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Endothelial dysfunction and monocyte adhesion to vascular endothelial cells are two critical steps in atherosclerosis development, and emerging evidence suggests that protein sialylation is involved in these processes. However, the mechanism underlying this phenomenon remains incompletely elucidated. In this study, we demonstrated that treatment with the proinflammatory cytokine TNF-α disrupted vascular endothelial cell-cell tight junctions and promoted monocyte endothelial cell adhesion. Western blotting and Sambucus nigra lectin (SNA) blotting analyses revealed that TNF-α treatment decreased α-2, 6-sialic acid transferase 1 (ST6Gal-I) levels and downregulated VE-Cadherin α-2, 6 sialylation. Further analysis demonstrated that TNF-α treatment upregulated β-site amyloid precursor protein enzyme 1 (BACE1) expression, thus resulting in sequential ST6Gal-I proteolytic degradation. Furthermore, our results revealed that PKC signaling cascades were involved in TNF-α-induced BACE1 upregulation. Together, these results indicated that the proinflammatory cytokine TNF-α impairs endothelial tight junctions and promotes monocyte-endothelial cell adhesion by upregulating BACE1 expression through activating PKC signaling and sequentially cleaving ST6Gal-I. Thus, inhibition of BACE1 expression may be a new approach for treating atherosclerosis.

Previous postmortem and animal studies have shown decreases in the prefrontal cortex (PFC) volume and the number of glial cells in the PFC of depression. Running exercise has been shown to alleviate depressive symptoms. However, the effects of running exercise on the medial prefrontal cortex (mPFC) volume and oligodendrocytes in the mPFC of depressed patients and animals have not been investigated. To address these issues, adult male rats were subjected to chronic unpredictable stress (CUS) for 5 weeks, followed by treadmill running for 6 weeks. Then, the mPFC volume and the mPFC oligodendrocytes were investigated using stereology, immunohistochemistry, immunofluorescence and western blotting. Using a CUS paradigm that allowed for the analysis of anhedonia, we found that running exercise alleviated the deficits in sucrose preference, as well as the decrease in the mPFC volume. Meanwhile, we found that running exercise significantly increased the number of CNPase+ oligodendrocytes and Olig2+ oligodendrocytes, reduced the ratio between Olig2+/NG2+ oligodendrocytes and Olig2+ oligodendrocytes and increased myelin basic protein (MBP), CNPase and Olig2 protein expression in the mPFC of the CUS rat model. However, running exercise did not change NG2+ oligodendrocyte number in the mPFC in these rats. These results indicated that running exercise promoted the differentiation of oligodendrocytes and myelin-forming ability in the mPFC in the context of depression. These findings suggest that the beneficial effects of running exercise on mPFC volume and oligodendrocytes in mPFC might be an important structural basis for the antidepressant effects of running exercise.

Running has been shown to improve depressive symptoms when used as an adjunct to medication. However, the mechanisms underlying the antidepressant effects of running are not fully understood. Changes of capillaries in white matter have been discovered in clinical patients and depression model rats. Considering the important part of white matter in depression, running may cause capillary structural changes in white matter. Chronic unpredictable stress (CUS) rats were provided with a 4-week running exercise (from the fifth week to the eighth week) for 20 minutes each day for 5 consecutive days each week. Anhedonia was measured by a behavior test. Furthermore, capillary changes were investigated in the control group, the CUS/Standard group, and the CUS/Running group using stereological methods. The 4-week running increased sucrose consumption significantly in the CUS/Running group and had significant effects on the total volume, total length, and total surface area of the capillaries in the white matter of depression rats. These results demonstrated that exercise-induced protection of the capillaries in white matter might be one of the structural bases for the exercise-induced treatment of depression. It might provide important parameters for further study of the vascular mechanisms of depression and a new research direction for the development of clinical antidepressant means. J. Comp. Neurol. 524:3577-3586, 2016. © 2016 Wiley Periodicals, Inc.

The antidepressive effects of exercise have been a focus of research and are hypothesized to remodel the brain networks constructed by myelinated fibers. However, whether the antidepressant effects of exercise are dependent on changes in white matter myelination are unknown. Therefore, we chose chronic unpredictable stress (CUS) as a model of depression and designed an experiment. After a 4-week CUS period, 40 animals were tested using the sucrose preference test (SPT) and the open field test (OFT). The depressed rats then underwent 4-week running exercise. Next, electron microscopy and unbiased stereological methods were used to investigate white matter changes in the rats. After the 4-week CUS stimulation, body weight, sucrose preference and scores on the OFT were significantly lower in the depression rats than in the unstressed rats (p < .05). After undergoing a 4-week running exercise, the depression rats showed a significantly greater sucrose preference than the depression control rats without running exercise (p < .05). Furthermore, the white matter parameters of the depression rats (including the white matter volumes, the length and volumes of myelinated fibers, and the volumes and thickness of the myelin sheaths) were significantly reduced after the CUS period (p < .05). However, these white matter parameters were significantly increased after running exercise (p < .05). The present study is the first to provide evidence that running exercise has positive effects on white matter and the myelinated fibers of white matter in depressed rats, and this evidence might provide an important theoretical basis for the exercise-mediated treatment of depression.

Running exercise is an effective method to improve depressive symptoms when combined with drugs. However, the underlying mechanisms are not fully clear. Cerebral blood flow perfusion in depressed patients is significantly lower in the hippocampus. Physical activity can achieve cerebrovascular benefits. The purpose of this study was to evaluate the impacts of running exercise on capillaries in the hippocampal CA1 and dentate gyrus (DG) regions. The chronic unpredictable stress (CUS) depression model was used in this study. CUS rats were given 4 weeks of running exercise from the fifth week to the eighth week (20 min every day from Monday to Friday each week). The sucrose consumption test was used to measure anhedonia. Furthermore, stereological methods were used to investigate the capillary changes among the control group, CUS/Standard group and CUS/Running group. Sucrose consumption significantly increased in the CUS/Running group. Running exercise has positive effects on the capillaries parameters in the hippocampal CA1 and DG regions, such as the total volume, total length and total surface area. These results demonstrated that capillaries are protected by running exercise in the hippocampal CA1 and DG might be one of the structural bases for the exercise-induced treatment of depression-like behavior. These results suggest that drugs and behavior influence capillaries and may be considered as a new means for depression treatment in the future.