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

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.

Oligodendrocyte lineage cells and depression

“…In agreement with these observations, animal studies on depression have also demonstrated that values of~30-40 genes were altered when mice were exposed to chronic unpredictable mild stress. Among them are OL-associated genes such as MBP, MOB and CNP [99][100][101]. For instance, the CNP gene encodes the enzyme 2′,3′-cyclic nucleotide 3′-phosphodiesterase (CNP), which is expressed in the development of OLs and increases with the onset of myelination and remains detectable throughout life [102].…”

Fear Deficits in HypomyelinatedTpppKnock-Out Mice

“…For motor learning, both mice subject to optogenetic stimuli and complex wheel activity display changes in myelin structure (Gibson et al, 2014;McKenzie et al, 2014;Xiao et al, 2016). In addition, mice housed in social isolation demonstrate changes in white matter (Liu et al, 2012) and mice subject to chronic social stress have decreased expression of oligodendrocyte genes and myelination (Lehmann et al, 2017;Cathomas et al, 2019). Thus, myelin plasticity may be crucial for behavioral responses to environmental changes and future studies should investigate the molecular involvement of TPPP in microtubule-based myelin structural in response to learning.…”

Adolescent maturation of the prefrontal cortex: Role of stress and sex in shaping adult risk for compromise

“…Studies of myelin after adolescent perturbations are still limited, but evidence from adult examination suggests this is an important area of study. Alterations of myelin thickness and oligodendrocyte number have been displayed following adult models of chronic stress . In adult male Sprague‐Dawley rats, 4 weeks of chronic unpredictable stress increased depressive‐like behaviors, as evidenced by a decrease of sucrose consumption.…”

“…Alterations of myelin thickness and oligodendrocyte number have been displayed following adult models of chronic stress. 63,107 In adult male Sprague-Dawley rats, 4 weeks of chronic unpredictable stress increased depressive-like behaviors, as evidenced by a decrease of sucrose consumption. This behavioral change was accompanied by a decrease in the oligodendrocyte markers MBP and oligodendrocyte transcription factor 2 (Olig2).…”