Évaluation de l'activité sérotoninergique du cortex préfrontal médian dans un modèle animal de psychose

Mémoire numérisé par la Division de la gestion de documents et des archives de l'Université de Montréal

Functional Contribution of the Medial Prefrontal Circuitry in Major Depressive Disorder and Stress-Induced Depressive-Like Behaviors

Despite decades of research on the neurobiology of major depressive disorder (MDD), the mechanisms underlying its expression remain unknown. The medial prefrontal cortex (mPFC), a hub region involved in emotional processing and stress response elaboration, is highly impacted in MDD patients and animal models of chronic stress. Recent advances showed alterations in the morphology and activity of mPFC neurons along with profound changes in their transcriptional programs. Studies at the circuitry level highlighted the relevance of deciphering the contributions of the distinct prefrontal circuits in the elaboration of adapted and maladapted behavioral responses in the context of chronic stress. Interestingly, MDD presents a sexual dimorphism, a feature recognized in the molecular field but understudied on the circuit level. This review examines the recent literature and summarizes the contribution of the mPFC circuitry in the expression of MDD in males and females along with the morphological and functional alterations that change the activity of these neuronal circuits in human MDD and animal models of depressive-like behaviors

Understanding Gene-Lifestyle Interaction in Obesity: The Role of Mediation versus Moderation

BACKGROUND: Obesity results from complex interactions between genetic susceptibility to weight gain and poor eating and lifestyle behaviors. The approach that has been traditionally used in genetics to investigate gene-environment/lifestyle interaction in obesity is based on the concept of moderation or effect modification. Another approach called mediation analysis can be used to investigate gene-environment interaction in obesity. The objective of this review article is to explain the differences between the concepts of moderation and mediation and summarize the studies that have used mediation analysis to support the role of eating or lifestyle behaviors as putative mediators of genetic susceptibility to obesity. SUMMARY: Moderation is used to determine whether the effect of an exposure (genes associated with obesity) on an outcome (obesity phenotype) differs in magnitude and/or direction across the spectrum of environmental exposure. Mediation analysis is used to assess the extent to which the effect of the exposure on the outcome is explained by a given set of hypothesized mediators with the aim of understanding how the exposure could lead to the outcome. In comparison with moderation, relatively few studies used mediation analyses to investigate gene-environment interaction in obesity. Most studies found evidence that traits related to appetite or eating behaviors partly mediated genetic susceptibility to obesity in either children or adults. KEY MESSAGES: Moderation and mediation represent two complementary approaches to investigate gene-environment interaction in obesity and address different research questions pertaining to the cause-effect relationship between genetic susceptibility to obesity and various obesity outcomes. More studies relying on mediation are needed to better understand the role of eating and lifestyle habits in mediating genetic susceptibility to obesity

Adolescent amphetamine exposure elicits dose-specific effects on monoaminergic neurotransmission and behaviour in adulthood.

Despite the growing non-medical consumption of amphetamine (Amph) during adolescence, its long-term neurobiological and behavioural effects have remained largely unexplored. The present research sought to characterize the behavioural profile and electrophysiological properties of midbrain monoaminergic neurons in adult rodents after Amph exposure during adolescence. Adolescent rats were administered vehicle, 0.5, 1.5, or 5.0 mg/kg.d Amph from postnatal day (PND) 30–50. At adulthood (PND 70), rats were tested in an open-field test (OFT) and elevated plus maze (EPM), paralleled by in-vivo extracellular recordings of serotonin (5-HT), dopamine (DA) and norepinephrine (NE) neurons from the dorsal raphe nucleus, ventral tegmental area, and locus coeruleus, respectively. 5-HT firing in adulthood was increased in rats that had received Amph (1.5 mg/kg.d) during adolescence. At this regimen, DA firing activity was increased, but not NE firing. Conversely, the highest Amph dose regimen (5.0 mg/kg.d) enhanced NE firing, but not DA or 5-HT firing rates. In the OFT, Amph (1.5 mg/kg.d) significantly increased the total distance travelled, while the other doses were ineffective. In the EPM, all three Amph doses increased time spent in the open arms and central platform, as well as the number of stretch-attend postures made. Repeated adolescent exposure to Amph differentially augments monoaminergic neuronal firing in a dose-specific fashion in adulthood, with corresponding alterations in locomotion, risk assessment (stretch-attend postures and central platform occupancy) and risk-taking behaviours (open-arm exploration). Thus, adolescent Amph exposure induces long-lasting neurophysiological alterations that may have implications for drug-seeking behaviour in the future

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

The epigenetics of suicide: the impact of early-life adversity on brain DNA methylation signature

Suicide is a problem resulting from the interaction between several factors. Among these factors, early-life adversity, characterized by child sexual and physical abuse as well as parental neglect, is one of the strongest risk factors for depression and suicidal behaviors. While it is clear that child abuse increases the risk for depression and suicide, the mechanisms mediating these effects are still unknown. Recent evidences suggest that epigenetic mechanisms may be involved in mediating the effects of early-life adversity on behavior. Early-life stress in animals has been shown to alter DNA methylation in genes regulatory regions what, in turn, has been associated with changes in gene expression and behavioral modifications. Importantly, similar changes have been reported in several genes in the human brain. However, although epigenetic modifications have been found in several genes, the extent of epigenetic changes induced by early-life adversity is still unknown and their impacts on increasing suicide risk are unclear. This thesis aims at expanding our understanding of suicide by investigating one potential mechanism by which early-life adversity may increase vulnerability to mood disorders and suicide, namely epigenetic regulation of gene expression. We first expanded our characterization of DNA methylation alterations induced by early and adult-life stress in the regulatory regions of the glucocorticoid receptor gene which is one of the most consistent alterations associated with stress, depression and suicidal behaviors. We then opted for a genome-wide characterization of DNA methylation alterations found in the brains of suicide completers with and without a history of child abuse using microarray analyses focusing on gene promoters throughout the genome. Our findings revealed several DNA methylation alterations in genes with known roles on behavioral regulation and identified several new genes and networks which may be specifically altered by early-life adversity. We also characterized the functional impact of these alterations on gene expression and promoter transcriptional activity. Overall, this work identifies and characterizes the molecular mechanisms by which environment induces behavioral changes conferring vulnerability toward mood disorders and suicidal behaviors.Le suicide est un problème qui résulte de l'interaction entre plusieurs facteurs. Un de ces facteurs, l'adversité durant l'enfance se définissant par une histoire d'abus sexuel et/ou physique de même que par la négligence parentale, est un des facteurs de risque les plus importants en ce qui à trait à l'augmentation des risques de développer des comportements dépressifs et suicidaires à l'âge adulte. Or, si une histoire d'abus augmente les risques de dépression et de suicide, les mécanismes responsables de ces effets comportementaux demeurent néanmoins méconnus. De récentes avancées laissent présager que l'impact comportemental d'une histoire d'abus serait transmis par des mécanismes épigénétiques. En effet, de nombreuses études suggèrent que le stress au cours du jeune âge chez les rongeurs interfère avec l'établissement des schémas de méthylation dans les régions régulatrices des gènes ce qui, en retour, modifie les niveaux d'expression des gènes et induit des changements comportementaux semblables aux symptômes de la dépression. Fait important, des changements semblables ont également été rapportés chez l'humain. Malgré tout, l'ampleur des modifications épigénétiques induites par une histoire d'abus durant l'enfance, de même que leurs conséquences comportementales, demeurent toujours inconnues. Cette thèse vise à améliorer notre compréhension du suicide en élucidant un mécanisme potentiel, soit les mécanismes épigénétiques, par lequel le stress au cours du jeune âge augmenterait la vulnérabilité aux troubles de l'humeur et au suicide. Nous avons premièrement poursuivit la caractérisation des changements de methylation de l'ADN induits par une histoire d'abus dans la région régulatrice du gène du récepteur des glucocorticoides, un des gènes les plus fréquemment associés au stress, la dépression et le suicide. Nous avons ensuite opté pour une approche globale visant à identifier l'ensemble des modifications de methylation de l'ADN dans les régions promotrices de l'ensemble du génome dans le cerveau des suicidaires avec ou sans histoire d'abus durant l'enfance. Nos résultats révèlent la présence de nombreux changements de methylation de l'ADN dans plusieurs gènes impliqués dans la régulation comportementale. Nos résultats supportent également l'implication de plusieurs autres gènes affectés spécifiquement par une histoire d'abus durant l'enfance. Les travaux de cette thèse ont également mis l'emphase sur l'impact fonctionnel de ces altérations sur l'expression des gènes et la régulation de l'activité transcriptionnelle des régions promotrices affectées. Dans l'ensemble, ce travail détaille et définit les mécanismes moléculaires par lesquels l'environnement induit des changements comportementaux conférant une vulnérabilité envers les troubles de l'humeur et les comportements suicidaires

Épigénétique : un lien entre l’environnement et le génome

L’adversité au cours du jeune âge est connue pour augmenter le risque de développer des problèmes de santé mentale à l’âge adulte. Récemment, des mécanismes épigénétiques ont été identifiés comme représentant une interface sur laquelle l’environnement agit pour induire des changements comportementaux. Ces changements, qui affectent l’expression de certains gènes, sans modifier la séquence d’ADN, interfèrent avec le fonctionnement des systèmes régulant la réponse au stress. À long terme, l’adversité durant l’enfance, en induisant ces changements épigénétiques, prédispose certains individus à développer des problèmes de santé mentale à l’âge adulte. Ce chapitre traite de l’impact épigénétique de l’adversité au cours du jeune âge et de ses conséquences comportementales sur la santé mentale.Adversity during childhood has for long been known to increase the risk of developing mental health problems in adulthood. Yet, it is only recently that epigenetic mechanisms have been identified as representing an interface on which the environment acts upon to induce behavioral changes. These changes affecting the expression of certain genes, without however modifying DNA sequences, particularly interfere with the functioning of systems regulating response to stress. In the long term, adversity during childhood, by inducing these epigenetic changes, predisposes some individuals in developing mental health problems in adulthood. This article examines the epigenetic impact of adversity during childhood and its behavioral consequences on mental health

Effects of promoter methylation on increased expression of polyamine biosynthetic genes in suicide

Suicide is among the leading causes of death worldwide. The polyamine system has been increasingly implicated in the neurobiology of suicide. Previous research has indicated that epigenetic mechanisms play a role in explaining dysregulation of polyamine genes in suicide completers. Nevertheless, regulatory mechanisms explaining polyamine biosynthetic genes displaying dysregulated expression in suicide completers, including ornithine decarboxylase antizymes 1 and 2 (OAZ1 and OAZ2), S-adenosylmethionine decarboxylase (AMD1), and arginase 2 (ARG2), have yet to be elucidated. In this study, we investigated methylation patterns in the promoter region of OAZ1, OAZ2, AMD1, and ARG2 in Brodmann area 44 from a group of 33 suicide completers and 31 non-suicide controls. We found significant site-specific differences in methylation in the promoter of ARG2 and AMD1 that were also significantly negatively correlated with gene expression. These findings provide further support for a role for the involvement of epigenetic modifications in the regulation of genes associated with polyamine biosynthesis, and which may contribute to the complexity of suicidal behaviors