Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV.
Enriched environment treatment reverses depression-like behavior and restores reduced hippocampal neurogenesis and protein levels of brain-derived neurotrophic factor in mice lacking its expression through promoter IV.
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DOI：
10.1038/tp.2011.33
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发表时间：
2011-09-13
影响因子：
6.8
通讯作者：
Sakata K
中科院分区：
文献类型：
--
作者：
Jha S;Dong B;Sakata K
启动子IV驱动的脑源性神经营养因子(BDNF)是一种主要的神经生长因子，参与了抑郁症的病理生理过程。我们以前曾报道，通过启动子IV缺乏BDNF表达的小鼠(BDNF-KIV小鼠)表现出抑郁样的表型。在这里，我们研究了由于启动子IV缺陷而导致的抑郁样表型和BDNF水平降低是否可以通过丰富环境(EE)治疗来挽救，这是一种潜在的抗抑郁干预措施。通过尾部悬吊试验、旷场试验和蔗糖偏好试验，EE治疗3周可以挽救BDNF-KIV小鼠的抑郁样行为。EE治疗还增加了由多种内源性启动子驱动的BDNF转录本，并恢复了BDNF-KIV小鼠海马区的BDNF蛋白水平。此外，我们研究了成年海马神经发生作为BDNF-KIV小鼠抑郁样行为及其恢复的可能的细胞机制。我们发现，与对照野生型小鼠相比，BDNF-KIV小鼠髋部齿状回中存活的祖细胞数量及其树突长度减少。EE治疗恢复了BDNF-KIV小鼠细胞存活和树突状细胞长度的减少，并增加了细胞的增殖。综上所述，这项研究证明EE可以挽救抑郁样行为，降低BDNF水平，并减少因缺乏启动子IV驱动的BDNF表达而导致的髋部神经发生缺陷。这些结果表明，由于一个启动子受损而导致的BDNF水平下降可以被其他BDNF启动子补偿，BDNF水平可能是通过海马神经发生调节抑郁和抗抑郁效应的关键因素之一。
Promoter IV-driven expression of brain-derived neurotrophic factor (BDNF), a major neuronal growth factor, is implicated in the pathophysiology of major depression. We previously reported that mice lacking expression of BDNF through promoter IV (BDNF-KIV mice) exhibit a depression-like phenotype. Here, we examined whether the depression-like phenotype and decreased levels of BDNF because of promoter IV deficit could be rescued by enriched environment (EE) treatment, a potential antidepressant intervention. Three weeks of EE treatment rescued depression-like behavior of BDNF-KIV mice as assessed by the tail suspension test, open-field test and sucrose preference test. EE treatment also increased BDNF transcripts driven by multiple endogenous promoters and restored BDNF protein levels in the hippocampus (HIP) of BDNF-KIV mice. Further, we investigated adult hippocampal neurogenesis as a possible cellular mechanism underlying the depression-like behavior and its recovery in BDNF-KIV mice. We found that the number of surviving progenitors and their dendritic length in the dentate gyrus of the HIP were reduced in BDNF-KIV mice compared with the control wild-type mice. EE treatment restored the reduction in cell survival and dendritic length and increased cell proliferation in BDNF-KIV mice. In conclusion, this study demonstrated that EE rescued depression-like behavior, decreased BDNF levels and defective neurogenesis in the HIP caused by lack of promoter IV-driven BDNF expression. These results suggest that decreased BDNF levels because of one impaired promoter can be compensated by other BDNF promoters and that BDNF levels may be one of the key factors regulating depression and antidepressant effects through hippocampal neurogenesis.
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影响因子：
10.6
作者：
Autry, Anita E.;Adachi, Megumi;Cheng, Pengfei;Monteggia, Lisa M.
通讯作者：
Monteggia, Lisa M.
影响因子：
2.7
作者：
Duman, Catharine H.;Schlesinger, Lee;Terwilliger, Rosemarie;Russell, David S.;Newton, Samuel S.;Duman, Ronald S.
通讯作者：
Duman, Ronald S.
影响因子：
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作者：
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通讯作者：
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影响因子：
2.5
作者：
Brown, JP;Couillard-Després, S;Kuhn, HG
通讯作者：
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影响因子：
3.3
作者：
Dwivedi, Y.;Rizavi, H. S.;Pandey, G. N.
通讯作者：
Pandey, G. N.