Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice

Antunes, Cláudia; Silva, Jorge Diogo Da; Guerra‐Gomes, Sónia; Alves, Nuno Dinis; Ferreira, Fábio; Loureiro‐Campos, Eduardo; Branco, Miguel R.; Sousa, Nuno; Reik, Wolf; Pinto, Luísa; Marques, C. Joana

doi:10.1038/s41380-020-0695-7

Cited by 43 publications

(32 citation statements)

References 58 publications

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“…The hippocampus is the negative feedback center of the hypothalamic-pituitary-adrenal (HPA) axis and has the highest expression of GR (Antunes et al, 2020). We examined GR protein level in the hippocampus of adolescent rats and found that it was decreased in PS females [t(10) = 3.728, P = 0.015; Figure 3B] but not PS males ( Figure 3C) relative to the respective controls.…”

Section: Effect Of Ps On Epigenetic Modification Of the Gr Gene In Admentioning

confidence: 99%

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

Lei

et al. 2020

Front. Neurosci.

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Prenatal stress (PS) can lead to neuroendocrine and emotional disorders later in adolescence. Sexual dimorphism in these neurodevelopmental outcomes have been observed; however, the underlying mechanisms are not fully understood. To address this issue, we investigated whether there are sex differences in epigenetic reprogramming in rats exposed to PS. Pregnant female rats were subjected to chronic restraint stress from gestational day (G)12 to G18. From postnatal day (P)38 to P45, subgroups of offspring including both males and females were subjected to behavioral testing and brain tissue specimens were analyzed by DNA pyrosequencing, western blotting, and Golgi staining to assess changes in methylation pattern of glucocorticoid receptor (GR) gene, expression of DNA methyltransferase (DNMT) and DNA demethylase, and dendrite morphology, respectively. The DNA methyltransferase inhibitor decitabine was administered to rats prior to PS to further evaluate the role of methylation in the sexually dimorphic effects of PS. The results showed that PS increased anxiety-like behavior in offspring, especially in females, while depression-like behavior was increased in male offspring compared to control littermates. The methylation pattern in the promoter region of the GR gene differed between males and females. Sex-specific changes in the expression of DNMTs (DNMT1 and DNMT3a) and DNA demethylase (Tet methylcytosine dioxygenase 2) were also observed. Interestingly, decitabine alleviated the behavioral disorder caused by PS and restored dendrite density and morphology in female but not male rats. These findings suggest that different change patterns of DNMT and demethylase in the two sexes after PS are responsible for the sexually dimorphism, which could have implications for the clinical management of stress-related disorders.

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Section: Effect Of Ps On Epigenetic Modification Of the Gr Gene In Admentioning

confidence: 99%

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

Lei

et al. 2020

Front. Neurosci.

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“…Could the antianxiety effect of resveratrol contribute to LBP relief? The hippocampus, which is sensitive to stress, has recently received increasing attention in anxiety 28,29 . Resveratrol promoted the phosphorylated of cAMP response element‐binding protein (pCREB) and brain‐derived neurotrophic factor (BDNF) synthesis in hippocampus, which are positively correlated with the relief of anxiety 30,31 .…”

Section: Introductionmentioning

confidence: 99%

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Chen

Gao

et al. 2021

FASEB j.

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Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety‐related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX−/− mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element‐binding protein (pCREB), and brain‐derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment‐enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL‐1β, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol‐mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX−/− mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety‐related behaviors. This study provides that resveratrol‐mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery‐induced LBP and hippocampus‐related anxiety.

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“…A recent study also reported MAP2K1 to regulate Neuronal Per Arnt Sim domain protein 4 (NPAS4), an immediate-early gene that controls a transcriptional program involving neural activity-regulated genes (Lin et al, 2008 ; Yun et al, 2013 ), including Bdnf , thus promoting neural circuitry plasticity, learning, and memory (Funahashi et al, 2019 ). Interestingly, our previous work revealed that Npas4 is epigenetically regulated in a conditional Tet3 KO mouse model that presents anxiety-like behavior and cognitive deficits (Antunes et al, 2020 ). Changes in epigenetic regulators have long been described in the context of stress, depression and antidepressant treatment (Nestler, 2014 ), with chronic stress being suggested to interact with susceptibility genes via epigenetic mechanisms to produce long-lasting changes in the brain that may partly explain the heterogeneity of depression etiology (Tsankova et al, 2007 ; Mateus-Pinheiro et al, 2011 ; Menke and Binder, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

miR-409 and miR-411 Modulation in the Adult Brain of a Rat Model of Depression and After Fluoxetine Treatment

Patrício

Mateus‐Pinheiro

Alves

et al. 2020

Front. Behav. Neurosci.

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Tet3 ablation in adult brain neurons increases anxiety-like behavior and regulates cognitive function in mice

Cited by 43 publications

References 58 publications

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

Differences in DNA Methylation Reprogramming Underlie the Sexual Dimorphism of Behavioral Disorder Caused by Prenatal Stress in Rats

Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

miR-409 and miR-411 Modulation in the Adult Brain of a Rat Model of Depression and After Fluoxetine Treatment

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