scholarly journals The Mitochondrial Antioxidant Sirtuin3 Cooperates with Lipid Metabolism to Safeguard Neurogenesis in Aging and Depression

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 90
Author(s):  
Sónia Sá Santos ◽  
João B. Moreira ◽  
Márcia Costa ◽  
Rui S. Rodrigues ◽  
Ana M. Sebastião ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Chronic Mild Stress ◽  
Adult Brain ◽  
Mild Stress ◽  
Differentiation Potential ◽  
Mitochondrial Oxidative Stress ◽  
Tert Butyl Hydroperoxide ◽  
Chain Acyl ◽  
Oxidative Protection

Neural stem cells (NSCs), crucial for memory in the adult brain, are also pivotal to buffer depressive behavior. However, the mechanisms underlying the boost in NSC activity throughout life are still largely undiscovered. Here, we aimed to explore the role of deacetylase Sirtuin 3 (SIRT3), a central player in mitochondrial metabolism and oxidative protection, in the fate of NSC under aging and depression-like contexts. We showed that chronic treatment with tert-butyl hydroperoxide induces NSC aging, markedly reducing SIRT3 protein. SIRT3 overexpression, in turn, restored mitochondrial oxidative stress and the differentiation potential of aged NSCs. Notably, SIRT3 was also shown to physically interact with the long chain acyl-CoA dehydrogenase (LCAD) in NSCs and to require its activation to prevent age-impaired neurogenesis. Finally, the SIRT3 regulatory network was investigated in vivo using the unpredictable chronic mild stress (uCMS) paradigm to mimic depressive-like behavior in mice. Interestingly, uCMS mice presented lower levels of neurogenesis and LCAD expression in the same neurogenic niches, being significantly rescued by physical exercise, a well-known upregulator of SIRT3 and lipid metabolism. Our results suggest that targeting NSC metabolism, namely through SIRT3, might be a suitable promising strategy to delay NSC aging and confer stress resilience.

scholarly journals Microstructural and Metabolic Recovery of Anhedonic Rat Brains: An In Vivo Diffusion MRI and 1H-MRS Approach

Data ◽  
2018 ◽  
Vol 3 (3) ◽  
pp. 29 ◽  
Author(s):  
Ahmad Khan ◽  
Sune Jespersen ◽  
Ove Wiborg ◽  
Christopher Kroenke ◽  
Brian Hansen
Keyword(s):  
Diffusion Mri ◽  
Imaging System ◽  
Chronic Mild Stress ◽  
Ventral Hippocampus ◽  
Control Group ◽  
Mild Stress ◽  
1H Mrs ◽  
Unpredictable Chronic Mild Stress ◽  
The Brain

This article presents longitudinal 1H-MR Spectroscopy (1H-MRS) data from ventral hippocampus and in vivo diffusion MRI (dMRI) data of the brain from control and anhedonic rats. The 1H-MRS and dMRI data were acquired using a 9.4 T preclinical imaging system. Before MRI experiments, animals were exposed to unpredictable chronic mild stress exposure for eight weeks and on the basis of a sucrose consumption test were identified as anhedonic and resilient. An age-matched group of animals, unexposed to the unpredictable chronic mild stress paradigm was considered as control. Data was acquired at the age of 18, 20 and 25 weeks in the anhedonic group and at the age of 18 and 22 weeks in the control group. This multimodal MRI data provides metabolic information of ventral hippocampus and dMRI based microstructural parameters of the brain.

scholarly journals Overexpression of Nudt7 decreases bile acid levels and peroxisomal fatty acid oxidation in the liver

2019 ◽  
Vol 60 (5) ◽  
pp. 1005-1019 ◽  
Author(s):  
Stephanie A. Shumar ◽  
Evan W. Kerr ◽  
Paolo Fagone ◽  
Aniello M. Infante ◽  
Roberta Leonardi
Keyword(s):  
Fatty Acid ◽  
Lipid Metabolism ◽  
Bile Acid ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Nudix Hydrolase ◽  
Peroxisomal Fatty Acid Oxidation ◽  
Chain Acyl ◽  
Peroxisomal Fatty Acid

Lipid metabolism requires CoA, an essential cofactor found in multiple subcellular compartments, including the peroxisomes. In the liver, CoA levels are dynamically adjusted between the fed and fasted states. Elevated CoA levels in the fasted state are driven by increased synthesis; however, this also correlates with decreased expression of Nudix hydrolase (Nudt)7, the major CoA-degrading enzyme in the liver. Nudt7 resides in the peroxisomes, and we overexpressed this enzyme in mouse livers to determine its effect on the size and composition of the hepatic CoA pool in the fed and fasted states. Nudt7 overexpression did not change total CoA levels, but decreased the concentration of short-chain acyl-CoAs and choloyl-CoA in fasted livers, when endogenous Nudt7 activity was lowest. The effect on these acyl-CoAs correlated with a significant decrease in the hepatic bile acid content and in the rate of peroxisomal fatty acid oxidation, as estimated by targeted and untargeted metabolomics, combined with the measurement of fatty acid oxidation in intact hepatocytes. Identification of the CoA species and metabolic pathways affected by the overexpression on Nudt7 in vivo supports the conclusion that the nutritionally driven modulation of Nudt7 activity could contribute to the regulation of the peroxisomal CoA pool and peroxisomal lipid metabolism.

scholarly journals Ginsenoside Rb1 Induces a Pro-Neurogenic Microglial Phenotype via PPARγ Activation in Male Mice Exposed to Chronic Mild Stress

2021 ◽  
Author(s):  
Zili You ◽  
Lijuan Zhang ◽  
Minmin Tang ◽  
Xiaofang Xie ◽  
Qiuying Zhao ◽  
...  
Keyword(s):  
Chronic Mild Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Immunofluorescence Staining ◽  
Mild Stress ◽  
Ginsenoside Rb1 ◽  
Male Mice ◽  
Antidepressant Effects

Abstract BackgroundAnti-inflammatory approaches are emerging as a new strategy for treatment of depressive disorders. Ginsenoside Rb1 (GRb1), a major component of Panax ginseng, can inhibit inflammatory cascade and alleviate depressive behaviors. Microglia can promote or inhibit adult hippocampal neurogenesis according to their functional phenotypes. Here, we examined whether GRb1 may exert antidepressant effects by promoting a pro-neurogenic phenotype of microglia and thereby increasing neurogenesis. MethodsThe antidepressant effects of GRb1 or the licensed antidepressant imipramine (IMI) were assessed in chronic mild stress (CMS)-exposed male mice. The depressive-like behaviors of mice were evaluated by sucrose preference test, forced swimming test (FST), and tail suspension test (TST). The microglial phenotypes were identified by molecular markers and morphological properties, analyzed by RT-qPCR, western blotting and immunofluorescence staining. Effect of GRb1-treated microglia on adult hippocampal neurogenesis in vivo and in vitro were detected using immunofluorescence staining. ResultsBehavioral assessment indicated that GRb1 or IMI treatment alleviated depressive-like behaviors in CMS-exposed mice. Immunofluorescence examinationdemonstrated that GRb1 induced a pro-neurogenic phenotype of microglia via activating PPARγ in vivo and in vitro, which were reversed by PPARγ inhibitor GW9662. In addition, GRb1-treated microglia increased the proliferation and differentiation of neural precursor cells.ConclusionsThese findings demonstrated that GRb1 alleviated depressive-like behaviors of CMS-exposed male mice mainly through PPARγ-mediated microglial activation and improvement of adult hippocampus neurogenesis.

scholarly journals Antidepression action of BDNF requires and is mimicked by Gαi1/3 expression in the hippocampus

2018 ◽  
Vol 115 (15) ◽  
pp. E3549-E3558 ◽  
Author(s):  
John Marshall ◽  
Xiao-zhong Zhou ◽  
Gang Chen ◽  
Su-qing Yang ◽  
Ya Li ◽  
...  
Keyword(s):  
Hippocampal Neurons ◽  
Adaptor Protein ◽  
Chronic Mild Stress ◽  
Mapk Signaling ◽  
Mild Stress ◽  
Limbic Structure ◽  
Double Knockout ◽  
Bdnf Expression ◽  
Functional Studies

Stress-related alterations in brain-derived neurotrophic factor (BDNF) expression, a neurotrophin that plays a key role in synaptic plasticity, are believed to contribute to the pathophysiology of depression. Here, we show that in a chronic mild stress (CMS) model of depression the Gαi1 and Gαi3 subunits of heterotrimeric G proteins are down-regulated in the hippocampus, a key limbic structure associated with major depressive disorder. We provide evidence that Gαi1 and Gαi3 (Gαi1/3) are required for the activation of TrkB downstream signaling pathways. In mouse embryonic fibroblasts (MEFs) and CNS neurons, Gαi1/3 knockdown inhibited BDNF-induced tropomyosin-related kinase B (TrkB) endocytosis, adaptor protein activation, and Akt–mTORC1 and Erk–MAPK signaling. Functional studies show that Gαi1 and Gαi3 knockdown decreases the number of dendrites and dendritic spines in hippocampal neurons. In vivo, hippocampal Gαi1/3 knockdown after bilateral microinjection of lentiviral constructs containing Gαi1 and Gαi3 shRNA elicited depressive behaviors. Critically, exogenous expression of Gαi3 in the hippocampus reversed depressive behaviors in CMS mice. Similar results were observed in Gαi1/Gαi3 double-knockout mice, which exhibited severe depressive behaviors. These results demonstrate that heterotrimeric Gαi1 and Gαi3 proteins are essential for TrkB signaling and that disruption of Gαi1 or Gαi3 function could contribute to depressive behaviors.

scholarly journals Ginsenoside Rb1 induces a pro-neurogenic microglial phenotype via PPARγ activation in male mice exposed to chronic mild stress

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lijuan Zhang ◽  
Minmin Tang ◽  
Xiaofang Xie ◽  
Qiuying Zhao ◽  
Nan Hu ◽  
...  
Keyword(s):  
Chronic Mild Stress ◽  
Hippocampal Neurogenesis ◽  
Adult Hippocampal Neurogenesis ◽  
Immunofluorescence Staining ◽  
Mild Stress ◽  
Ginsenoside Rb1 ◽  
Male Mice ◽  
Antidepressant Effects

Abstract Background Anti-inflammatory approaches are emerging as a new strategy for the treatment of depressive disorders. Ginsenoside Rb1 (GRb1), a major component of Panax ginseng, can inhibit inflammatory cascade and alleviate depressive-like behaviors. Microglia can promote or inhibit adult hippocampal neurogenesis according to their functional phenotypes. Here, we examine whether GRb1 may exert antidepressant effects by promoting a pro-neurogenic phenotype of microglia and thereby increasing neurogenesis. Methods The antidepressant effects of GRb1 or the licensed antidepressant imipramine (IMI) were assessed in chronic mild stress (CMS)-exposed male mice. The depressive-like behaviors of mice were evaluated by sucrose preference test, forced swimming test (FST), and tail suspension test (TST). The microglial phenotypes were identified by pro- and anti-inflammatory cytokine expression and morphological properties, analyzed by RT-qPCR, western blotting, and immunofluorescence staining. The effect of GRb1-treated microglia on adult hippocampal neurogenesis in vivo and in vitro was detected using immunofluorescence staining. Results Behavioral assessment indicated that GRb1 or IMI treatment alleviated depressive-like behaviors in CMS-exposed mice. Immunofluorescence examination demonstrated that GRb1 induced a pro-neurogenic phenotype of microglia via activating PPARγ in vivo and in vitro, which were effectively reversed by the PPARγ inhibitor GW9662. In addition, GRb1-treated microglia increased the proliferation and differentiation of neural precursor cells. Conclusions These findings demonstrated that GRb1 alleviated depressive-like behaviors of CMS-exposed male mice mainly through PPARγ-mediated microglial activation and improvement of adult hippocampus neurogenesis.

scholarly journals Involvement of Scratch2 in GalR1-mediated depression-like behaviors in the rat ventral periaqueductal gray

2021 ◽  
Vol 118 (24) ◽  
pp. e1922586118
Author(s):  
Yutao Yang ◽  
Yueting Li ◽  
Bo Liu ◽  
Chenchen Li ◽  
Zijin Liu ◽  
...  
Keyword(s):  
Promoter Activity ◽  
Chronic Mild Stress ◽  
Periaqueductal Gray ◽  
Upstream Region ◽  
Mild Stress ◽  
Behavioral Experiments ◽  
E Box ◽  
Elevated Expression

Galanin receptor1 (GalR1) transcript levels are elevated in the rat ventral periaqueductal gray (vPAG) after chronic mild stress (CMS) and are related to depression-like behavior. To explore the mechanisms underlying the elevated GalR1 expression, we carried out molecular biological experiments in vitro and in animal behavioral experiments in vivo. It was found that a restricted upstream region of the GalR1 gene, from −250 to −220, harbors an E-box and plays a negative role in the GalR1 promoter activity. The transcription factor Scratch2 bound to the E-box to down-regulate GalR1 promoter activity and lower expression levels of the GalR1 gene. The expression of Scratch2 was significantly decreased in the vPAG of CMS rats. Importantly, local knockdown of Scratch2 in the vPAG caused elevated expression of GalR1 in the same region, as well as depression-like behaviors. RNAscope analysis revealed that GalR1 mRNA is expressed together with Scratch2 in both GABA and glutamate neurons. Taking these data together, our study further supports the involvement of GalR1 in mood control and suggests a role for Scratch2 as a regulator of depression-like behavior by repressing the GalR1 gene in the vPAG.

scholarly journals Chronic mild stress alters synaptic plasticity in the nucleus accumbens through GSK3β-dependent modulation of Kv4.2 channels

2020 ◽  
Vol 117 (14) ◽  
pp. 8143-8153 ◽  
Author(s):  
Giuseppe Aceto ◽  
Claudia Colussi ◽  
Lucia Leone ◽  
Salvatore Fusco ◽  
Marco Rinaudo ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Nucleus Accumbens ◽  
Viral Vector ◽  
Glycogen Synthase ◽  
Chronic Mild Stress ◽  
Long Term Potentiation ◽  
Spike Timing ◽  
Mild Stress

Although major depressive disorder (MDD) is highly prevalent, its pathophysiology is poorly understood. Recent evidence suggests that glycogen-synthase kinase 3β (GSK3β) plays a key role in memory formation, yet its role in mood regulation remains controversial. Here, we investigated whether GSK3β activity in the nucleus accumbens (NAc) is associated with depression-like behaviors and synaptic plasticity. We performed whole-cell patch-clamp recordings of medium spiny neurons (MSNs) in the NAc and determined the role of GSK3β in spike timing-dependent long-term potentiation (tLTP) in the chronic unpredictable mild stress (CUMS) mouse model of depression. To assess the specific role of GSK3β in tLTP, we used in vivo genetic silencing by an adeno-associated viral vector (AAV2) short hairpin RNA against GSK3β. In addition, we examined the role of the voltage-gated potassium Kv4.2 subunit, a molecular determinant of A-type K+currents, as a potential downstream target of GSK3β. We found increased levels of active GSK3β and augmented tLTP in CUMS mice, a phenotype that was prevented by selective GSK3β knockdown. Furthermore, knockdown of GSK3β in the NAc ameliorated depressive-like behavior in CUMS mice. Electrophysiological, immunohistochemical, biochemical, and pharmacological experiments revealed that inhibition of the Kv4.2 channel through direct phosphorylation at Ser-616 mediated the GSK3β-dependent tLTP changes in CUMS mice. Our results identify GSK3β regulation of Kv4.2 channels as a molecular mechanism of MSN maladaptive plasticity underlying depression-like behaviors and suggest that the GSK3β–Kv4.2 axis may be an attractive therapeutic target for MDD.

scholarly journals Stress and behavioral correlates in the head-fixed method

2020 ◽  
Author(s):  
Konrad Juczewski ◽  
Jonathan A. Koussa ◽  
Andrew J. Kesner ◽  
Jeong O. Lee ◽  
David M. Lovinger
Keyword(s):  
Neural Circuits ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Behavioral Experiments ◽  
Behavioral Correlates ◽  
Blood Samples ◽  
Head Fixation ◽  
Freely Moving

AbstractHead-fixation of awake rodents is a method that allows for sophisticated investigation and manipulation of neural circuits in vivo, that would otherwise be impossible in completely freely moving animals. However, while it is known that head-fixation induces stress, its scale and habituation dynamics remain unclear. Thus, interpretation of physiological and behavioral experiments would greatly benefit from the characterization of the stress response. In our study, we used the Mobile HomeCage system (Neurotar, Finland) where animals are head-fixed to an aluminum frame, but otherwise freely moving in an ultralight carbon container floating above an air-dispensing base. To better understand this experimental environment, we analyzed locomotion and stress during an extended habituation protocol. For 25 consecutive days, mice were prepared as they would be for recording experiments, i.e. head-fixed while standing on the air-lifted platform for 2 hours per day. Throughout 25 days, blood samples were taken periodically from the tail vein to measure variation in the stress-related hormone, corticosterone. These data were compared and contrasted with behavioral data including locomotion during the 2-hours head-fixed habituation sessions and several classical behavioral measurements known to be affected by chronic mild stress.

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