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Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression - PubMed Skip to main page content
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. 2024 May 14:31:100643.
doi: 10.1016/j.ynstr.2024.100643. eCollection 2024 Jul.

Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression

Bente M Hofstra  1   2 , Emmy E Hoeksema  2 , Martien Jh Kas  2 , Dineke S Verbeek  1
Affiliations

Cross-species analysis uncovers the mitochondrial stress response in the hippocampus as a shared mechanism in mouse early life stress and human depression

Bente M Hofstra et al. Neurobiol Stress. .

Abstract

Depression, or major depressive disorder, poses a significant burden for both individuals and society, affecting approximately 10.8% of the general population. This psychiatric disorder leads to approximately 800,000 deaths per year. A combination of genetic and environmental factors such as early life stress (ELS) increase the risk for development of depression in humans, and a clear role for the hippocampus in the pathophysiology of depression has been shown. Nevertheless, the underlying mechanisms of depression remain poorly understood, resulting in a lack of effective treatments. To better understand the core mechanisms underlying the development of depression, we used a cross-species design to investigate shared hippocampal pathophysiological mechanisms in mouse ELS and human depression. Mice were subjected to ELS by a maternal separation paradigm, followed by RNA sequencing analysis of the adult hippocampal tissue. This identified persistent transcriptional changes linked to mitochondrial stress response pathways, with oxidative phosphorylation and protein folding emerging as the main mechanisms affected by maternal separation. Remarkably, there was a significant overlap between the pathways involved in mitochondrial stress response we observed and publicly available RNAseq data from hippocampal tissue of depressive patients. This cross-species conservation of changes in gene expression of mitochondria-related genes suggests that mitochondrial stress may play a pivotal role in the development of depression. Our findings highlight the potential significance of the hippocampal mitochondrial stress response as a core mechanism underlying the development of depression. Further experimental investigations are required to expand our understanding of these mechanisms.

Keywords: Cross-species analysis; Depression; Early life stress; Hippocampus; Maternal separation; Mitochondrial stress response; RNA-Sequencing; Transcriptome.

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Conflict of interest statement

The authors report no conflict of interest.

Figures

Fig. 1
Fig. 1
A) Timeline and visualization of the MS paradigm B) PCA analysis of batch effects between different nests. Nests are represented by symbols and rearing conditions are represented by color, red for ELS and blue for SR. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 2
Fig. 2
A) Volcano plot of DEGs. Each gene is represented by a dot. Statistical significance is illustrated by the horizontal line, biological relevance is illustrated by the vertical lines. Genes that fulfill both these parameters are represented by blue (downregulated) and red (upregulated) coloring. B) Heatmap of biologically- and significantly relevant DEGs. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 3
Fig. 3
Protein-protein interaction network and STRING analysis of all DEGs. Shapes represent biological relevance, fold change is represented by a blue (down regulated) to red (upregulated) color gradient. Node size increases with increased significance. Genes that are part of one or more enriched pathways are surrounded by a halo, in which each color corresponds to a pathway as presented in the table. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
Fig. 4
Fig. 4
Heatmap of the 20 most significantly enriched pathways for human depression and mouse MS. Significance is represented by a color gradient. (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)
See this image and copyright information in PMC

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