Chronic social defeat reduces myelination in the mouse medial prefrontal cortex

Abstract

The medial prefrontal cortex (mPFC) plays a key role in top-down control of the brain’s stress axis, and its structure and function are particularly vulnerable to stress effects, which can lead to depression in humans and depressive-like states in animals. We tested whether chronic social defeat produces structural alterations in the mPFC in mice. We first performed a microarray analysis of mPFC gene expression changes induced by defeat, and biological pathway analysis revealed a dominant pattern of down-regulation of myelin-associated genes. Indeed, 69% of the most significantly down-regulated genes were myelin-related. The down regulation was confirmed by in situ hybridization histochemistry for two strongly down-regulated genes, myelin oligodendrocyte glycoprotein (Mog) and ermin (Ermn), and by immunohistochemistry for myelin basic protein. To test for stress-induced changes in myelin integrity, aurophosphate (Black Gold) myelin staining was performed on mPFC sections. Quantitative stereologic analysis showed reduced myelinated fiber length and density. Behavioral analysis confirmed that the 14-day social defeat sessions resulted in induction of depressive-like states measured in social interaction and light/dark tests. The combined data suggest that chronic social defeat induces molecular changes that reduce myelination of the prefrontal cortex, which may be an underlying basis for stress-induced depressive states.

Adult neurogenesis and its role in brain injury and psychiatric diseases

“…Glucocorticoids have been shown to suppress the self-renewal of NSCs derived from the SEZ and the proliferation of OPCs in the white and gray matter of the adult mouse brain (Gould et al 1992;Cameron et al 1993;Alonso 2000;Hitoshi et al 2007). As expected, reduced proliferation of OPCs and subsequent loss of myelin fibers was observed in the frontal cortex of rodent MDD models following chronic stress and this reduction was rescued by treatment with antidepressants or infusion of fibroblast growth factor-2 to the lateral ventricles, which has potential antidepressant properties (Banasr et al 2007;Czeh et al 2007;Elsayed et al 2012;Lehmann et al 2017). Interestingly, the ability of antidepressants to stimulate OPC proliferation appears to be brain region-specific (Kodama et al 2004), suggesting that OPCs localized within regions associated with mood affective disorder are sensitive to chronic psychosocial stress but are also responsive to treatment.…”

“…; Lehmann et al . ). Interestingly, the ability of antidepressants to stimulate OPC proliferation appears to be brain region‐specific (Kodama et al .…”

Oligodendroglia-lineage cells in brain plasticity, homeostasis and psychiatric disorders

“…In addition to reduced cell densities [85,86] and compromised white matter integrity [87,88] within the cortex and subcortical regions in postmortem tissue collected from the schizophrenia patients, a large set of transcriptomic analyses consistently indicated alterations in myelin-related gene expression networks [89–94]. Social isolation and chronic stress, as key environmental risk factors for schizophrenia [95,96], have additionally been shown to irreversibly alter myelination in the PFC of both postnatal and adult mice [34,35,97]. Reductions in NG2-glial density in the PFC and hippocampus have also been reported in rodent models of stress [69,98,99].…”

Widespread transcriptional alternations in oligodendrocytes in the adult mouse brain following chronic stress

“…It has been increasingly appreciated that myelination and oligodendrocyte development are sensitive to stressful experience, even during adult life (Liu et al, 2012(Liu et al, , 2016Makinodan et al, 2012;Birey et al, 2015;Yang et al, 2016;Lehmann et al, 2017). Neuroimaging studies have demonstrated abnormal myelin structure and reduced oligodendrocyte function that nicely correlated with evidence of decreased oligodendrocyte-related gene expression and reduced oligodendrocyte numbers and density in postmortem human brains from subjects with psychiatric disorders, including major depressive disorder, schizophrenia, and bipolar disorder (Tkachev et al, 2003;Aston et al, 2005;Katsel et al, 2005;Takahashi et al, 2011;Tham et al, 2011;Haroutunian et al, 2014;Birey et al, 2015).…”