The epigenetic changes of the chromatin represent an attractive molecular substrate for adaptation to the environment. We examined here the role of CREB‐binding protein (CBP), a histone acetyltransferase involved in mental retardation, in the genesis and maintenance of long‐lasting systemic and behavioural adaptations to environmental enrichment (EE). Morphological and behavioural analyses demonstrated that EE ameliorates deficits associated to CBP deficiency. However, CBP‐deficient mice also showed a strong defect in environment‐induced neurogenesis and impaired EE‐mediated enhancement of spatial navigation and pattern separation ability. These defects correlated with an attenuation of the transcriptional programme induced in response to EE and with deficits in histone acetylation at the promoters of EE‐regulated, neurogenesis‐related genes. Additional experiments in CBP restricted and inducible knockout mice indicated that environment‐induced adult neurogenesis is extrinsically regulated by CBP function in mature granule cells. Overall, our experiments demonstrate that the environment alters gene expression by impinging on activities involved in modifying the epigenome and identify CBP‐dependent transcriptional neuroadaptation as an important mediator of EE‐induced benefits, a finding with important implications for mental retardation therapeutics.

Advances in light-sheet and confocal microscopy now allow imaging of cleared large biological tissue samples and enable the three-dimensional appreciation of cell and protein localization in their native organ environment. However, the sample 2 preparations for such imaging are often onerous and their capability for antigen detection limited. Here we describe FLASH (Fast Light-microscopic analysis of Antibody-Stained wHole organs), a simple and rapid, fully customizable technique for molecular phenotyping of intact tissue volumes. FLASH utilizes non-degradative epitope recovery and membrane solubilisation to enable the detection of a multitude of membranous, cytoplasmic and nuclear antigens in whole mouse organs and embryos, human biopsies, organoids and Drosophila. Retrieval and immunolabelling of epithelial markers, an obstacle for previous clearing techniques, can be achieved with FLASH. Upon volumetric imaging, FLASH-processed samples preserve their architecture and integrity, and can be paraffin-embedded for subsequent histopathological analysis. The technique can be performed by scientists trained in light microscopy and yields results in less than one week.

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