A meta-analysis of more than 300 previous studies on the effects of environmental enrichment on the rodent brain has identified common patterns in the expression of genes associated with communication between neurons and synaptic plasticity, processes that are essential for brain adaptation. The study, published in the journal Molecular Neurobiology , is co-led by Federico Miozzo , a researcher at the Institute for Neurosciences (IN), a joint centre of the Spanish National Research Council (CSIC) and Miguel Hernández University of Elche (UMH), and Bartek Wilczyński , a researcher at the University of Warsaw (Poland). The findings also reinforce the role of the AP-1 transcription factor in the changes associated with environmental stimulation, in line with previous research by the team led by Ángel Barco at the Institute for Neurosciences.
The brain changes in response to experiences, but identifying the molecular mechanisms underlying these changes is challenging because each study may involve different experimental conditions. “One of the strengths of meta-analysis is that, although the studies differ from one another, analysing them together increases the number of samples available. This makes it possible to detect common patterns that might otherwise go unnoticed in individual studies”, explains Federico Miozzo, a researcher in the Transcriptional and Epigenetic Mechanisms of Neuronal Plasticity laboratory at the IN CSIC-UMH .
To identify these patterns, the team jointly analysed data from previous studies on gene expression in the brains of rodents exposed to an enriched environment. These animals have more opportunities to explore, engage in physical activity and interact with other animals than they would under standard housing conditions.
The initial search identified more than 300 publications. After checking which studies had the necessary data available, the researchers selected 20 studies based on RNA sequencing, a technique that measures which genes are expressed and to what extent, for a more detailed analysis. The aim was to identify a molecular signature associated with environmental enrichment, that is, a set of changes in gene expression consistently detected across different studies. Processing the data according to the same criteria and combining the results using three different statistical methods made it possible to identify recurrent molecular changes across studies, beyond the specific characteristics of each experiment.
Connections between neurons among the key findings
The meta-analysis identified a prominent presence of genes associated with synapses—the structures that enable communication between neurons—and synaptic plasticity, the ability of these connections to modify their function in response to activity and experience. The findings also highlighted genes involved in rapid responses to neuronal activation, such as those belonging to the Fos and Jun families, which encode proteins that form part of the AP-1 complex.
This transcription factor regulates the expression of numerous genes involved in communication between neurons and synaptic plasticity. This finding is particularly relevant to the team at the Institute for Neurosciences, which had previously investigated the role of AP-1 in a study published in Nature Communications . That research demonstrated in mice that this complex is involved in the mechanisms linking experiences during early life to long-lasting changes in cognitive abilities.
“The fact that the AP-1 transcription factor emerges again in this broader analysis is important because it reinforces and generalises our findings, pointing to these proteins as key regulators of the brain’s molecular response to environmental enrichment”, says Ángel Barco, who leads the Transcriptional and Epigenetic Mechanisms of Neuronal Plasticity laboratory at the IN CSIC-UMH.
The researchers emphasise that the findings must be interpreted in light of the diversity of the studies included. Differences in experimental designs and animal housing conditions introduce variability, and results obtained in rodents cannot be directly extrapolated to humans. The meta-analysis identifies consistent patterns in gene expression, but determining the causal role of each mechanism will require further experimental studies.
An open-access tool to explore the findings
The team has developed mEEtaBrain , a freely accessible web application that allows users to explore the results of the meta-analysis. The tool enables users to search for specific genes, select brain regions, and adjust analysis criteria to access the data they are interested in. “The application allows researchers to navigate the results according to their specific interests—for example, by looking up a particular gene or focusing on a specific brain region. The idea is to make the data reusable and provide a starting point for new research questions”, explains Miozzo.
This study is part of the international EPI-3E project (JPND2022-115), funded by the Instituto de Salud Carlos III (AC22-00030) under the European Joint Programme for Neurodegenerative Disease Research (JPND). The research was also supported by the Spanish State Research Agency, the European Regional Development Fund (ERDF), the ”la Caixa” Foundation and the Generalitat Valenciana . The Institute for Neurosciences CSIC-UMH is a Severo Ochoa Centre of Excellence.
Molecular Neurobiology
Meta-analysis
Not applicable
Systematic Review and Transcriptomic Meta-analysis of Environmental Enrichment Reveal Core Molecular Programs of Brain Plasticity
26-Aug-2026