ORIGINAL RESEARCH article
Front. Cell. Neurosci.
Sec. Cellular Neurophysiology
Volume 19 - 2025 | doi: 10.3389/fncel.2025.1646883
This article is part of the Research TopicMemory processing in health and disease: linking behavioral, circuits, and molecular scales.View all 3 articles
Cognitive enrichment improves spatial memory and alters hippocampal synaptic connectivity in a mouse model for early-life stress
Provisionally accepted
Justin L Shobe1*
Elham Ghanbarian2
Robert Bain1Rajat Saxena1Meenakshi Chandrasekaran1
Bruce McNaughton1- 1University of California Irvine Department of Neurobiology and Behavior, Irvine, United States
- 2University of California, Irvine, Irvine, United States
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Early life stress (ELS) and enrichment often have opposing effects on long-term cognitive abilities. Deprivation, such as institutionalized care during early childhood neurodevelopmental periods, results in lifelong working memory and recall deficits. In contrast, enrichment facilitates new learning and slows cognitive decline due to aging and neurodegenerative diseases. Similarly, in rodent models, enrichment facilitates learning whereas ELS induces prominent spatial memory deficits. Environmental enrichment (EE) and ELS can cause opposing changes in hippocampal structure (e.g. shifts in synaptic density) that largely depend on experimental conditions. However, it remains untested whether EE can rescue the behavioral disruptions caused by ELS and how this would impact the hippocampus at advanced ages. To address this, we conducted a longitudinal study on ELS mice, extensively training them on a cognitive enrichment track (ET) or an exercise alone control track (CT). After this, the mice underwent repeated memory testing followed by brain extraction for anatomical analysis of their hippocampus. We found that ET reversed spatial memory deficits at 6, 13 and 20 months and reduced the number of dentate gyrus (DG) to CA3 synapses. Surprisingly, this reduction occurred at excitatory MF synapses surrounding CA3 somas in the stratum pyramidale—a layer not typically associated with MF terminals. Collectively, these findings suggest that cognitive enrichment during early adulthood may reverse ELS-induced spatial memory deficits by adjusting synaptic connectivity between the DG and CA3.
Keywords: Memory, synaptic plasticity, Behavior, Hippocampus, Enrichment
Received: 14 Jun 2025; Accepted: 22 Sep 2025.
Copyright: © 2025 Shobe, Ghanbarian, Bain, Saxena, Chandrasekaran and McNaughton. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Justin L Shobe, jshobe@uci.edu
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