Systematic Review and Transcriptomic Meta-analysis of Environmental Enrichment Reveal Core Molecular Programs of Brain Plasticity.

Overview

1. Faculty of Mathematics, Informatics and Mechanics, University of Warsaw,00-927 Warsaw, Poland
2. Instituto de Neurociencias, Universidad Miguel Hernández - Consejo Superior de Investigaciones Científicas,Av. Santiago Ramón y Cajal S/N. Sant Joan d’Alacant, 03550 Alicante, Spain
3. Department for Epigenetics and Systems Medicine in Neurodegenerative Diseases, German Center for Neurodegenerative Diseases (DZNE),Von Siebold Str. 3 A, 37077 Göttingen, Germany
4. Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL),03010, Alicante, Spain
5. Centro de Investigación en Red-Enfermedades Neurodegenerativas (CIBERNED),28031 Madrid, Spain
6. Laboratoire de Neuroscience Cognitives Et Adaptatives (LNCA), UMR7364 CNRS, University of Strasbourg,67000 Strasbourg, France
7. Cluster of Excellence “Multiscale Bioimaging: From Molecular Machines to Networks of Excitable Cells” (MBExC), University of Göttingen,Von Siebold Str. 3 A, 37077 Göttingen, Germany
8. German Center for Cardiovascular Diseases (DZKH), Göttingen, Von Siebold Str. 3 A, 37077 Göttingen, Germany
9. Department for Psychiatry and Psychotherapy, University Medical Center of Göttingen, Georg-August University,Von Siebold Str. 3 A, 37077 Göttingen, Germany

Abstract

Environmental enrichment (EE) paradigms in rodents have long demonstrated that enhanced sensory, cognitive, social, and motor stimulation positively impacts brain function, improving learning, memory, and neuroplasticity. These effects have significant implications for understanding cognitive development and mitigating cognitive decline and brain aging. While numerous transcriptomic studies have explored EE-induced molecular changes, a unified view of the genes and pathways consistently modulated remains lacking. To address this gap, we performed a systematic review and meta-analysis. We conducted a comprehensive PubMed search for all studies published up to February 2025 that matched all the following inclusion criteria: (1) employed EE paradigms; (2) were conducted on rodents; (3) utilized genome-wide transcriptomic methods; (4) examined brain regions or neuronal populations. The 323 retrieved articles were manually screened for relevance to the study aims and data availability. Datasets from 20 eligible RNA-seq reports were reprocessed using a unified analysis pipeline and subjected to a meta-analysis with three complementary statistical methods. Despite considerable heterogeneity across studies, our integrative analysis identified consistent gene expression signatures linked to synaptic function, plasticity and their transcriptional regulation. In particular, our findings highlight the upregulation of the activity-dependent transcriptional program, including Fos and Jun family members. These molecular insights advance our understanding of how EE impacts on neuronal and behavioral outcomes, and may inform therapeutic strategies aimed at replicating or enhancing EE benefits. To promote open science and foster further research, we developed an accessible web application, mEEtaBrain, that enables the neuroscience community to navigate and interrogate our meta-analysis results. Substantial methodological heterogeneity across source studies increased variability in the meta-analysis outcomes. The use of stressors or disease models, particularly in rat studies, introduced a major confounding factor and limited reliable interspecies comparison. Overall, the studies exhibited a low to moderate risk of bias.

Supplementary Information: The online version contains supplementary material available at 10.1007/s12035-026-06133-y.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

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Data

Datasets cited

• zenodo:21355440, at Zenodo; found in “Data Availability”

Data Availability

All data analyzed in this study were obtained from publicly available databases, with the exception of the dataset from Utsunomiya et al., which is not publicly available and was provided directly by the authors upon request. Detailed information on each dataset is available in Supplementary Tables 1 and 2, and all publicly accessible data can be retrieved through the respective platforms. Scripts used for preprocessing raw FASTQ files, including Fastp trimming and RSEM quantification, are available in Supplementary File 1. All pre-processed datasets used in the mEEtaBrain application (http://regulomics.mimuw.edu.pl/mEEtaBrain/), representing the results of DESeq2 differential expression analyses, are publicly available via the Zenodo repository at https://zenodo.org/records/21355440. A video tutorial demonstrating the use of the mEEtaBrain application is available at https://www.youtube.com/watch?v=neqPSVcyRwA.

Reproduced under the paper's license (CC BY), from the paper cited above.

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Version 2, 28 September 2026

• Publisher: n/a → Springer Science+Business Media

Version 1, 27 September 2026: the first record

Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 5 keywords, 6 MeSH terms, 6 funders, 112 references.

Cite

This paper

Kurowska, M., Miozzo, F., Schroeder, R., Machnicka, M. A., Pérez-González, R., Merienne, K., Fischer, A., Barco, A., Boutillier, A.-L., & Wilczyński, B. (2026). Systematic Review and Transcriptomic Meta-analysis of Environmental Enrichment Reveal Core Molecular Programs of Brain Plasticity. Molecular neurobiology, 63(1), 857. https://doi.org/10.1007/s12035-026-06133-y

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