Fluoxetine prevents development of an early stress-related molecular signature in the rat infralimbic medial prefrontal cortex. Implications for depression?
Fluoxetine prevents development of an early stress-related molecular signature in the rat infralimbic medial prefrontal cortex. Implications for depression?
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DOI：
10.1186/1471-2202-13-125
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发表时间：
2012-10-18
期刊：
影响因子：
2.4
通讯作者：
Smith DW
中科院分区：
文献类型：
--
作者：
Barreto RA;Walker FR;Dunkley PR;Day TA;Smith DW
心理压力，特别是长期的心理压力，会导致情绪和认知功能障碍，是发展成抑郁状态的主要危险因素。压力是如何影响大脑并导致精神病理的还不完全清楚。我们试图通过分析边缘下内侧前额叶皮层（ILmPFC）的基因表达和分子通路来描述潜在的抑郁相关机制，遵循重复的心理压力范式。上皮层前额叶皮层被认为参与处理情感背景信息和协调相关的自主神经反应，它是与压力反应和抑郁有关的大脑区域之一。基因表达的全基因组微阵列分析显示，亚慢性抑制应激在最后一次应激发作后24小时主要导致转录本减少，239个基因显著减少，而只有24个基因的转录本丰度增加。利用DAVID进行分子通路分析，在差异表达基因列表中发现了8条显著富集的通路，其中脑源性神经营养因子-神经营养因子受体酪氨酸激酶2 （BDNF-Ntrk2）通路的基因富集最多。在Ntrk2下游的三条细胞内信号通路中，实时定量PCR证实，只有PI3K-AKT-GSK3B和MAPK/ERK通路受到亚慢性应激的影响，PLCγ通路不受影响。有趣的是，用选择性血清素再摄取抑制剂氟西汀进行慢性抗抑郁治疗，可以阻止应激诱导的Ntrk2和PI3K通路的变化，但对MAPK/ERK通路没有影响。这些发现表明，异常的BDNF-Ntrk2信号可能在相对较早的时间点表现出来，并且与抑郁症在抑郁样行为发生之前发生的分子特征相一致。预防性地针对这一途径，特别是在抑郁症易感个体中，可能具有治疗益处。
Psychological stress, particularly in chronic form, can lead to mood and cognitive dysfunction and is a major risk factor in the development of depressive states. How stress affects the brain to cause psychopathologies is incompletely understood. We sought to characterise potential depression related mechanisms by analysing gene expression and molecular pathways in the infralimbic medial prefrontal cortex (ILmPFC), following a repeated psychological stress paradigm. The ILmPFC is thought to be involved in the processing of emotionally contextual information and in orchestrating the related autonomic responses, and it is one of the brain regions implicated in both stress responses and depression. Genome-wide microarray analysis of gene expression showed sub-chronic restraint stress resulted predominantly in a reduction in transcripts 24 hours after the last stress episode, with 239 genes significantly decreased, while just 24 genes had increased transcript abundance. Molecular pathway analysis using DAVID identified 8 pathways that were significantly enriched in the differentially expressed gene list, with genes belonging to the brain-derived neurotrophic factor – neurotrophin receptor tyrosine kinase 2 (BDNF-Ntrk2) pathway most enriched. Of the three intracellular signalling pathways that are downstream of Ntrk2, real-time quantitative PCR confirmed that only the PI3K-AKT-GSK3B and MAPK/ERK pathways were affected by sub-chronic stress, with the PLCγ pathway unaffected. Interestingly, chronic antidepressant treatment with the selective serotonin reuptake inhibitor, fluoxetine, prevented the stress-induced Ntrk2 and PI3K pathway changes, but it had no effect on the MAPK/ERK pathway. These findings indicate that abnormal BDNF-Ntrk2 signalling may manifest at a relatively early time point, and is consistent with a molecular signature of depression developing well before depression-like behaviours occur. Targeting this pathway prophylactically, particularly in depression-susceptible individuals, may be of therapeutic benefit.
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影响因子：
5.3
作者：
Genoud, C;Knott, GW;Welker, E
通讯作者：
Welker, E
影响因子：
4.7
作者：
Coppell, AL;Pei, Q;Zetterström, TSC
通讯作者：
Zetterström, TSC
影响因子：
4.5
作者：
Brown, Amanda L.;Smith, Doug W.
通讯作者：
Smith, Doug W.
影响因子：
10.6
作者：
Dwivedi, Yogesh;Rizavi, Hooriyah S.;Zhang, Hui;Mondal, Amal C.;Roberts, Rosalinda C.;Conley, Robert R.;Pandey, Ghanshyam N.
通讯作者：
Pandey, Ghanshyam N.
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y