Department of Psychiatry and Neurosciences, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima 734-8551, Japan.
J Psychiatr Res. 2011 Apr;45(4):460-8. doi: 10.1016/j.jpsychires.2010.08.009. Epub 2010 Sep 21.
Because the majority of patients with posttraumatic stress disorder (PTSD) exhibit long-lasting traumatic fear memory, we hypothesize that enhanced fear memory consolidation is closely involved in the pathophysiology of PTSD. Brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are crucial for hippocampal-dependent learning and memory. In particular, differential induction of BDNF gene transcripts mediated by histone acetylation plays a role in the consolidation of fear memory. In the present study, total and exon-specific mRNA and protein levels of BDNF and TrkB in the hippocampus after contextual fear conditioning (FC) were compared between rats subjected to single prolonged stress (SPS) and sham treatment. In addition, we examined the degree of histone acetylation at the promoter of each exon of the BDNF gene by chromatin immunoprecipitation (ChIP). We previously demonstrated a significant increase in contextual freezing in SPS rats. In the present study, SPS rats also showed increased total BDNF mRNA (including exons I, IV) and BDNF protein levels in the hippocampus after FC, accompanied by increased acetylation of histone H3 and H4 at the promoter of exon I and IV relative to sham-treated rats. Furthermore, the TrkB protein levels in the hippocampus of SPS rats were significantly higher than those in sham rats. These findings suggest that the enhanced levels of BDNF as well as TrkB along with epigenetic regulation of the BDNF gene during fear memory consolidation is, at least in part, associated with long-lasting fear memory in patients with PTSD.
由于大多数创伤后应激障碍（PTSD）患者表现出持久的创伤性恐惧记忆，我们假设增强的恐惧记忆巩固与 PTSD 的病理生理学密切相关。脑源性神经营养因子（BDNF）及其受体酪氨酸激酶受体 B（TrkB）对于海马依赖性学习和记忆至关重要。特别是，组蛋白乙酰化介导的 BDNF 基因转录本的差异诱导在恐惧记忆的巩固中起作用。在本研究中，在情景恐惧条件（FC）后，比较了接受单次延长应激（SPS）和假处理的大鼠海马中 BDNF 和 TrkB 的总 mRNA 和特异性 mRNA 及蛋白水平。此外，我们通过染色质免疫沉淀（ChIP）检查了 BDNF 基因每个外显子启动子处组蛋白乙酰化的程度。我们之前证明 SPS 大鼠的情景性冻结显著增加。在本研究中，SPS 大鼠在 FC 后海马中总 BDNF mRNA（包括外显子 I、IV）和 BDNF 蛋白水平也增加，与假处理大鼠相比，外显子 I 和 IV 的组蛋白 H3 和 H4 乙酰化增加。此外，SPS 大鼠海马中的 TrkB 蛋白水平明显高于假处理大鼠。这些发现表明，在恐惧记忆巩固过程中 BDNF 及其 TrkB 的水平增强以及 BDNF 基因的表观遗传调控至少部分与 PTSD 患者的持久恐惧记忆有关。
