Buurstede Jacobus C, van Weert Lisa T C M, Colucci Paola, Gentenaar Max, Viho Eva M G, Koorneef Lisa L, Schoonderwoerd Robin A, Lanooij Suzanne D, Moustakas Ioannis, Balog Judit, Mei Hailiang, Kielbasa Szymon M, Campolongo Patrizia, Roozendaal Benno, Meijer Onno C
Division of Endocrinology, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Department of Cognitive Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
Eur J Neurosci. 2022 May;55(9-10):2666-2683. doi: 10.1111/ejn.15226. Epub 2021 May 6.
Glucocorticoids enhance memory consolidation of emotionally arousing events via largely unknown molecular mechanisms. This glucocorticoid effect on the consolidation process also requires central noradrenergic neurotransmission. The intracellular pathways of these two stress mediators converge on two transcription factors: the glucocorticoid receptor (GR) and phosphorylated cAMP response element-binding protein (pCREB). We therefore investigated, in male rats, whether glucocorticoid effects on memory are associated with genomic interactions between the GR and pCREB in the hippocampus. In a two-by-two design, object exploration training or no training was combined with post-training administration of a memory-enhancing dose of corticosterone or vehicle. Genomic effects were studied by chromatin immunoprecipitation followed by sequencing (ChIP-seq) of GR and pCREB 45 min after training and transcriptome analysis after 3 hr. Corticosterone administration induced differential GR DNA-binding and regulation of target genes within the hippocampus, largely independent of training. Training alone did not result in long-term memory nor did it affect GR or pCREB DNA-binding and gene expression. No strong evidence was found for an interaction between GR and pCREB. Combination of the GR DNA-binding and transcriptome data identified a set of novel, likely direct, GR target genes that are candidate mediators of corticosterone effects on memory consolidation. Cell-specific expression of the identified target genes using single-cell expression data suggests that the effects of corticosterone reflect in part non-neuronal cells. Together, our data identified new GR targets associated with memory consolidation that reflect effects in both neuronal and non-neuronal cells.
糖皮质激素通过 largely 未知的分子机制增强情绪唤起事件的记忆巩固。这种糖皮质激素对巩固过程的影响也需要中枢去甲肾上腺素能神经传递。这两种应激介质的细胞内途径汇聚于两种转录因子：糖皮质激素受体（GR）和磷酸化的 cAMP 反应元件结合蛋白（pCREB）。因此，我们在雄性大鼠中研究了糖皮质激素对记忆的影响是否与海马体中 GR 和 pCREB 之间的基因组相互作用有关。在二乘二设计中，物体探索训练或无训练与训练后给予增强记忆剂量的皮质酮或赋形剂相结合。通过染色质免疫沉淀测序（ChIP-seq）在训练后 45 分钟研究 GR 和 pCREB 的基因组效应，并在 3 小时后进行转录组分析。给予皮质酮诱导了海马体内 GR DNA 结合和靶基因调控的差异，很大程度上独立于训练。单独训练不会导致长期记忆，也不会影响 GR 或 pCREB 的 DNA 结合和基因表达。未发现 GR 和 pCREB 之间相互作用的有力证据。GR DNA 结合和转录组数据的组合确定了一组新的、可能直接的 GR 靶基因，它们是皮质酮对记忆巩固作用的候选介质。使用单细胞表达数据对鉴定出的靶基因进行细胞特异性表达表明，皮质酮的作用部分反映在非神经元细胞中。总之，我们的数据确定了与记忆巩固相关的新 GR 靶标，反映了神经元和非神经元细胞中的作用。
