Coping with stressful events is part of everyone’s daily life. It is thought that changes in gene expression are involved in the neuroplasticity processes underlying stress coping. Gene expression is controlled by transcription factors whose activity is governed by a variety of signal transduction cascades. Control of gene expression is tight and normally part of the genome is silent with the nucleosomes structurally organized in condensed chromatin. The nucleosomes consist of highly organized complexes of DNA and histone molecules and in condensed chromatin they are inaccessible for transcription factors. Nuclear receptors such as the glucocorticoid receptor (GR) are an exception to this rule as they are able to access their hormone responsive elements and ‘unlock’ the nucleosome rendering it accessible for molecules involved in chromatin remodelling and gene transcription (1). Recently, the concept has arisen that distinct post-translational modifications in the N-terminal tails of histone molecules play a decisive role in chromatin remodelling. The phosphorylation of histone H3 at Ser10 and its acetylation at Lys14 (i.e. P(Ser10)-Ac(Lys14)-H3) have been associated with the local opening of condensed chromatin allowing the transcriptional activation of dormant genes (2). It appears that the Ser10 residue in histone H3 comprises a converging point of multiple signal transduction pathways and kinases but these have been hardly investigated in vivo. Recently, we demonstrated for the first time that psychologically stressful stimuli such as forced swimming, predator exposure and novelty increase the phospho-acetylation of histone H3 in dentate gyrus granule neurons of rats and mice (3; Y. Chandramohan, SK Droste & JMHM Reul, unpublished observations). The nuclei of these neurons showed a speckled staining pattern which has been shown to be associated with transcriptional activation (e.g. (4)). The enhanced histone H3 phospho-acetylation was neuroanatomically quite specific because the stress-induced increase in P(Ser10)-Ac(Lys14)H3-positive neurons was only observed in mature (NeuN-positive) neurons in the middle and superficial aspects of the granular cell layer of the dorsal blade of the dentate gyrus (3; Y. Chandramohan, S.K. Droste & J.M.H.M. Reul, unpublished observations; Y. Chandramohan, S.K. Droste, J.S. Arthur, J.M.H.M. Reul, unpublished observations), suggesting that only mature neurons of a particular part of the dentate gyrus are recruited in the response to stress. Follow-up studies revealed that stress-induced histone H3 phospho-acetylation is mediated by both glucocorticoid receptor (GR) and NMDA receptor (NMDA-R) signalling suggesting an integration of these two signalling pathways (3; Y. Chandramohan, S.K. Droste & J.M.H.M. Reul, unpublished observations). Blockade of the mineralocorticoid receptor (MR) was ineffective (Y. Chandramohan, S.K. Droste & J.M.H.M. Reul, unpublished observations). Furthermore, the forced swimming-induced increases in dentate histone modifications could be blocked by inhibiting the MAPK-ERK (mitogen-activated protein kinase–extracellular signal-regulated kinase) pathway and by genetic deletion of the mitogen- and stress-induced kinases 1 and 2 (MSK1/2; Y. Chandramohan et al. unpublished observations). Thus, the stress-evoked histone H3 modifications were mediated by GR signalling as well as signalling through the NMDA-R/MAPK/ERK/MSK1/2 pathway (3; Y. Chandramohan, S.K. Droste & J.M.H.M. Reul, unpublished observations). If rats or mice are subjected a second time to forced swimming 24 h after the first forced swim session, they attain an immobile posture in the water for about 70% of the 5 min re-test time. This is a stress-related cognitive response as the animal has learned from the first forced swim session that escape from the water is impossible. We observed that blockade of GR signalling or NMDA-R/MAPK/ERK/MSK signalling, but not MR signalling, resulted in a strong impairment of the behavioural immobility response (Chandramohan et al. unpublished observations). Therefore, based on the strict correlation between the biochemical and behavioural responses, we have postulated that the histone H3 phospho-acetylation response after the initial forced swim session is required for the acquisition of the behavioural immobility response observed in the re-test. The histone modification response occurred in a distinct population of dentate gyrus granule neurons and required recruitment of both the GR and the NMDA/MAPK/ERK/MSK signalling pathways.