Application of a pharmacological transcriptome filter identifies a shortlist of mouse glucocorticoid receptor target genes associated with memory consolidation

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.