Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands.
Brain Plasticity Group, Swammerdam Institute for Life Sciences, SILS-CNS, University of Amsterdam, Amsterdam, the Netherlands; Neuroscience and Behavioural Sciences Department, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto, Brazil.
Neuropharmacology. 2022 Sep 15;216:109186. doi: 10.1016/j.neuropharm.2022.109186. Epub 2022 Jul 11.
Glucocorticoids regulate memory consolidation, facilitating long-term storage of relevant information to adequately respond to future stressors in similar conditions. This effect of glucocorticoids is well-established and is observed in multiple types of behaviour that depend on various brain regions. By and large, higher glucocorticoid levels strengthen event-related memory, while inhibition of glucocorticoid signalling impairs consolidation. The mechanism underlying this glucocorticoid effect remains unclear, but it likely involves the transcriptional effects of the glucocorticoid receptor (GR). We here used a powerful paradigm to investigate the transcriptional effects of GR in the dorsal hippocampus of mice after training in an auditory fear conditioning task, aiming to identify a shortlist of GR target genes associated to memory consolidation. Therefore, we utilized in an explorative study the properties of selective GR modulators (CORT108297 and CORT118335), alongside the endogenous agonist corticosterone and the classical GR antagonist RU486, to pinpoint GR-dependent transcriptional changes. First, we confirmed that glucocorticoids can modulate memory strength via GR activation. Subsequently, by assessing the specific effects of the available GR-ligands on memory strength, we established a pharmacological filter which we imposed on the hippocampal transcriptome data. This identified a manageable shortlist of eight genes by which glucocorticoids may modulate memory consolidation, warranting in-depth follow-up. Overall, we showcase the strength of the concept of pharmacological transcriptome filtering, which can be readily applied to other research topics with an established role of glucocorticoids.
糖皮质激素调节记忆巩固，促进相关信息的长期储存，以便在类似条件下对未来的应激源做出适当反应。糖皮质激素的这种作用已经得到充分证实，并在多种依赖于不同脑区的行为中观察到。总的来说，较高的糖皮质激素水平会增强与事件相关的记忆，而糖皮质激素信号的抑制则会损害巩固。这种糖皮质激素作用的机制尚不清楚，但可能涉及糖皮质激素受体（GR）的转录效应。在这里，我们使用一种强大的范式，在听觉恐惧条件反射任务中训练后，研究了 GR 在小鼠背侧海马中的转录效应，旨在确定与记忆巩固相关的 GR 靶基因的候选列表。因此，我们在一项探索性研究中利用了选择性 GR 调节剂（CORT108297 和 CORT118335）的特性，以及内源性激动剂皮质酮和经典 GR 拮抗剂 RU486，以确定 GR 依赖性转录变化。首先，我们证实糖皮质激素可以通过 GR 激活来调节记忆强度。随后，通过评估现有 GR 配体对记忆强度的具体影响，我们建立了一个药理学筛选器，并将其应用于海马转录组数据。这确定了一个由 8 个基因组成的可管理的候选列表，糖皮质激素可能通过这些基因来调节记忆巩固，值得进一步深入研究。总的来说，我们展示了药理学转录组筛选概念的优势，该概念可以很容易地应用于其他具有糖皮质激素既定作用的研究课题。
