ORIGINAL RESEARCH article
Front. Psychiatry
Sec. Molecular Psychiatry
Early life stress-induced depression reveals distinct region-specific modulation of unfolded protein response genes in the prefrontal cortex and hippocampus of rats
Provisionally accepted
- University of Alabama at Birmingham, Birmingham, United States
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Early-life stress (ELS) has been implicated in the onset of major depressive disorder (MDD) in adulthood. Recent studies suggest that the unfolded protein response (UPR), a cellular response to stress, could be a precipitating factor in depressive symptoms. The present study examined the expression of genes associated with UPR in the prefrontal cortex (PFC) and the hippocampus using a rodent model of ELS-induced depression, in which male pups experienced maternal separation (MS) with or without subsequent environmental enrichment (MS-E). Expression of UPR genes was determined by quantitative polymerase chain reaction using rat-specific primers. Of the six key UPR genes (Xbp1, sXbp1, Atf4, Atf6, Grp94, and Chop) studied, four genes, including Xbp-1, sXbp-1, Chop, and Grp94, showed a trend toward downregulation in the PFC of MS group; however, none of them were significantly downregulated. On the other hand, significant downregulation in all six UPR genes was noted in the hippocampus when the control group was compared with the MS group. Under the enriched conditions, these genes did not improve, showing their ineffectiveness in reversing the changes induced by maternal separation. In conclusion, our study indicates that ELS disrupts the UPR specifically in the hippocampus, suggesting a stress-induced, region-specific molecular signature linked to depression pathophysiology. On the other hand, changes in hippocampal and prefrontal UPR gene expression remain evident in the MS-enrichment group, suggesting that environmental enrichment can improve these changes but does not fully reverse them.
Keywords: early-life stress, environmental enrichment, hippocampu, Major Depressive Disorder, Prefrontal Cortex, Unfolded Protein Response
Received: 19 Nov 2025; Accepted: 27 Jan 2026.
Copyright: © 2026 Griffin, Roy and Dwivedi. 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: Yogesh Dwivedi
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