The Effect of Acute and Chronic Social Stress on the Hippocampal Transcriptome in Mice

Stankiewicz, Adrian; Gościk, Joanna; Majewska, Alicja; Świergiel, Artur H.; Juszczak, Grzegorz R.

doi:10.1371/journal.pone.0142195

Cited by 123 publications

(104 citation statements)

References 126 publications

(160 reference statements)

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“…This is congruent with a previous study showing that 8 days of stress increased CTGF (36). Because CTGF is also known to interact with numerous molecules, and the signaling and feedback is extremely complex, more research on CTGF is needed to elucidate the dynamics of the stress response.…”

Section: Discussionsupporting

confidence: 93%

Connective Tissue Growth Factor Is a Novel Prodepressant

Turner

Sharma

Hagenauer

et al. 2018

Biological Psychiatry

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BACKGROUND: While downregulation of several growth factors in major depressive disorder is well established, less attention has been paid to the upregulation of other growth factors. Yet, upregulated growth factors may offer better therapeutic targets. We show that connective tissue growth factor (CTGF) represents a target based on its upregulation in major depressive disorder and studies in animal models implicating it in negative affect. METHODS: CTGF gene expression was first evaluated in the postmortem human amygdala. The findings were followed up in outbred rats and in two rat lines that were selectively bred for differences in novelty-seeking and anxiety behavior (bred low responders and bred high responders). We studied the impact of social defeat and early-life treatment with fibroblast growth factor 2 on CTGF expression. Finally, we assessed the ability of an anti-CTGF antibody (FG-3019) to alter CTGF expression and emotionality. RESULTS: In the human amygdala, CTGF expression was significantly increased in major depressive disorder compared with control subjects. CTGF expression was also significantly increased in the dentate gyrus of adult bred low responders compared with bred high responders. Social defeat stress in bred low responders significantly increased CTGF expression in the dentate gyrus. Early-life fibroblast growth factor 2, a treatment that reduces anxiety-like behavior throughout life, decreased CTGF expression in the adult dentate gyrus. In outbred rats, CTGF administration increased depression-like behavior. Chronic treatment with FG-3019 decreased CTGF expression, and acute and chronic treatment was antidepressant. CONCLUSIONS: This study is the first to implicate CTGF as a prodepressant molecule that could serve as a target for the development of novel therapeutics.

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Section: Discussionsupporting

confidence: 93%

Connective Tissue Growth Factor Is a Novel Prodepressant

Turner

Sharma

Hagenauer

et al. 2018

Biological Psychiatry

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“…(9) reported acute stress-induced reduction in expression of a set of genes in hippocampal samples that overlap with those reported here (Fig. 1) and in the Cho et al .…”

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confidence: 89%

Comment on “Multiple repressive mechanisms in the hippocampus during memory formation”

Mathew

Mullan

Blusztajn

et al. 2016

Science

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Cho et al. (Reports, 02 October, p.82) report that gene repression following contextual fear conditioning regulates hippocampal memory formation. We observe low levels of expression for many of the top candidate genes in the hippocampus, and robust expression in choroid plexus, as well as repression at 4 hours following contextual fear conditioning, suggesting the inclusion of choroid plexus mRNAs in Cho et al. hippocampal samples.

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“…As DAMPs, Mrp8 and its binding partner Mrp14 are upregulated after chronic stress exposure [26] and impact numerous inflammatory diseases [42]. Our findings showed that Mrp8 and Mrp14 increased with depressive-like behaviors in CUMS-treated mice.…”

Section: Discussionmentioning

confidence: 55%

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice

Gong

Cao

et al. 2018

J Neuroinflammation

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BackgroundDepression is one of the most common mental disorders characterized mainly by low mood and loss of interest or pleasure. About a third of patients with depression do not respond to classic antidepressant treatments. Recent evidence suggests that Mrp8/14 (myeloid-related protein 8/14) plays a crucial role in cognitive dysfunction and neuroinflammatory diseases, yet its role in mood regulation remains largely uninvestigated. In the present work, we explored the potential role of Mrp8/14 in the progression of depression.MethodsAfter 4 weeks of chronic unpredictable mild stress (CUMS), depressive-like symptoms and Mrp8/14 were determined. To verify the effects of Mrp8/14 on depressive-like behaviors, the inhibitor TAK-242 and recombinant Mrp8/14 were used. Furthermore, the molecular mechanisms in Mrp8/14-induced behavioral and biological changes were examined in vivo and ex vivo.ResultsFour-week CUMS contributed to the development of depressive symptoms. Mrp8 and Mrp14 were upregulated in the hippocampus and serum after exposure to CUMS. Pharmacological inhibition of Mrp14 attenuated CUMS-induced TLR4/NF-κB signaling activation and depressive-like behaviors. Furthermore, central administration of recombinant Mrp8, Mrp14, and Mrp8/14 resulted in neuroinflammation and depressive-like behaviors. Mrp8/14-provoked proinflammatory effects and depressive-like behaviors were improved by pretreatment with a TLR4 inhibitor. Moreover, pharmacological inhibition of TLR4 reduced the release of nitric oxide and reactive oxygen species in Mrp8/14-activated BV2 microglia.ConclusionsThese data suggest that the hippocampal Mrp8/14-TLR4-mediated neuroinflammation contributes to the development of depressive-like behaviors. Targeting the Mrp8/14 may be a novel promising antidepressant approach.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1296-0) contains supplementary material, which is available to authorized users.

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The Effect of Acute and Chronic Social Stress on the Hippocampal Transcriptome in Mice

Cited by 123 publications

References 126 publications

Connective Tissue Growth Factor Is a Novel Prodepressant

Connective Tissue Growth Factor Is a Novel Prodepressant

Comment on “Multiple repressive mechanisms in the hippocampus during memory formation”

Hippocampal Mrp8/14 signaling plays a critical role in the manifestation of depressive-like behaviors in mice

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