of long-term depression. We further observed that the stress-induced changes were restored by fluoxetine and that resilient mice-those resistant to chronic stress-showed patterns of molecular regulation in the NAc that overlapped dramatically with those seen with fluoxetine treatment. Behaviorally, restoration of NR2B loss prevented the behavioral sensitization of mice to chronic stress. Conclusions: Our results identify NR2B in the NAc as a key regulator in the modulation of persistent psychomotor plasticity in response to chronic stress.
引用
收藏
页码:145 / 155
页数:11
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