scholarly journals Fto in the hippocampus mediates depression-like behaviors

2021 ◽  
Author(s):  
Shu Liu ◽  
Jianbo Xiu ◽  
Caiyun Zhu ◽  
Chen Li ◽  
Kexin Meng ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Learning And Memory ◽  
Mouse Models ◽  
Epigenetic Regulation ◽  
Critical Role ◽  
Major Depressive ◽  
Rna Methylation ◽  
Antidepressant Effects ◽  
Beta 2

Abstract Dynamic and reversible RNA methylation has emerged as a new layer of epigenetic regulation of behaviors such as learning and memory; however, whether RNA methylation plays a critical role in the pathophysiology of depression is unclear. Here, we report that expression of the fat mass and obesity associated gene (FTO), a primary RNA demethylase, is downregulated in the hippocampi of both major depressive disorder (MDD) patients and mouse models of depression. Suppressing Fto expression in the hippocampus induces depression-like behaviors in mice, while elevating its expression leads to antidepressant effects. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampi of Fto knockdown (KD), Fto knockout (cKO), and Fto-overexpressing (OE) mice identified adrenoceptor beta 2 (Adrb2) mRNA as a target of Fto. Adrb2 stimulation reverses the depression-like behaviors and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal Sirt1 expression by c-Myc. These findings reveal that Fto in the hippocampus mediates depression-like behaviors and highlight the importance of reversible RNA methylation in driving depression.

The association of oxytocin with major depressive disorder: role of confounding effects of antidepressants

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Shiyi Xie ◽  
Yan Hu ◽  
Li Fang ◽  
Shijia Chen ◽  
Benson O.A. Botchway ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Receptor Gene ◽  
Predictive Ability ◽  
High Rate ◽  
Future Research ◽  
Targeted Prevention ◽  
Major Depressive ◽  
Antidepressant Effects ◽  
Psychiatric Syndrome

Abstract Major depressive disorder is a genetic susceptible disease, and a psychiatric syndrome with a high rate of incidence and recurrence. Because of its complexity concerning etiology and pathogenesis, the cure rate of first-line antidepressants is low. In recent years, accumulative evidences revealed that oxytocin act as a physiological or pathological participant in a variety of complex neuropsychological activities, including major depressive disorder. Six electronic databases (Web of Science, PubMed, Scopus, Google Scholar, CNKI, and Wanfang) were employed for researching relevant publications. At last, 226 articles were extracted. The current review addresses the correlation of the oxytocin system and major depressive disorder. Besides, we summarize the mechanisms by which the oxytocin system exerts potential antidepressant effects, including regulating neuronal activity, influencing neuroplasticity and regeneration, altering neurotransmitter release, down regulating hypothalamic–pituitary–adrenal axis, anti-inflammatory, antioxidation, and genetic effects. Increasing evidence shows that oxytocin and its receptor gene may play a potential role in major depressive disorder. Future research should focus on the predictive ability of the oxytocin system as a biomarker, as well as its role in targeted prevention and early intervention of major depressive disorder.

scholarly journals Pro-inflammatory cytokines as predictors of antidepressant effects of exercise in major depressive disorder

2012 ◽  
Vol 18 (10) ◽  
pp. 1119-1124 ◽  
Author(s):  
C D Rethorst ◽  
M S Toups ◽  
T L Greer ◽  
P A Nakonezny ◽  
T J Carmody ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Inflammatory Cytokines ◽  
Major Depressive ◽  
Antidepressant Effects ◽  
Pro Inflammatory Cytokines

scholarly journals Does Duloxetine Improve Cognitive Function Independently of Its Antidepressant Effect in Patients with Major Depressive Disorder and Subjective Reports of Cognitive Dysfunction?

2014 ◽  
Vol 2014 ◽  
pp. 1-13 ◽  
Author(s):  
Tracy L. Greer ◽  
Prabha Sunderajan ◽  
Bruce D. Grannemann ◽  
Benji T. Kurian ◽  
Madhukar H. Trivedi
Keyword(s):  
Decision Making ◽  
Major Depressive Disorder ◽  
Executive Function ◽  
Depressive Disorder ◽  
Learning And Memory ◽  
Cognitive Deficits ◽  
Verbal Learning ◽  
Small Sample ◽  
Major Depressive ◽  
Response Control

Introduction. Cognitive deficits are commonly reported by patients with major depressive disorder (MDD). Duloxetine, a dual serotonin/noradrenaline reuptake inhibitor, may improve cognitive deficits in MDD. It is unclear if cognitive improvements occur independently of antidepressant effects with standard antidepressant medications.Methods. Thirty participants with MDD who endorsed cognitive deficits at screening received 12-week duloxetine treatment. Twenty-one participants completed treatment and baseline and posttreatment cognitive testing. The Cambridge Neuropsychological Test Automated Battery was used to assess the following cognitive domains: attention, visual memory, executive function/set shifting and working memory, executive function/spatial planning, decision making and response control, and verbal learning and memory.Results. Completers showed significant cognitive improvements across several domains on tasks assessing psychomotor function and mental processing speed, with additional improvements in visual and verbal learning and memory, and affective decision making and response control. Overall significance tests for executive function tasks were also significant, although individual tasks were not, perhaps due to the small sample size. Most notably, cognitive improvements were observed independently of symptom reduction on all domains except verbal learning and memory.Conclusions. Patients reporting baseline cognitive deficits achieved cognitive improvements with duloxetine treatment, most of which were independent of symptomatic improvement. This trial is registered withNCT00933439.

scholarly journals Citalopram plus low-dose pipamperone versus citalopram plus placebo in patients with major depressive disorder: an 8-week, double-blind, randomized study on magnitude and timing of clinical response

2011 ◽  
Vol 41 (10) ◽  
pp. 2089-2097 ◽  
Author(s):  
A. G. Wade ◽  
G. M. Crawford ◽  
C. B. Nemeroff ◽  
A. F. Schatzberg ◽  
T. Schlaepfer ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Depressive Disorder ◽  
Therapeutic Effect ◽  
Selective Serotonin Reuptake Inhibitors ◽  
Receptor Activation ◽  
Double Blind Study ◽  
Major Depressive ◽  
Double Blind ◽  
Madrs Score ◽  
Antidepressant Effects

BackgroundSelective serotonin reuptake inhibitors take several weeks to achieve their full antidepressant effects. Post-synaptic 5-HT2A receptor activation is thought to be involved in this delayed therapeutic effect. Pipamperone acts as a highly selective 5-HT2A/D4 antagonist when administered in low doses. The purpose of this study was to compare citalopram 40 mg once daily plus pipamperone 5 mg twice daily (PipCit) versus citalopram plus placebo twice daily for magnitude and onset of therapeutic effect.MethodAn 8-week, randomized, double-blind study in patients with major depressive disorder was carried out.ResultsThe study population comprised 165 patients (citalopram and placebo, n=82; PipCit, n=83) with a mean baseline Montgomery–Asberg Depression Rating Scale (MADRS) score of 32.6 (s.d.=5.5). In the first 4 weeks, more citalopram and placebo than PipCit patients discontinued treatment (18% v. 4%, respectively, p=0.003). PipCit patients had significantly greater improvement in MADRS score at week 1 [observed cases (OC), p=0.021; last observation carried forward (LOCF), p=0.007] and week 4 (LOCF, p=0.025) but not at week 8 compared with citalopram and placebo patients. Significant differences in MADRS scores favoured PipCit in reduced sleep, reduced appetite, concentration difficulties and pessimistic thoughts. Mean Clinical Global Impression–Improvement scores were significantly improved after 1 week of PipCit compared with citalopram and placebo (OC and LOCF, p=0.002).ConclusionsAlthough the MADRS score from baseline to 8 weeks did not differ between groups, PipCit provided superior antidepressant effects and fewer discontinuations compared with citalopram and placebo during the first 4 weeks of treatment, especially in the first week.

scholarly journals The role of m6A-RNA methylation in stress response regulation

2017 ◽  
Author(s):  
Mareen Engel ◽  
Simone Röh ◽  
Carola Eggert ◽  
Paul M. Kaplick ◽  
Lisa Tietze ◽  
...  
Keyword(s):  
Major Depressive Disorder ◽  
Synaptic Plasticity ◽  
Stress Response ◽  
Depressive Disorder ◽  
Psychiatric Disorders ◽  
Fear Memory ◽  
Receptor Activation ◽  
Major Depressive ◽  
Rna Methylation ◽  
Transcriptome Response

SummaryN6-Methyladenosine (m6A) is an abundant internal RNA modification that regulates transcript processing and translation. The regulation of brain m6A by stressful stimuli in vivo and its role in the stress response are currently unknown.Here, we provide a detailed analysis of the stress-epitranscriptome using m6A-Seq, global and gene-specific m6A measurements. We show that stress exposure and glucocorticoids alter m6A and its regulatory network in a region- and time-specific manner. We demonstrate that depletion of the methyltransferase Mettl3 and the demethylase Fto in adult neurons increases fear memory, and alters the transcriptome response to fear as well as synaptic plasticity. Finally, we report that regulation of m6A is impaired in major depressive disorder patients following glucocorticoid receptor activation.Our findings indicate that brain m6A represents a novel layer of complexity in gene expression regulation after stress and that dysregulation of the m6A-response may contribute to the pathophysiology of stress-related psychiatric disorders.Highlightsm6A RNA methylation in adult mouse brain is regulated by stressBrain m6A levels are temporally and spatially regulated by stressMettl3 and Fto-KO alter fear memory, transcriptome response and synaptic plasticityThe m6A-glucocorticoid-response is impaired in major depressive disorder patientseTOC blurbEngel et al. demonstrate a brain-area-specific and time-dependent role for the mRNA modification, m6A, in stress-response regulation. Manipulating m6A-enzymes alters fear-memory, transcriptome-response and synaptic-plasticity. Altered m6A dynamics in depressed patients suggest an involvement of m6A-modifications in stress-related psychiatric disorders.

scholarly journals Fat mass and obesity-associated protein regulates RNA methylation associated with depression-like behavior in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Shu Liu ◽  
Jianbo Xiu ◽  
Caiyun Zhu ◽  
Kexin Meng ◽  
Chen Li ◽  
...  
Keyword(s):  
Major Depression ◽  
Mouse Models ◽  
Fat Mass ◽  
Critical Role ◽  
Major Depression Disorder ◽  
Rna Methylation ◽  
Adult Mice ◽  
Mouse Hippocampus ◽  
Beta 2 ◽  
Depression Disorder

AbstractPost-transcriptional modifications of RNA, such as RNA methylation, can epigenetically regulate behavior, for instance learning and memory. However, it is unclear whether RNA methylation plays a critical role in the pathophysiology of major depression disorder (MDD). Here, we report that expression of the fat mass and obesity associated gene (FTO), an RNA demethylase, is downregulated in the hippocampus of patients with MDD and mouse models of depression. Suppressing Fto expression in the mouse hippocampus results in depression-like behaviors in adult mice, whereas overexpression of FTO expression leads to rescue of the depression-like phenotype. Epitranscriptomic profiling of N6-methyladenosine (m6A) RNA methylation in the hippocampus of Fto knockdown (KD), Fto knockout (cKO), and FTO-overexpressing (OE) mice allows us to identify adrenoceptor beta 2 (Adrb2) mRNA as a target of FTO. ADRB2 stimulation rescues the depression-like behaviors in mice and spine loss induced by hippocampal Fto deficiency, possibly via the modulation of hippocampal SIRT1 expression by c-MYC. Our findings suggest that FTO is a regulator of a mechanism underlying depression-like behavior in mice.

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