Szewczyk Bernadeta, Kotarska Katarzyna, Daigle Mireille, Misztak Paulina, Sowa-Kucma Magdalena, Rafalo Anna, Curzytek Katarzyna, Kubera Marta, Basta-Kaim Agnieszka, Nowak Gabriel, Albert Paul R
Department of Neurobiology,Institute of Pharmacology, Polish Academy of Sciences,Smetna 12, 31-343 Krakow,Poland.
Ottawa Hospital Research Institute (Neuroscience), University of Ottawa,451 Smyth Road, Ottawa, ON,Canada.
Int J Neuropsychopharmacol. 2014 Nov;17(11):1763-75. doi: 10.1017/S146114571400100X. Epub 2014 Jun 19.
The effect of stress on the mRNA and protein level of the 5-HT1A receptor and two of its key transcriptional modulators, NUDR and Freud-1, was examined in the prefrontal cortex (PFC) and hippocampus (Hp) using rodent models: olfactory bulbectomy (OB) and prenatal stress (PS) in male and female rats; chronic mild stress in male rats (CMS) and pregnancy stress. In PFC, CMS induced the most widespread changes, with significant reduction in both mRNA and protein levels of NUDR, 5-HT1A receptor and in Freud-1 mRNA; while in Hp 5-HT1A receptor and Freud-1 protein levels were also decreased. In male, but not female OB rats PFC Freud-1 and 5-HT1A receptor protein levels were reduced, while in Hp 5-HT1A receptor, Freud-1 and NUDR mRNA's but not protein were reduced. In PS rats PFC 5-HT1A receptor protein was reduced more in females than males; while in Hp Freud-1 protein was increased in females. In pregnancy stress, PFC NUDR, Freud-1 and 5-HT1A protein receptor levels were reduced, and in HP 5-HT1A receptor protein levels were also reduced; in HP only NUDR and Freud-1 mRNA levels were reduced. Overall, CMS and stress during pregnancy produced the most salient changes in 5-HT1A receptor and transcription factor expression, suggesting a primary role for altered transcription factor expression in chronic regulation of 5-HT1A receptor expression. By contrast, OB (in males) and PS (in females) produced gender-specific reductions in PFC 5-HT1A receptor protein levels, suggesting a role for post-transcriptional regulation. These and previous data suggest that chronic stress might be a key regulator of NUDR/Freud-1 gene expression.
利用啮齿动物模型，即雄性和雌性大鼠的嗅球切除术（OB）和产前应激（PS）；雄性大鼠的慢性轻度应激（CMS）和妊娠应激，研究了应激对前额叶皮质（PFC）和海马体（Hp）中5-羟色胺1A受体（5-HT1A receptor）及其两个关键转录调节因子NUDR和Freud-1的mRNA和蛋白质水平的影响。在PFC中，CMS诱导的变化最为广泛，NUDR、5-HT1A受体的mRNA和蛋白质水平以及Freud-1 mRNA均显著降低；而在Hp中，5-HT1A受体和Freud-1蛋白质水平也降低。在雄性而非雌性OB大鼠中，PFC中Freud-1和5-HT1A受体蛋白质水平降低，而在Hp中，5-HT1A受体、Freud-1和NUDR的mRNA降低，但蛋白质未降低。在PS大鼠中，PFC中5-HT1A受体蛋白质在雌性中比雄性中降低得更多；而在Hp中，Freud-1蛋白质在雌性中增加。在妊娠应激中，PFC中NUDR、Freud-1和5-HT1A蛋白质受体水平降低，在Hp中5-HT1A受体蛋白质水平也降低；在Hp中只有NUDR和Freud-1 mRNA水平降低。总体而言，CMS和妊娠期间的应激在5-HT1A受体和转录因子表达方面产生了最显著的变化，表明转录因子表达改变在5-HT1A受体表达的慢性调节中起主要作用。相比之下，OB（雄性）和PS（雌性）在PFC中5-HT1A受体蛋白质水平上产生了性别特异性降低，表明转录后调节起作用。这些数据和先前的数据表明，慢性应激可能是NUDR/Freud-1基因表达的关键调节因子。
