Neuronal type-specific modulation of cognition and AP-1 signaling by early-life rearing conditions. [CUT&Tag]

Environmental conditions profoundly influence cognitive development, particularly during early life. Transcriptional and epigenetic mechanisms may serve as molecular substrates for the lasting effects of environmental enrichment (EE) and impoverished environment (IE) on cognitive abilities and hippocampal function. However, the specific gene programs driving these changes remain largely unknown. In this study, we employed EE and IE paradigms to modulate cognitive abilities in opposing directions in mice. By combining hippocampal microdissection and genetic tagging of neuronal nuclei with genome-wide analyses of gene expression, chromatin accessibility, histone acetylation, and DNA methylation, we uncovered cell type-specific genomic changes induced by EE and IE in CA1 pyramidal neurons and dentate gyrus (DG) granule neurons. This multiomic screen identified the activity-regulated transcription factor AP-1 as a crucial mediator of neuroadaptation to environmental conditions during early life in both neuronal populations, albeit through distinct downstream mechanisms. Conditional deletion of Fos, a core AP-1 subunit, in excitatory neurons hampered EE-induced cognitive enhancement, further underscoring the pivotal role of this transcription factor in neuroadaptation.