The hippocampus is a limbic brain region that plays an important role in stress-related adaptive processes at the molecular, cellular and behavioural level. Recently, we have obtained evidence that adaptation to stress may entail chromatin remodelling as a critical step in transcriptional regulation. The aim of this study was to examine whether a mild psychological stressor (i.e. exposure to a novel environment) would affect the number of (P(Ser10)-H3)⁺ and (P(Ser10)-Ac(Lys14)-H3)⁺ neurons in the rat dentate gyrus (DG). Male Wistar rats were exposed to a novel environment by placing them singly in a new cage for 30 min. They were humanely killed 30 min (n=8), 2 h (n=6) or 24 h (n=10) after the start of novelty. P(Ser10)-H3 and P(Ser10)-Ac(Lys14)-H3 staining in neuronal nuclei was detected by immunohistochemistry. The numbers of P(Ser10)-H3⁺ and P(Ser10)-Ac(Lys14)-H3⁺ neurons were counted and expressed as number per DG per animal. In later experiments, the positive neurons were analysed with regard to localisation, i.e. closest to hilus, middle or closest to molecular layer, within the granular cell layer of the DG. Exposure to a novel environment for 30 min induced a marked increase in P(Ser10)-H3⁺ (control (n=6) 6.7±0.50; 30 min: 11.0±0.57 (P<0.05, post-hoc Dunnett's test); 2 h: 13.5±0.42 (P<0.05, post-hoc Dunnett's test); 24 h: 6.7±0.37) and P(Ser10)-Ac(Lys14)-H3⁺ neurons (control: 10.1±0.74; 30 min: 17.3±0.39 (P<0.05, post-hoc Dunnett's test); 2 h: 19.9±0.62 (P<0.05, post-hoc Dunnett's test); 24 h: 10.4±0.42), an effect which was virtually restricted to the DG. Both P(Ser10)-H3 and P(Ser10)-Ac(Lys14)-H3 modifications followed similar time courses with peak levels between 30 min and 2 h, returning to baseline within 24 h. This pattern of histone modifications was evident throughout the rostro-caudal axis of the hippocampus. Furthermore, the novelty-induced rise in P(Ser10)-H3⁺ and P(Ser10)-Ac(Lys14)-H3⁺ neurons was exclusively found in the middle and superficial aspects of the DG granular cell layer. Previous studies have suggested that these neurons are morphologically and functionally more developed and differentiated than those in the deep part of the granular cell layer [1]. Thus, the neurons recruited in response to novelty stress are most likely mature ones. In conclusion, the present study shows for the first time that novelty exposure evokes histone modifications in specific neurons of the hippocampal circuitry. Our data indicate that novelty enhances plasticity of DG neurons, a notion which is supported by the recent observation that this psychological challenge enhances long-term potentiation in the DG [2].