CircSYNDIG1 ameliorates stress-induced abnormal behaviors by suppressing miR-344-5p in mice

Wang, Xi; Song, Han Ho; Du, Yuru; Zhao, Ye; Fu, Yan; Meng, Qingyu; Gao, Yuan; Gong, Miao; Li, Song; Wang, Sheng; Yuan, Fang; Shi, Yun; Shi, Haishui

doi:10.1016/j.brainresbull.2023.02.010

Cited by 6 publications

(2 citation statements)

References 44 publications

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“…The TST was conducted according to the methods described in previous reports (Wang et al., 2023 ). The tail of each mouse was fixed with adhesive tape, and the mice were hung 40 cm above the floor for 6 min.…”

Section: Methodsmentioning

confidence: 99%

Dulaglutide treatment reverses depression‐like behavior and hippocampal metabolomic homeostasis in mice exposed to chronic mild stress

Jin,

Zhang,

Huang

et al. 2024

Brain and Behavior

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IntroductionTreatment strategies for depression based on interventions for glucose and lipid metabolism disorders are receiving increasing attention. Investigating the mechanism of their antidepressant effect and exploring new diagnostic and therapeutic biomarkers have attracted increasing attention. Dulaglutide, a long‐acting GLP‐1 receptor agonist, has been reported to alleviate cognitive deficits and neuronal damage. However, the antidepressant effect of dulaglutide and, especially, the underlying mechanism are still poorly understood. In this study, we aimed to explore the underlying biomarkers of depression and potential modulatory targets of dulaglutide in chronic mild stress (CMS) mice.MethodsSixty mice were randomly divided into a control group (CON group), a CMS+Vehicle group (CMS+Veh group), a CMS+0.3 mg/kg dulaglutide group (Low Dula group), and a CMS+0.6 mg/kg dulaglutide group (High Dula group). Numerous behavioral tests, mainly the open field test, forced swimming test, and tail suspension test, were applied to evaluate the potential effect of dulaglutide treatment on anxiety‐ and depression‐like behaviors in mice exposed to chronic stress. Furthermore, a liquid chromatography–tandem mass spectrometry‐based metabolomics approach was utilized to investigate the associated mechanisms of dulaglutide treatment.ResultsThree weeks of dulaglutide treatment significantly reversed depressive‐like but not anxiety‐like behaviors in mice exposed to chronic stress for 4 weeks. The results from the metabolomics analysis showed that a total of 20 differentially expressed metabolites were identified between the CON and CMS+Veh groups, and 46 metabolites were selected between the CMS+Veh and High Dula groups in the hippocampus of the mice. Comprehensive analysis indicated that lipid metabolism, amino acid metabolism, energy metabolism, and tryptophan metabolism were disrupted in model mice that experienced depression and underwent dulaglutide therapy.ConclusionThe antidepressant effects of dulaglutide in a CMS depression model were confirmed. We identified 64 different metabolites and four major pathways associated with metabolic pathophysiological processes. These primary data provide a new perspective for understanding the antidepressant‐like effects of dulaglutide and may facilitate the use of dulaglutide as a potential therapeutic strategy for depression.

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Section: Methodsmentioning

confidence: 99%

Dulaglutide treatment reverses depression‐like behavior and hippocampal metabolomic homeostasis in mice exposed to chronic mild stress

Jin,

Zhang,

Huang

et al. 2024

Brain and Behavior

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“…Zhou et al showed that ceRNAs (circRNA-miRNA-mRNA and lncRNA-miRNA-mRNA) are differentially expressed in patients with depression and normal people, and they can be used as biomarkers for depression [ 148 , 149 ]. Xi Wang et al found that by inhibiting miR-344-5p, CircSYNDIG1 reduced the aberrant behaviors induced by stress in mice [ 150 ]. By regulating the miR-497a-5p/HECTD1 axis, Circ-Bnc2 mitigates neuroinflammation in LPS-stimulated microglial cells to prevent neuronal cell death, thereby impacting depression [ 151 ].…”

Section: Interconnections Between Ncrnas In Depressionmentioning

confidence: 99%

The role of ncRNAs in depression

Luan,

Xing,

Guo

et al. 2024

Heliyon

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CircSpna2 attenuates cuproptosis by mediating ubiquitin ligase Keap1 to regulate the Nrf2‐Atp7b signalling axis in depression after traumatic brain injury in a mouse model

Du,

Fu,

Zhang

et al. 2024

Clinical & Translational Med

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BackgroundDepression is a common but often overlooked consequence in individuals with post‐traumatic brain injury (TBI). Circular RNAs (circRNAs) play essential roles in the nervous system, yet their involvement in the cell death mechanism known as cuproptosis and in TBI‐related depression remains unclear.ObjectivesThis study aimed to investigate the role of circRNA, specifically circSpna2, in the regulation of cuproptosis and its association with depression in TBI patients.MethodsRNA sequencing (RNA‐Seq) was used to assess the differential expression of circRNAs. Depression was evaluated using subjective and objective rating scales, and circSpna2 expression levels in plasma were measured. Further functional experiments were conducted in TBI mouse models, including knockdown and overexpression of circSpna2, to explore its impact on the Keap1‐Nrf2‐Atp7b pathway and cuproptosis.ResultsTBI patients exhibited decreased levels of circSpna2, which correlated with depression (p < 0.0001). Knocking down circSpna2 in TBI mice aggravated depression‐like symptoms (p < 0.0001). Mechanistically, circSpna2 was found to bind ubiquitin ligase Keap1, modulating the Nrf2‐Atp7b signaling pathway and influencing cuproptosis (docking score: −331.88). Overexpression of circSpna2 alleviated cuproptosis after TBI through the Keap1/Nrf2/Atp7b axis.ConclusionsCircSpna2 plays a regulatory role in cuproptosis and may serve as a novel biomarker and therapeutic target for depression following TBI. Enhancing circSpna2 expression could mitigate depression after TBI by modulating the Keap1/Nrf2/Atp7b pathway.Key pointsThis study explores the role of circSpna2 in depression following traumatic brain injury (TBI). It was found that circSpna2 is significantly downregulated in TBI patients, and its expression levels correlate with depressive symptoms. In TBI mouse models, overexpression of circSpna2 alleviated depression‐like behaviours, while its knockdown exacerbated these symptoms, suggesting its potential as both a biomarker and a therapeutic target for post‐TBI depression. Mechanistically, circSpna2 regulates the Nrf2‐Atp7b signalling pathway by binding to the DGR domain of Keap1, which prevents Nrf2 ubiquitination and enhances Nrf2 activity. This in turn promotes the transcription of Atp7b, a copper transport protein, helping to maintain copper homeostasis and mitigate copper‐induced oxidative stress, a key driver of cell death (cuproptosis). The overexpression of circSpna2 also improved mitochondrial function and synaptic integrity, which are typically impaired by copper dysregulation. These findings highlight the therapeutic potential of circSpna2 in managing TBI‐related depression through the regulation of oxidative stress and copper homeostasis.

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CircSYNDIG1 ameliorates stress-induced abnormal behaviors by suppressing miR-344-5p in mice

Cited by 6 publications

References 44 publications

Dulaglutide treatment reverses depression‐like behavior and hippocampal metabolomic homeostasis in mice exposed to chronic mild stress

Dulaglutide treatment reverses depression‐like behavior and hippocampal metabolomic homeostasis in mice exposed to chronic mild stress

The role of ncRNAs in depression

CircSpna2 attenuates cuproptosis by mediating ubiquitin ligase Keap1 to regulate the Nrf2‐Atp7b signalling axis in depression after traumatic brain injury in a mouse model

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