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Genes Brain Behav. 2019 Jan;18(1):e12475. doi: 10.1111/gbb.12475. Epub 2018 Apr 17.

Oligodendrocyte gene expression is reduced by and influences effects of chronic social stress in mice.

Author information

1
Preclinical Laboratory for Translational Research into Affective Disorders, Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
2
Department of Psychiatry, Psychotherapy and Psychosomatics, Psychiatric Hospital, University of Zurich, Zurich, Switzerland.
3
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
4
Institute of Human Movement Sciences and Sport, ETH Zurich, Zurich, Switzerland.
5
Department of Neurogenetics, Max Planck Institute of Experimental Medicine, Goettingen, Germany.
6
Center of Neurochemistry, University of Strasbourg, UMR 7357, Strasbourg, France.
7
Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, Virginia.
8
School of Mathematics, Statistics & Applied Mathematics, National University of Ireland, Galway, Ireland.
9
Target Discovery Germany, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany.
10
CNS Diseases Research Germany, Boehringer Ingelheim Pharma GmbH & Co. KG., Biberach, Germany.

Abstract

Oligodendrocyte gene expression is downregulated in stress-related neuropsychiatric disorders, including depression. In mice, chronic social stress (CSS) leads to depression-relevant changes in brain and emotional behavior, and the present study shows the involvement of oligodendrocytes in this model. In C57BL/6 (BL/6) mice, RNA-sequencing (RNA-Seq) was conducted with prefrontal cortex, amygdala and hippocampus from CSS and controls; a gene enrichment database for neurons, astrocytes and oligodendrocytes was used to identify cell origin of deregulated genes, and cell deconvolution was applied. To assess the potential causal contribution of reduced oligodendrocyte gene expression to CSS effects, mice heterozygous for the oligodendrocyte gene cyclic nucleotide phosphodiesterase (Cnp1) on a BL/6 background were studied; a 2 genotype (wildtype, Cnp1+/- ) × 2 environment (control, CSS) design was used to investigate effects on emotional behavior and amygdala microglia. In BL/6 mice, in prefrontal cortex and amygdala tissue comprising gray and white matter, CSS downregulated expression of multiple oligodendroycte genes encoding myelin and myelin-axon-integrity proteins, and cell deconvolution identified a lower proportion of oligodendrocytes in amygdala. Quantification of oligodendrocyte proteins in amygdala gray matter did not yield evidence for reduced translation, suggesting that CSS impacts primarily on white matter oligodendrocytes or the myelin transcriptome. In Cnp1 mice, social interaction was reduced by CSS in Cnp1+/- mice specifically; using ionized calcium-binding adaptor molecule 1 (IBA1) expression, microglia activity was increased additively by Cnp1+/- and CSS in amygdala gray and white matter. This study provides back-translational evidence that oligodendrocyte changes are relevant to the pathophysiology and potentially the treatment of stress-related neuropsychiatric disorders.

KEYWORDS:

amygdala; cell deconvolution; depression; differential gene expression; gray and white matter; inflammation; mouse; myelin transcriptome; myelin-axon integrity; oligodendrocyte; social stress

PMID:
29566304
DOI:
10.1111/gbb.12475
[Indexed for MEDLINE]

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