Abstract
BackgroundNeuroinflammation occupies a pivotal position in the pathogenesis of most nervous system diseases, including depression. However, the underlying molecular mechanisms of neuroinflammation associated with neuronal injury in depression remain largely uncharacterized. Therefore, identifying potential molecular mechanisms and therapeutic targets would serve to better understand the progression of this condition.MethodsChronic unpredictable stress (CUS) was used to induce depression-like behaviors in rats. RNA-sequencing was used to detect the differentially expressed microRNAs. Stereotactic injection of AAV virus to overexpress or knockdown the miR-204-5p. The oxidative markers and inflammatory related proteins were verified by immunoblotting or immunofluorescence assay. The oxidative stress enzyme and products were verified using enzyme-linked assay kit. Electron microscopy analysis was used to observe the synapse and ultrastructural pathology. Finally, electrophysiological recording was used to analyze the synaptic transmission.ResultsHere, we found that the expression of miR-204-5p within the hippocampal dentate gyrus (DG) region of rats was significantly down-regulated after chronic unpredicted stress (CUS), accompanied with the oxidative stress-induced neuronal damage within DG region of these rats. In contrast, overexpression of miR-204-5p within the DG region of CUS rats alleviated oxidative stress and neuroinflammation by directly targeting the regulator of G protein signaling 12 (RGS12), effects which were accompanied with amelioration of depressive-like behaviors in these CUS rats. In addition, down-regulation of miR-204-5p induced neuronal deterioration in DG regions and depressive-like behaviors in rats.ConclusionTaken together, these results suggest that miR-204-5p plays a key role in regulating oxidative stress damage in CUS-induced pathological processes of depression. Such findings provide evidence of the involvement of miR-204-5p in mechanisms underlying oxidative stress associated with depressive phenotype.Graphical
Highlights
Neuroinflammation occupies a pivotal position in the pathogenesis of most nervous system diseases, including depression
Oxidative damage was enhanced in specific brain regions of chronic unpredicted stress (CUS) rats Depression is usually accompanied by neuronal damage to specific brain regions and the production of excessive Reactive oxygen species (ROS), which can lead to inflammation and cell apoptosis
After 4–6 weeks of CUS stimulation, the immobility time of CUS rats significantly increased in the forced swimming test (P < 0.0001), and the sucrose preference test confirmed that the CUS rats were experiencing anhedonia (P < 0.0001) which indicated depression-like behavior of rat (Fig. 1A)
Summary
Neuroinflammation occupies a pivotal position in the pathogenesis of most nervous system diseases, including depression. Results from clinical studies have provided evidence of oxidative stress damage in the brain and peripheral blood of patients with depression [9, 10]. This link between oxidative stress and depression represents a significant issue underlying a better understanding of the pathophysiology of depression. By regulating relative changes in miRNA levels involved with pathological processes, there is a possibility to reduce pathological damage and achieve a level of neuroprotection [15] In this way, the elucidation of interactive mechanisms among oxidative stress, miRNAs and their targeted genes, as associated with specific neurological diseases, would be of great significance for a targeted treatment of these disorders
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