Hippocampal glucocorticoid target genes associated with enhancement of memory consolidation

• Published in: The European journal of neuroscience 2022-05, Vol.55 (9-10), p.2666-2683
• Main Authors: Buurstede, Jacobus C., 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.
• Format: Article
• Language: English
• Subjects: Chromatin; Corticosterone; cyclic AMP response element binding; Deoxyribonucleic acid; DNA; Gene expression; Gene regulation; Genomics; glucocorticoid receptor; Glucocorticoids; Hippocampus; Immunoprecipitation; learning; Molecular modelling; Neurotransmission; Norepinephrine; object location memory; Special Issue; Transcription factors; Transcriptomes
• ISSN: 0953-816X; 1460-9568
• DOI: 10.1111/ejn.15226

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. Administration of corticosterone after object location training enhanced long‐term hippocampal memory. Glucocorticoid receptor and phosphorylated cAMP response element‐binding protein were co‐bound at the hippocampal genome and exclusively GR DNA‐binding levels were altered after corticosterone, yet binding of these two transcription factors was not affected by training nor was any interaction detected. Corticosterone altered the transcriptome in a context‐independent manner—partially via direct GR‐regulation—and reflects involvement of both neuronal and non‐neuronal cells in the male rat hippocampus.