Neuronal type-specific modulation of cognition and AP-1 signaling by early-life rearing conditions

Marta Alaiz-Noya, Federico Miozzo, Miguel Fuentes-Ramos, Magdalena A. Machnicka, Marcelina Kurowska, Macarena L. Herrera, Beatriz del Blanco, Sergio Ninerola, Isabel Bustos-Martínez, Bartek Wilczynski and Angel Barco ()
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Marta Alaiz-Noya: Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
Federico Miozzo: Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
Miguel Fuentes-Ramos: Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
Magdalena A. Machnicka: University of Warsaw
Marcelina Kurowska: University of Warsaw
Macarena L. Herrera: Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
Beatriz del Blanco: Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
Sergio Ninerola: Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
Isabel Bustos-Martínez: Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant
Bartek Wilczynski: University of Warsaw
Angel Barco: Instituto de Neurociencias (Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas). Av. Santiago Ramón y Cajal s/n. Sant Joan d’Alacant

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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 impoverishment (IE) on cognitive abilities and hippocampal function. However, the specific gene programs driving these changes remain largely unknown. In this study using female mice, EE and IE produced opposite effects on cognitive performance. 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 profound differences in the transcriptional and epigenetic profiles of CA1 pyramidal neurons and dentate gyrus (DG) granule neurons. These analyses revealed cell type-specific genomic changes induced by EE and IE, highlighting distinct patterns of neuroadaptation within each population. This multiomic screen pinpointed the activity-regulated transcription factor AP-1 as a crucial mediator of neuroadaptation to conditions during early life in both cell types, 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.

Date: 2025
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DOI: 10.1038/s41467-025-65343-5

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