Exosomes are a class of extracellular vesicles of endocytic origin, which are released by cells and are accessible in biofluids, such as saliva, urine, and plasma. These vesicles are enriched with ...small RNA, and they play a role in many physiological processes. In the brain, they are involved in processes including synaptic plasticity, neuronal stress response, cell-to-cell communication and neurogenesis. While exosomes have been implicated previously in cancer and neurodegenerative diseases, research regarding their role in mental disorders remains scarce. Given their functional significance in the brain, investigation in this field is warranted. Additionally, because exosomes can cross the blood-brain barrier, they may serve as accessible biomarkers of neural dysfunction. Studying exosomes may provide information towards diagnosis and therapeutic intervention, and specifically those derived from the brain may provide a mechanistic view of the disease phenotype. This review will discuss the roles of exosomes in the brain, and relate novel findings to current insights into mental disorders.
Suicide and suicidal behaviour Turecki, Gustavo, Prof; Brent, David A, Prof
The Lancet,
03/2016, Letnik:
387, Številka:
10024
Journal Article
Recenzirano
Odprti dostop
Summary Suicide is a complex public health problem of global importance. Suicidal behaviour differs between sexes, age groups, geographic regions, and sociopolitical settings, and variably associates ...with different risk factors, suggesting aetiological heterogeneity. Although there is no effective algorithm to predict suicide in clinical practice, improved recognition and understanding of clinical, psychological, sociological, and biological factors might help the detection of high-risk individuals and assist in treatment selection. Psychotherapeutic, pharmacological, or neuromodulatory treatments of mental disorders can often prevent suicidal behaviour; additionally, regular follow-up of people who attempt suicide by mental health services is key to prevent future suicidal behaviour.
Abstract The early-life social environment can induce stable changes that influence neurodevelopment and mental health. Research focused on early-life adversity revealed that early-life experiences ...have a persistent impact on gene expression and behavior through epigenetic mechanisms. The hypothalamus-pituitary-adrenal axis is sensitive to changes in the early-life environment that associate with DNA methylation of a neuron-specific exon 17 promoter of the glucocorticoid receptor (GR) ( Nr3c1 ). Since initial findings were published in 2004, numerous reports have investigated GR gene methylation in relationship to early-life experience, parental stress, and psychopathology. We conducted a systematic review of this growing literature, which identified 40 articles (13 animal and 27 human studies) published since 2004. The majority of these examined the GR exon variant 1F in humans or the GR17 in rats, and 89% of human studies and 70% of animal studies of early-life adversity reported increased methylation at this exon variant. All the studies investigating exon 1F /17 methylation in conditions of parental stress (one animal study and seven human studies) also reported increased methylation. Studies examining psychosocial stress and psychopathology had less consistent results, with 67% of animal studies reporting increased exon 17 methylation and 17% of human studies reporting increased exon 1F methylation. We found great consistency among studies investigating early-life adversity and the effect of parental stress, even if the precise phenotype and measures of social environment adversity varied among studies. These results are encouraging and warrant further investigation to better understand correlates and characteristics of these associations.
Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past ...molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.
The miRNome of Depression Żurawek, Dariusz; Turecki, Gustavo
International journal of molecular sciences,
10/2021, Letnik:
22, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Depression is an effect of complex interactions between genetic, epigenetic and environmental factors. It is well established that stress responses are associated with multiple modest and often ...dynamic molecular changes in the homeostatic balance, rather than with a single genetic factor that has a strong phenotypic penetration. As depression is a multifaceted phenotype, it is important to study biochemical pathways that can regulate the overall allostasis of the brain. One such biological system that has the potential to fine-tune a multitude of diverse molecular processes is RNA interference (RNAi). RNAi is an epigenetic process showing a very low level of evolutionary diversity, and relies on the posttranscriptional regulation of gene expression using, in the case of mammals, primarily short (17-23 nucleotides) noncoding RNA transcripts called microRNAs (miRNA). In this review, our objective was to examine, summarize and discuss recent advances in the field of biomedical and clinical research on the role of miRNA-mediated regulation of gene expression in the development of depression. We focused on studies investigating post-mortem brain tissue of individuals with depression, as well as research aiming to elucidate the biomarker potential of miRNAs in depression and antidepressant response.
Abstract Despite increasing evidence supporting the neuroinflammatory theory of depression, little is known about cerebral macrophages in individuals suffering from major depression. In the present ...study, we investigated the morphology and distribution of cells immunostained for the macrophage-specific marker ionized calcium binding adaptor molecule 1 (IBA1) in the dorsal anterior cingulate cortex (dACC) white matter of middle-aged depressed suicides and matched non-psychiatric controls. This region is known for its implication in mood disorders, and its white matter compartment was previously found to display hypertrophic astrocytes in depressed suicides. Distributions of IBA1-immunoreactive (IBA-IR) microglial phenotypes were assessed using stereology and cell morphometry, and blood vessels were characterized as being intimately associated with either a high or a low density of IBA1-IR amoeboid-like cells. Total densities of IBA1-IR microglia did not differ between depressed suicides and controls. However, a finer analysis examining relative proportions of microglial phenotypes revealed that the ratio of primed over ramified (“resting”) microglia was significantly increased in depressed suicides. Strikingly, the proportion of blood vessels surrounded by a high density of macrophages was more than twice higher in depressed suicides than in controls, and this difference was strongly significant. Consistent with these observations, gene expression of IBA1 and MCP-1, a chemokine involved in the recruitment of circulating monocytes, was significantly upregulated in depressed suicides. Furthermore, mRNA for CD45, a marker enriched in perivascular macrophages, was also significantly increased in samples from depressed suicides. An increase compared to controls was also observed in the proportion of blood vessels surrounded by a high density of CD45-IR cells, but this difference did not reach significance. These histological and molecular data suggest the recruitment of monocytes in dACC white matter of depressed suicides, although it cannot be excluded that other types of macrophages (including microglia) account for the observed accumulation of macrophages closely associated with blood vessels. Altogether, these findings suggest that the previously reported depression- and suicide-associated increases in circulating pro-inflammatory cytokines may be associated with low-grade cerebral neuroinflammation involving the recruitment of circulating monocytes.
Preclinical and clinical studies suggest that inflammation and vascular dysfunction contribute to the pathogenesis of major depressive disorder (MDD). Chronic social stress alters blood–brain barrier ...(BBB) integrity through loss of tight junction protein claudin-5 (cldn5) in male mice, promoting passage of circulating proinflammatory cytokines and depression-like behaviors. This effect is prominent within the nucleus accumbens, a brain region associated with mood regulation; however, the mechanisms involved are unclear. Moreover, compensatory responses leading to proper behavioral strategies and active resilience are unknown. Here we identify active molecular changes within the BBB associated with stress resilience that might serve a protective role for the neurovasculature. We also confirm the relevance of such changes to human depression and antidepressant treatment. We show that permissive epigenetic regulation of cldn5 expression and low endothelium expression of repressive cldn5-related transcription factor foxo1 are associated with stress resilience. Regionand endothelial cell-specific whole transcriptomic analyses revealed molecular signatures associated with stress vulnerability vs. resilience. We identified proinflammatory TNFα/NFκB signaling and hdac1 as mediators of stress susceptibility. Pharmacological inhibition of stress-induced increase in hdac1 activity rescued cldn5 expression in the NAc and promoted resilience. Importantly, we confirmed changes in HDAC1 expression in the NAc of depressed patients without antidepressant treatment in line with CLDN5 loss. Conversely, many of these deleterious CLDN5-related molecular changes were reduced in postmortem NAc from antidepressanttreated subjects. These findings reinforce the importance of considering stress-induced neurovascular pathology in depression and provide therapeutic targets to treat this mood disorder and promote resilience.
Suicide ranks among the leading causes of death around the world and takes a heavy emotional and public health toll on most societies. Both distal and proximal factors contribute to suicidal ...behaviour. Distal factors - such as familial and genetic predisposition, as well as early-life adversity - increase the lifetime risk of suicide. They alter responses to stress and other processes through epigenetic modification of genes and associated changes in gene expression, and through the regulation of emotional and behavioural traits. Proximal factors are associated with the precipitation of a suicidal event and include alterations in key neurotransmitter systems, inflammatory changes and glial dysfunction in the brain. This Review explores the key molecular changes that are associated with suicidality and discusses some promising avenues for future research.
To test whether adolescents who are victimized by peers are at heightened risk for suicidal ideation and suicide attempt, using both cross-sectional and prospective investigations.
Participants are ...from the Quebec Longitudinal Study of Child Development, a general population sample of children born in Quebec in 1997 through 1998 and followed up until 15 years of age. Information about victimization and serious suicidal ideation and suicide attempt in the past year was obtained at ages 13 and 15 years from self-reports (N = 1,168).
Victims reported concurrently higher rates of suicidal ideation at age 13 years (11.6-14.7%) and suicide attempt at age 15 years (5.4-6.8%) compared to those who had not been victimized (2.7-4.1% for suicidal ideation and 1.6-1.9% for suicide attempt). Being victimized by peers at 13 years predicted suicidal ideation (odds ratio OR = 2.27; 95% CI = 1.25-4.12) and suicide attempt (OR = 3.05, 95% CI = 1.36-6.82) 2 years later, even after adjusting for baseline suicidality and mental health problems and a series of confounders (socioeconomic status, intelligence, family's functioning and structure, hostile-reactive parenting, maternal lifetime suicidal ideation/suicide attempt). Those who were victimized at both 13 and 15 years had the highest risk of suicidal ideation (OR = 5.41, 95% CI = 2.53-11.53) and suicide attempt (OR = 5.85, 95% CI = 2.12-16.18) at 15 years.
Victimization is associated with an increased risk of suicidal ideation and suicide attempt over and above concurrent suicidality and prior mental health problems. The longer the history of victimization, the greater the risk.
ABSTRACT BACKGROUND Exposure to peer victimization is relatively common. However, little is known about its developmental course and its effect on impairment associated with mental illnesses. We ...aimed to identify groups of children following differential trajectories of peer victimization from ages 6 to 13 years and to examine predictive associations of these trajectories with mental health in adolescence. METHODS Participants were members of the Quebec Longitudinal Study of Child Development, a prospective cohort of 2120 children born in 1997/98 who were followed until age 15 years. We included 1363 participants with self-reported victimization from ages 6 to 13 years and data available on their mental health status at 15 years. RESULTS We identified 3 trajectories of peer victimization. The 2 prevailing groups were participants with little or moderate exposure to victimization (441/1685 26.2% and 1000/1685 59.3%, respectively); the third group (244 14.5%) had been chronically exposed to the most severe and long-lasting levels of victimization. The most severely victimized individuals had greater odds of reporting debilitating depressive or dysthymic symptoms (odds ratio OR 2.56, 95% confidence interval CI 1.27–5.17), debilitating generalized anxiety problems (OR 3.27, CI 1.64–6.51) and suicidality (OR 3.46, CI 1.53–7.81) at 15 years than those exposed to the lowest levels of victimization, after adjustment for sex, childhood mental health, family hardship and victimization perpetration. The association with suicidality remained significant after controlling for concurrent symptoms of depression or dysthymia and generalized anxiety problems. INTERPRETATION Adolescents who were most severely victimized by peers had an increased risk of experiencing severe symptoms consistent with mental health problems. Given that peer victimization trajectories are established early on, interventions to reduce the risk of being victimized should start before enrolment in the formal school system.
PDF
