Regulation of impulsive and aggressive behaviours by a novel lncRNA

14 páginas, 5 figuras. a través de PubMed Central se puede consultar: versión post-print e información suplementaria: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436429/pdf/nihms-1604033.pdfHigh impulsive and aggressive traits associate with poor behavioural self-control. Despite their importance in predicting behavioural negative outcomes including suicide, the molecular mechanisms underlying the expression of impulsive and aggressive traits remain poorly understood. Here, we identified and characterized a novel long noncoding RNA (lncRNA), acting as a regulator of the monoamine oxidase A (MAOA) gene in the brain, and named it MAOA-associated lncRNA (MAALIN). Our results show that in the brain of suicide completers, MAALIN is regulated by a combination of epigenetic mechanisms including DNA methylation and chromatin modifications. Elevated MAALIN in the dentate gyrus of impulsive-aggressive suicides was associated with lower MAOA expression. Viral overexpression of MAALIN in neuroprogenitor cells decreased MAOA expression while CRISPR-mediated knock out resulted in elevated MAOA expression. Using viral-mediated gene transfer, we confirmed that MAALIN in the hippocampus significantly decreases MAOA expression and exacerbates the expression of impulsive-aggressive behavioural traits in CD1 aggressive mice. Overall, our findings suggest that variations in DNA methylation mediate the differential expression of a novel lncRNA that acts on MAOA expression to regulate impulsive-aggressive behaviours.GT holds a Canada Research Chair (Tier 1) and a NARSAD Distinguished Investigator Award. He is supported by grants from the Canadian Institute of Health Research (CIHR) (FDN148374 and EGM141899), by the FRQS through the Quebec Network on Suicide, Mood Disorders and Related Disorders. BL holds a Sentinelle Nord Research Chair, is supported by a NARSAD young investigator award, a CIHR (SVB397205) and Natural Science and Engineering Research Council (NSERC; RGPIN-2019-06496) grants and receives FRQS Junior-1 salary support; this work was also made possible by resources supported by the Quebec Network on Suicide, Mood Disorders and Related Disorders.Peer reviewe

Liberalisation, surveillance and suicide at La Poste

This article examines how the contradictory dynamics of freedom and control that characterise neoliberal capitalism are played out on lived experiences of work in the context of the newly liberalised and restructured French postal services (La Poste). At La Poste, liberalisation was framed as a great emancipatory project that would reinvigorate a moribund state-owned company, remove regulatory constraints, deepen economic freedoms and strip away deadening bureaucracy. Yet, whilst liberalisation freed La Poste of regulatory controls, it was accompanied by an intensified surveillance and control of everyday working life. The new control measures were not limited to external working practices and structures, but sought to capture the individual worker’s personality, communication and values and harness them towards the company’s redefined commercial goals. Drawing on critical scholarship on neoliberal capitalism and labour, the article shows that when capitalist rationality extends beyond working activity and encroaches on complex, intimate and vulnerable dimensions of the person, this can have dangerous human consequences. At La Poste, liberalisation triggered a profound crisis across the company, transforming it into an ‘entreprise en souffrance’ characterised by escalating levels of psychological distress, chronic stress and a series of employee suicides

Mécanismes moléculaires liés aux dérégulations de deux gènes, SLC25A12 et MARK1, associés aux troubles autistiques

L'autisme est une pathologie neuropsychiatrique diagnostiquée chez l'enfant. SLC25A12 et MARK1 sont des gènes associés à l'autisme. J'ai mis en évidence leur surexpression dans l'aire de Brodmann 46 des patients autistes. SLC25A12 code un transporteur aspartate/giutamate mitochondrial. MARK1 code une sérine/thréonine kinase régulant l'affinité entre les MAPs et les microtubules. La modulation de leur expression affecte la croissance dendritique et le trafic des mitochondries. Les variations d'expression de SLC25A12 modifient la structure des épines dendritiques. Les variations d'expression de MARK1 altèrent la polarité neuronale. Nous avons mis en évidence des dérégulations de l'expression des gènes CAMKIIA, RIM1 et BDNF dans les échantillons provenant de patients autistes. Ces gènes codent des protéines synaptiques. En conclusion, des modifications transcriptionnelles de gènes associés à l'autisme induisent des anomalies dendritiques qui peuvent modifier la plasticité synaptique.Autism is a neuropsychiatric disorder diagnosed in the first years of childhood. SLC25A12 and MARK1 are genes associated to autism. I evidenced the overexpression of these genes in Brodmann Area 46 in autistic patients. SLC25A12 encodes a mitochondrial aspartate/giutamate transporter. MARK1 encodes a serine/threonine kinase regulating interactions between MAPs and microtubules. By modulating the expression of these genes, we observed modifications in the length of dendrites and in velocity of mitochondria. Variations in SLC25A12 expression modify structure of dendritic spines. Changes in MARK1 expression alter neuronal polarity. We found that CAMKIIA, RIM1 and BDNF gene expression levels are deregulated in autistic patients. These genes encode proteins involved in synaptic plasticity. In conclusion, transcriptional modifications of genes that are associated to autism induce dendritic abnormalities that consequently alter synaptic plasticity in sub-regions of central nervous system.PARIS5-BU Méd.Cochin (751142101) / SudocSudocFranceF

Epigenetic Regulation of the Kappa Opioid Receptor by Child Abuse

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Nrxn3 upregulation in the globus pallidus of mice developing cocaine addiction.: Nrxn3 and cocaine addiction

International audienceDysfunctions affecting the connections of basal ganglia lead to major neurological and psychiatric disorders. We investigated levels of mRNA for three neurexins (Nrxn) and three neuroligins (Nlgn) in the globus pallidus, subthalamic nucleus, and substantia nigra, in control conditions and after short-term exposure to cocaine. The expression of Nrxn2beta and Nlgn3 in the substantia nigra and Nlgn1 in the subthalamic nucleus depended on genetic background. The development of short-term cocaine appetence induced an increase in Nrxn3beta expression in the globus pallidus. Human NRXN3 has recently been linked to several addictions. Thus, NRXN3 adhesion molecules may play an important role in the synaptic plasticity of neurons involved in the indirect pathways of basal ganglia, in which they regulate reward-related learning

Regulation of a Truncated Form of Tropomyosin-Related Kinase B (TrkB) by Hsa-miR-185* in Frontal Cortex of Suicide Completers

<div><h3>Background</h3><p>TrkB-T1 is a BDNF receptor lacking a tyrosine kinase domain that is highly expressed in astrocytes and regulates BDNF-evoked calcium transients. Previous studies indicate that downregulation of TrkB-T1 in frontal cortex may be involved in neurobiological processes underlying suicide.</p> <h3>Methods</h3><p>In a microarray screening study (N = 8), we interrogated all known microRNA in the frontal cortex of suicide completers with low expression of TrkB-T1 and normal controls. These findings were validated and followed up in a larger sample of cases and controls (N = 55). Functional analyses included microRNA silencing, microRNA overexpression and luciferase assays to investigate specificity and to validate interactions between differentially expressed microRNA and TrkB-T1.</p> <h3>Results</h3><p>MicroRNAs Hsa-miR-185* and Hsa-miR-491-3p were upregulated in suicide completers with low expression of TrkB.T1 (P_nominal: 9.10⁻⁵ and 1.8.10⁻⁴ respectively; FDR-corrected p = 0.031). Bioinformatic analyses revealed five putative binding sites for the DiGeorge syndrome linked microRNA Hsa-miR-185*in the 3′UTR of TrkB-T1, but none for Hsa-miR-491-3P. The increase of Hsa-miR-185* in frontal cortex of suicide completers was validated then confirmed in a larger, randomly selected group of suicide completers, where an inverse correlation between Hsa-miR-185* and TrkB-T1 expression was observed (R = −0.439; p = 0.001). Silencing and overexpression studies performed in human cell lines confirmed the inverse relationship between hsa-mir-185* and trkB-T1 expression. Luciferase assays demonstrated that Hsa-miR-185* binds to sequences in the 3′UTR of TrkB-T1.</p> <h3>Conclusion</h3><p>These results suggest that an increase of Hsa-miR-185* expression levels regulates, at least in part, the TrkB-T1 decrease observed in the frontal cortex of suicide completers and further implicate the 22q11 region in psychopathology.</p> </div

Effect of Hsa-miR-185* exogenous expression on TrkB-T1 levels in HEK293 cell line.

<p>A: Decrease of <i>TrkB-T1</i> in cells transfected with mimic compared to the negative control. B: No significant change of <i>TrkB-T2</i> expression levels in cells transfected with mimic compared to negative control. C: No significant change of <i>TrkB-FL</i> in cells transfected with mimic compared to negative control. *:p<0.05 n.s: not significant. N_{negativecontrol} = 5 N_mimic = 5 Error bars indicate standard errors of the mean. All statistical comparisons were done by t test.</p

Microarray investigation and real-time PCR validation of microRNA differentially expressed in BA10 tissue from a screening sample composed of suicide completers selected according to extreme low <i>TrkB-T1</i> levels and controls with normal <i>TrkB-T1</i> expression values (N = 8).

<p>A: MA plot of the average probeset differential expression between groups. Hsa-miR-185* and Hsa-miR-491-3P are indicated by a red square. B: MicroRNAs differentially expressed after correction for multiple testing (FDR : 0.05) C: Quantification of Hsa-miR-491-3P in the microarray samples by real time PCR. D: Validation of Hsa-miR-185* in the microarray samples by real time PCR. Comparison was done by t test. *: p<0.05. n.s: not significant. Errors bars indicate standard errors of the mean.</p