Ribosomal protein S6 kinase 1 signaling in prefrontal cortex controls depressive behavior

Current treatments for major depressive disorder (MDD) have a time lag and are ineffective for a large number of patients. Development of novel pharmacological therapies requires a comprehensive understanding of the molecular events that contribute to MDD pathophysiology. Recent evidence points toward aberrant activity of synaptic proteins as a critical contributing factor. In the present studies, we used viral-mediated gene transfer to target a key mediator of activity-dependent synaptic protein synthesis downstream of mechanistic target of rapamycin complex 1 (mTORC1) known as p70 S6 kinase 1 (S6K1). Targeted delivery of two mutants of S6K1, constitutively active or dominant-negative, to the medial prefrontal cortex (mPFC) of rats allowed control of the mTORC1/S6K1 translational pathway. Our results demonstrate that increased expression of S6K1 in the mPFC produces antidepressant effects in the forced swim test without altering locomotor activity. Moreover, expression of active S6K1 in the mPFC blocked the anhedonia caused by chronic stress, resulting in a state of stress resilience. This antidepressant response was associated with increased neuronal complexity caused by enhanced S6K1 activity. Conversely, expression of dominant-negative S6K1 in the mPFC resulted in prodepressive behavior in the forced swim test and was sufficient to cause anhedonia in the absence of chronic stress exposure. Together, these data demonstrate a critical role for S6K1 activity in depressive behaviors, and suggest that pathways downstream of mTORC1 may underlie the pathophysiology and treatment of MDD.

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Standardised ginseng extract G115® potentiates the antidepressant-like properties of fluoxetine in the forced swim test

Acta Neuropsychiatrica ◽

10.1017/neu.2021.2 ◽

2021 ◽

pp. 1-7

Author(s):

Dylan J. Terstege ◽

Debra S. MacDonald ◽

R. Andrew Tasker

Keyword(s):

Prefrontal Cortex ◽

Forced Swim Test ◽

Ginseng Root ◽

Group Differences ◽

Post Mortem ◽

Ginseng Extract ◽

Significant Group ◽

Swim Test ◽

Forced Swim ◽

Plus Maze

Abstract Objective: Ginsenosides, biologically active components of the root of Panax ginseng, have been reported to have therapeutic benefits in a number of disease states including psychiatric conditions such as major depressive disorder. Our objective was to determine if a standardised commercial ginseng extract, G115®, could reduce the signs of behavioural despair commonly observed in animal models of depression either alone or in combination with the selective serotonin reuptake inhibitor (SSRI) fluoxetine. Methods: Male Sprague-Dawley (SD) rats (N = 51) were divided into four groups: vehicle control, G115® ginseng root extract, fluoxetine and fluoxetine plus G115®. Rats were trained to voluntarily consume treatments twice daily for 14 days and were then tested in an open field (OF), elevated plus maze (EPM) and forced swim test (FST). Post-mortem hippocampal and prefrontal cortex tissue was analysed for expression of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase B (TrkB) by western blot. Results: One-way Analysis of Variance revealed no significant group differences in the OF or plus-maze performance on any variable examined. In the FST, fluoxetine significantly reduced immobility time and increased latency to immobility. The effects of fluoxetine were further significantly potentiated by co-administration of G115®. Post-mortem tissue analysis revealed significant group differences in BDNF expression in the left hippocampus and left prefrontal cortex without any accompanying changes in TrkB expression. Conclusions: We conclude that oral G115® significantly potentiates the antidepressant-like effect of fluoxetine in the FST in the absence of potentially confounding effects on locomotion and anxiety.

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Antidepressant-like effects induced by NMDA receptor blockade and NO synthesis inhibition in the ventral medial prefrontal cortex of rats exposed to the forced swim test

Psychopharmacology ◽

10.1007/s00213-014-3853-2 ◽

2015 ◽

Vol 232 (13) ◽

pp. 2263-2273 ◽

Cited By ~ 18

Author(s):

Vitor Silva Pereira ◽

Angélica Romano ◽

Gregers Wegener ◽

Sâmia R. L. Joca

Keyword(s):

Prefrontal Cortex ◽

Nmda Receptor ◽

Medial Prefrontal Cortex ◽

Forced Swim Test ◽

Receptor Blockade ◽

Synthesis Inhibition ◽

Swim Test ◽

Ventral Medial Prefrontal Cortex ◽

Forced Swim ◽

Nmda Receptor Blockade

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P.1.d.008 The involvement of an intact prefrontal cortex–hippocampal circuit in the forced swim test in male and female rats

European Neuropsychopharmacology ◽

10.1016/s0924-977x(12)70267-5 ◽

2012 ◽

Vol 22 ◽

pp. S186

Author(s):

V. Kafetzopoulos ◽

N. Kokras ◽

C. Dalla ◽

T. Mavridis ◽

Z. Papadopoulou-Daifoti

Keyword(s):

Prefrontal Cortex ◽

Forced Swim Test ◽

Female Rats ◽

Male And Female ◽

Swim Test ◽

Forced Swim ◽

Male And Female Rats

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Data on the effect of maternal separation coupled with social isolation in a forced swim test and gene expression of glial fibrillary acid protein in the prefrontal cortex of rats

Data in Brief ◽

10.1016/j.dib.2018.03.055 ◽

2018 ◽

Vol 18 ◽

pp. 496-500 ◽

Cited By ~ 2

Author(s):

Yosuke Yamawaki ◽

Misako Nishida ◽

Kana Harada ◽

Hiroyuki Akagi

Keyword(s):

Gene Expression ◽

Prefrontal Cortex ◽

Social Isolation ◽

Maternal Separation ◽

Forced Swim Test ◽

Glial Fibrillary Acid Protein ◽

Swim Test ◽

Forced Swim ◽

Acid Protein

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The antidepressant effects of asperosaponin VI are mediated by the suppression of microglial activation and reduction of TLR4/NF-ĸB induced IDO expression

10.1101/2020.03.15.992529 ◽

2020 ◽

Author(s):

Jinqiang Zhang ◽

Saini Yi ◽

Yahui Li ◽

Chenghong Xiao ◽

Chan Liu ◽

...

Keyword(s):

Prefrontal Cortex ◽

Signaling Pathway ◽

Microglial Activation ◽

Forced Swim Test ◽

Kynurenine Pathway ◽

Antidepressant Effect ◽

Dependent Manner ◽

Swim Test ◽

Forced Swim ◽

Glutamate Transmission

AbstractAimIndoleamine 2, 3-dioxygenase (IDO) is responsible for the progression of the kynurenine pathway, which has been implicated in the pathophysiology of inflammation-induced depression. It has been reported that asperosaponin VI (ASA VI) could play a neuroprotective role through anti-inflammatory and antioxidant. In this study, we examined the antidepressant effect of ASA VI in LPS-treated mice and further explored its molecular mechanism by insight into the microglial kynurenine pathway.MethodsTo produce the model, lipopolysaccharide (LPS) (0.83 mg/kg) was administered intraperitoneally to mice. The mice received ASA VI (10 mg/kg, 20mg/kg, 40mg/kg and 80mg/kg, i.p.) thirty minutes prior to LPS injection. Depressive-like behaviors were evaluated based on the duration of immobility in the forced swim test. Microglial activation and inflammatory cytokines were detected by immunohistochemistry, real-time PCR and ELISA. The TLR4/NF-ĸB signaling pathway and the expression of IDO, GluA2, and CamKIIβ were measured by western blotting.ResultsASA VI demonstrated significant antidepressant activity in the presence of LPS on immobility and latency times in the forced swim test. The LPS-induced activation of microglia and inflammatory response were inhabited by ASA VI in a dose-dependent manner. TLR4/NF-κB signaling pathway also was suppressed by ASA VI in the hippocampus and prefrontal cortex of LPS-treated mice. Furthermore, ASA VI inhibited the increase in IDO protein expression and normalized the aberrant glutamate transmission in the hippocampus and prefrontal cortex as a result of LPS administration.ConclusionOur results propose a promising antidepressant effect for ASA VI possibly through the downregulation of IDO expression and normalization of the aberrant glutamate transmission. This remedying effect of ASA VI could be attributed to suppress microglia-mediated neuroinflammatory response via inhibiting the TLR4/NF-κB signaling pathway.

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Jiao-Tai-Wan Ameliorates Depressive-Like Behavior through the A1R Pathway in Ovariectomized Mice after Unpredictable Chronic Stress

BioMed Research International ◽

10.1155/2020/1507561 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Lina Xiang ◽

Yuan Feng ◽

Qianqian Hu ◽

Jiahui Zhu ◽

Ren Ye ◽

...

Keyword(s):

Prefrontal Cortex ◽

Locomotor Activity ◽

Chronic Stress ◽

Forced Swim Test ◽

Brain Regions ◽

Depression Symptoms ◽

Tail Suspension ◽

Ovariectomized Mice ◽

Forced Swim ◽

Menopausal Depression

Objective. This study was aimed at observing the effect Jiao-Tai-Wan in menopausal depression. Methods. In this paper, we used ovariectomized mice subjected to chronic unpredictable stress as a menopausal depression model. After the chronic stress, mice were administrated with JTW (3.3 and 6.6mg/kg) and imipramine (10 mg/kg) for 14 days. On the 14th day, mice were subjected to the behavior test like the forced swim test, tail suspension test, and locomotor activity or were sacrificed to assess the protein changes in different brain regions. Results. The administration of JTW at doses of 3.3 and 6.6mg/kg (p.o.) significantly shortened the duration of immobility in forced swim and tail suspension tests. There was no obvious difference in locomotor activity among all the groups. The western blot analysis data indicated that treatment with JTW (3.3 and 6.6 mg/kg, p.o.) prominently increased the A1R protein and the downstream protein ERK1/2 levels in the prefrontal cortex and hippocampus. However, the administration of JTW did not influence c-Fos protein in either the prefrontal cortex or hippocampus. Conclusion. Our findings suggest that JTW plays a vital role in ameliorating menopausal depression symptoms in the A1R-ERK1/2 pathway in the prefrontal cortex and hippocampus.

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