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  • Previous studies have shown that peripheral growth factors s


    Previous studies have shown that peripheral growth factors, such as basic epidermal growth factor, and treatments affecting peripheral cytokines can induce adult order moexipril neurogenesis and neuroprotection, as these molecules can cross the blood brain barrier and stimulate mitosis. Therefore, increases in cell proliferation markers seen 48h after stress in our study could be associated with the early phase of enhanced compensatory cell proliferation seen 4 weeks after the last defeat in SS animals by Legace et al. Taken together, our data suggest that the effects on serum molecules in the SS and SR animals may reflect changes in neuronal compensation for trauma-induced plasticity following SD stress. It should be noted however, that the majority of proteins assessed by the multiplex immunoassay are involved in inflammatory and immune-related functions. Nevertheless, despite this fact the SS and SR mice showed different profiles in proteins associated with this molecular function, underlining the methodical need to detect a diverse range of proteins in already implicated common disease pathways in the peripheral pathophysiology of depression. One of the trade-offs of high throughput screening techniques (the same is true for the LCMSE approach) is the requirement for strict correction for multiple hypothesis testing. This could mask the detection of some effects of SD (e.g. reductions in serum testosterone or corticosterone) to be detected as not significant in the current pilot study (compare Supplementary Table 2, uncorrected p-value for corticosterone in the SD group: 0.0627; FC 1.37). Interestingly, the LCMSE profiling analysis identified no changes in the frontal cortex from the SS mice. This could reflect the possibility that these mice showed few or no fronto-cortical adaptive changes to stress, or that the SD protocol resulted in macroscopic structural changes that could not be detected using our proteomics approach. In contrast, 10 proteins were found to be altered in frontal cortex tissue from the SR mice following relative quantification and these were mostly involved in synaptic or myelin-related functions. This suggests that animals failing to up-regulate such proteins may suffer negative effects associated with SD or that animals with increased synaptic and myelin density prior to the defeat procedure are more stress resistant. MBP and CN37 are markers of mature oligodendrocytes. These specialised cells are an important part of the CNS maintenance of axonal integrity and signal transduction. Frontal cortex upregulation of oligodendrogenesis has previously been linked to processes that ameliorate depression-related behaviour. Chronic unpredictable stress has been shown to decrease fronto-cortical proliferation of oligodendrocytes and to be reversible by antidepressant treatment. Additionally, electroconvulsive seizure treatment in rodents has been demonstrated to increase hippocampal and frontal cortex gliogenesis. On the other hand, chronic stress hormone exposure leads to a decrease in cortical oligodendrocyte proliferation. This is noteworthy since ACTH was only found to be significantly increased in the susceptible animals in our study, suggesting that only this group shows HPA-axis activation and subsequently develops abnormal behaviour. Increased myelination as a marker of resilience against stressors could represent an interesting translational finding. The overall frontal cortex oligodendrocyte density in post-mortem brain of depressive patients has been found to be decreased, although targeted proteomic studies suggested no expression changes of oligodendrocyte-related proteins. Future preclinical studies should investigate the time course of myelin-related pathologies following stress exposure and the possibility to rescue depressive phenotypes by pharmacological myelin enhancement. Previous studies have shown that neurons of the frontal cortex are sensitive to stress and undergo remodelling following stress exposure [reviewed in Ref. 48] which may further support our results. Additionally, the frontal cortex plays a major role in orchestrating the behavioural and systemic responses to stress and is involved in working memory, decision making, social interactions and emotional processing [reviewed in Ref. 49], which overlap with the current molecular findings. Our results suggest the intriguing possibility that resilience in this model is associated with increased oligodendrogenesis in the frontal cortex. Recently it has been shown that stress hormones increase oligodendrogenesis in the hippocampus, a limbic brain region important for memory and emotional control. Since neuronal and synaptic remodelling as well as the strength of synaptic transmission has been associated with memory and learning [reviewed in Refs. 51,52] and the frontal cortex has inhibitory control over the limbic system, the present findings suggest that the SR mice cope with traumata-induced stress by compensating for decreased hippocampal neurogenesis with increased fronto-cortical oligodendrogenesis. This is in line with findings that fronto-cortical integrity and increased frontal neuronal activity are mediators of antidepressant-like effects in SD mice. In concordance with this hypothesis Bartzokis has already suggested myelin as a central point of convergence of multiple psychotropic treatments including antidepressants. Alterations in network synchronicity and overall transmission speed have been suggested as the underlying pathophysiology. Interestingly, the frontal cortex is a particularly vulnerable brain region, as it is one of the late-myelinating areas.