Microstructural Correlates of Resilience against Major Depressive Disorder: Epigenetic Mechanisms?

Mental disorders are a major cause of long-term disability and are a direct cause of mortality, with approximately 800.000 individuals dying from suicide every year worldwide - a high proportion of them related to major depressive disorder (MDD)^1^. Healthy relatives of patients with major depressive disorder (MDD) are at risk to develop the disease. This higher vulnerability is associated with structural^2-4^ and functional brain changes^5^. However, we found using high angular resolution diffusion imaging (HARDI) with 61 diffusion directions that neuron tracts between frontal cortices and limbic as well as temporal and parietal brain regions are characterized by better diffusion coefficients in unaffected relatives (UHR), who managed to stay healthy, compared to healthy volunteers without any family history for a psychiatric disease (HC). Moreover, those UHR with stronger fibre connections better managed incidences of adversity in early life without later developing depression, while in HC axonal connections were found to be decreased when they had early-life adversity. Altogether these findings indicate the presence of stronger neural fibre connections in UHR, which seem to be associated with resilience against environmental stressors, which we suggest occur through epigenetic mechanisms

Broad Epigenetic Signature of Maternal Care in the Brain of Adult Rats

BACKGROUND: Maternal care is associated with long-term effects on behavior and epigenetic programming of the NR3C1 (GLUCOCORTICOID RECEPTOR) gene in the hippocampus of both rats and humans. In the rat, these effects are reversed by cross-fostering, demonstrating that they are defined by epigenetic rather than genetic processes. However, epigenetic changes at a single gene promoter are unlikely to account for the range of outcomes and the persistent change in expression of hundreds of additional genes in adult rats in response to differences in maternal care. METHODOLOGY/PRINCIPAL FINDINGS: We examine here using high-density oligonucleotide array the state of DNA methylation, histone acetylation and gene expression in a 7 million base pair region of chromosome 18 containing the NR3C1 gene in the hippocampus of adult rats. Natural variations in maternal care are associated with coordinate epigenetic changes spanning over a hundred kilobase pairs. The adult offspring of high compared to low maternal care mothers show epigenetic changes in promoters, exons, and gene ends associated with higher transcriptional activity across many genes within the locus examined. Other genes in this region remain unchanged, indicating a clustered yet specific and patterned response. Interestingly, the chromosomal region containing the protocadherin-α, -β, and -γ (Pcdh) gene families implicated in synaptogenesis show the highest differential response to maternal care. CONCLUSIONS/SIGNIFICANCE: The results suggest for the first time that the epigenetic response to maternal care is coordinated in clusters across broad genomic areas. The data indicate that the epigenetic response to maternal care involves not only single candidate gene promoters but includes transcriptional and intragenic sequences, as well as those residing distantly from transcription start sites. These epigenetic and transcriptional profiles constitute the first tiling microarray data set exploring the relationship between epigenetic modifications and RNA expression in both protein coding and non-coding regions across a chromosomal locus in the mammalian brain

Effects of Neonatal Neural Progenitor Cell Implantation on Adult Neuroanatomy and Cognition in the Ts65Dn Model of Down Syndrome

As much of the aberrant neural development in Down syndrome (DS) occurs postnatally, an early opportunity exists to intervene and influence life-long cognitive development. Recent success using neural progenitor cells (NPC) in models of adult neurodegeneration indicate such therapy may be a viable option in diseases such as DS. Murine NPC (mNPC, C17.2 cell line) or saline were implanted bilaterally into the dorsal hippocampus of postnatal day 2 (PND 2) Ts65Dn pups to explore the feasibility of early postnatal treatment in this mouse model of DS. Disomic littermates provided karyotype controls for trisomic pups. Pups were monitored for developmental milestone achievement, and then underwent adult behavior testing at 14 weeks of age. We found that implanted mNPC survived into adulthood and migrated beyond the implant site in both karyotypes. The implantation of mNPC resulted in a significant increase in the density of dentate granule cells. However, mNPC implantation did not elicit cognitive changes in trisomic mice either neonatally or in adulthood. To the best of our knowledge, these results constitute the first assessment of mNPC as an early intervention on cognitive ability in a DS model

Hyperoxemia and excess oxygen use in early acute respiratory distress syndrome : Insights from the LUNG SAFE study

Publisher Copyright: © 2020 The Author(s). Copyright: Copyright 2020 Elsevier B.V., All rights reserved.Background: Concerns exist regarding the prevalence and impact of unnecessary oxygen use in patients with acute respiratory distress syndrome (ARDS). We examined this issue in patients with ARDS enrolled in the Large observational study to UNderstand the Global impact of Severe Acute respiratory FailurE (LUNG SAFE) study. Methods: In this secondary analysis of the LUNG SAFE study, we wished to determine the prevalence and the outcomes associated with hyperoxemia on day 1, sustained hyperoxemia, and excessive oxygen use in patients with early ARDS. Patients who fulfilled criteria of ARDS on day 1 and day 2 of acute hypoxemic respiratory failure were categorized based on the presence of hyperoxemia (PaO2 > 100 mmHg) on day 1, sustained (i.e., present on day 1 and day 2) hyperoxemia, or excessive oxygen use (FIO2 ≥ 0.60 during hyperoxemia). Results: Of 2005 patients that met the inclusion criteria, 131 (6.5%) were hypoxemic (PaO2 < 55 mmHg), 607 (30%) had hyperoxemia on day 1, and 250 (12%) had sustained hyperoxemia. Excess FIO2 use occurred in 400 (66%) out of 607 patients with hyperoxemia. Excess FIO2 use decreased from day 1 to day 2 of ARDS, with most hyperoxemic patients on day 2 receiving relatively low FIO2. Multivariate analyses found no independent relationship between day 1 hyperoxemia, sustained hyperoxemia, or excess FIO2 use and adverse clinical outcomes. Mortality was 42% in patients with excess FIO2 use, compared to 39% in a propensity-matched sample of normoxemic (PaO2 55-100 mmHg) patients (P = 0.47). Conclusions: Hyperoxemia and excess oxygen use are both prevalent in early ARDS but are most often non-sustained. No relationship was found between hyperoxemia or excessive oxygen use and patient outcome in this cohort. Trial registration: LUNG-SAFE is registered with ClinicalTrials.gov, NCT02010073publishersversionPeer reviewe

Effect of childhood maltreatment on brain structure in adult patients with major depressive disorder and healthy participants.

BACKGROUND: Childhood maltreatment has been found to play a crucial role in the development of psychiatric disorders. However, whether childhood maltreatment is associated with structural brain changes described for major depressive disorder (MDD) is still a matter of debate. The aim of this study was to investigate whether patients with MDD and a history of childhood maltreatment display more structural changes than patients without childhood maltreatment or healthy controls. METHODS: Patients with MDD and healthy controls with and without childhood maltreatment experience were investigated using high-resolution magnetic resonance imaging (MRI), and data were analyzed using voxel-based morphometry. RESULTS: We studied 37 patients with MDD and 46 controls. Grey matter volume was significantly decreased in the hippocampus and significantly increased in the dorsomedial prefrontal cortex (DMPFC) and the orbitofrontal cortex (OFC) in participants who had experienced childhood maltreatment compared with those who had not. Patients displayed smaller left OFC and left DMPFC volumes than controls. No significant difference in hippocampal volume was evident between patients with MDD and healthy controls. In regression analyses, despite effects from depression, age and sex on the DMPFC, OFC and hippocampus, childhood maltreatment was found to independently affect these regions. LIMITATIONS: The retrospective assessment of childhood maltreatment; the natural problem that patients experienced more childhood maltreatment than controls; and the restrictions, owing to sample size, to investigating higher order interactions among factors are discussed as limitations. CONCLUSION: These results suggest that early childhood maltreatment is associated with brain structural changes irrespective of sex, age and a history of depression.Thus, the study highlights the importance of childhood maltreatment when investigating brain structures

Aquatic ecosystem responses to Holocene climate change and biome development in boreal central Asia

Borealecosystems are highly vulnerable to climatechange, and severe ecological impacts in the near future are virtually certain to occur. We undertook a multiproxy study on an alpine lake (ESM-1) at the modern tree-line in boreal, southern Siberia. Steppe and tundra biomes were extensive in eastern Sayan landscapes during the early Holocene. Boreal forest quickly expanded by 9.1 ka BP, and dominated the landscape until c 0.7 ka BP, when the greatest period of compositional turnover occurred. At this time, alpine meadow landscape expanded and Picea obovata colonised new habitats along river valleys and lake shorelines, because of prevailing cool, moist conditions. During the early Holocene, chironomid assemblages were dominated by cold stenotherms. Diatoms for much of the Holocene were dominated by alkaliphilous, fragilarioid taxa, up until 0.2 ka BP, when epiphytic species expanded, indicative of increased habitat availability. C/N mass ratios ranged between 9.5 and 13.5 (11.1–15.8 C/N atomic ratios), indicative of algal communities dominating organic matter contributions to bottom sediments with small, persistent contributions from vascular plants. However, ?13C values increased steadily from ?34.9‰ during the early Holocene (9.3 ka BP) to ?24.8‰ by 0.6 ka BP. This large shift in magnitude may be due to a number of factors, including increasing within-lake productivity, increasing disequilibrium between the isotopic balance of the lake with the atmosphere as the lake became isotopically ‘mature’, and declining soil respiration linked to small, but distinct retreat in forest biomes. The influence of climatic variables on landscape vegetation was assessed using redundancy analysis (RDA), a linear, direct ordination technique. Changes in July insolation at 60 °N significantly explained over one-fifth of the variation in species composition, while changes in estimates of northern hemisphere temperature and ice-rafted debris events in the North Atlantic were also significant, but considerably less important. The potential importance of climate and biomedevelopment (tundra, steppe, cold deciduous forest and taiga) on different trophic levels (i.e. chironomid and diatom communities) in lake ESM-1 was also assessed using RDA. Climate predictors had a more significant influence on Holocene chironomid assemblages, especially July insolation at 60 °N, estimates of regional precipitation and estimates of northern hemisphere temperature, while only the development of the taiga biome had a significant impact on these primary consumers. Diatom communities also had a small, but significant influence on Holocene chironomid populations, perhaps linked to variation in faunal feeding strategies. In contrast, climatic and biome predictors explained similar amounts of variation in the Holocene diatom assemblage (approximately 20% each), while chironomids themselves as predictors explained just under 7% of diatom variation. Lake acidity was inferred using a diatom inference model. Results suggest that after deglaciation, the lake did not undergo a process of gradual acidification, most likely due to the presence of continuous permafrost and low levels of precipitation, preventing base cations and dissolved organic carbon entering the lake (except for the period between 1.7 and 0.7 ka BP). We conclude that lakes in continental, boreal regions undergo different models of lake ontogeny than oceanic boreal regions. Unlike other regions discussed, climate is a more important driver of ecosystemchange than catchment changes. We also demonstrate that the start of the period coincident with the onset of the Little Ice Age resulted in important thresholds crossed in catchment vegetation and aquatic communitie