Sex-dependent differences in stress-induced depression in Wistar rats are accompanied predominantly by changes in phosphatidylcholines and sphingomyelins.

With a high annual and lifetime prevalence, depression is becoming the leading contributor to the global disease burden. During the COVID-19 crisis, the depression and mood disorders accelerated significantly. Despite the growing evidence, the precise underlying mechanisms of depression disorders (DD) remain unknown. When studying DD in humans, there are many uncontrollable factors such as medication history, age of the patient or living conditions. In this regard, animal models provide an essential step for examining neural circuitry or molecular and cellular pathways in a controlled environment. As far as we know, women have a consistently higher prevalence of DD than men. Thus, the aim of our study was to evaluate sex-related changes in blood metabolites in a model of stress-induced depression in Wistar rats. Pregnant females were stressed using restriction of mobility in the final week of the pregnancy three times a day for 45 minutes each, three following days. After the birth, the progeny aged 60 days was stressed repeatedly. The perturbation in overall energy metabolism as well as in lipid metabolism was found. While in males, phosphatidylcholines (the most phosphatidylcholine with acyl-alkyl residue sum C40:4 - PC ae C40:4), sphingomyelins, and acylcarnitines were changed, in females, lipid metabolism perturbation was seen with the most critical alteration in hydroxysphingomyelin with acyl residue sum C16:1 (SM OH C16:1). Our results confirm that the animal model may be used further in the research of depression. Our results may provide an essential insight into the sex-dependent pathogenesis of depression and contribute to the search for effective treatment and prevention of depression with respect to sex.

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

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.