There is growing evidence of abnormal epigenetic processes playing a role in the neurobiology of psychiatric disorders, although the precise nature of these anomalies remains largely unknown. To ...study neurobiological (including epigenetic) factors that influence emotionality, we use rats bred for distinct behavioral responses to novelty. Rats bred for low novelty response (low responder LR) exhibit high levels of anxiety- and depressive-like behavior compared with high novelty responder (HR) rats. Prior work revealed distinct limbic brain development in HR versus LR rats, including altered expression of genes involved in DNA methylation. This led us to hypothesize that DNA methylation differences in the developing brain drive the disparate HR/LR neurobehavioral phenotypes. Here we report altered DNA methylation markers (altered DNA methyltransferase protein levels and increased global DNA methylation levels) in the early postnatal amygdala of LR versus HR male rats. Next-generation sequencing methylome profiling identified numerous differentially methylated regions across the genome in the early postnatal HR/LR amygdala. We also contrasted methylation profiles of male HRs and LRs with a control rat strain that displays an intermediate behavioral phenotype relative to the HR/LR extremes; this revealed that the LR amygdalar methylome was abnormal, with the HR profile more closely resembling that of the control group. Finally, through two methylation manipulations in early life, we found that decreasing DNA methylation in the developing male and female amygdala improves adult anxiety- and depression-like behavior. These findings suggest that inborn DNA methylation differences play important roles in shaping brain development and lifelong emotional behavior.
Epigenetic changes are biological mechanisms that regulate the expression and function of genes throughout the brain and body. DNA methylation, one type of epigenetic mechanism, is known to be altered in brains of psychiatric patients, which suggests a role for DNA methylation in the pathogenesis of psychiatric disorders, such as depression and anxiety. The present study examines brains of rats that display high versus low levels of anxiety- and depression-like behavior to investigate how neural DNA methylation levels differ in these animals and how such differences shape their emotional behavioral differences. Studying how epigenetic processes affect emotional behavior may improve our understanding of the neurobiology of psychiatric disorders and lead to improved treatments.
The genome of the cnidarian Nematostella vectensis (starlet sea anemone) provides a molecular genetic view into the first nervous systems, which appeared in a late common ancestor of cnidarians and ...bilaterians. Nematostella has a surprisingly large and diverse set of neuronal signaling genes including paralogs of most neuronal signaling molecules found in higher metazoans. Several ion channel gene families are highly expanded in the sea anemone, including three subfamilies of the Shaker K(+) channel gene family: Shaker (Kv1), Shaw (Kv3) and Shal (Kv4). In order to better understand the physiological significance of these voltage-gated K(+) channel expansions, we analyzed the function of 18 members of the 20 gene Shaker subfamily in Nematostella. Six of the Nematostella Shaker genes express functional homotetrameric K(+) channels in vitro. These include functional orthologs of bilaterian Shakers and channels with an unusually high threshold for voltage activation. We identified 11 Nematostella Shaker genes with a distinct "silent" or "regulatory" phenotype; these encode subunits that function only in heteromeric channels and serve to further diversify Nematostella Shaker channel gating properties. Subunits with the regulatory phenotype have not previously been found in the Shaker subfamily, but have evolved independently in the Shab (Kv2) family in vertebrates and the Shal family in a cnidarian. Phylogenetic analysis indicates that regulatory subunits were present in ancestral cnidarians, but have continued to diversity at a high rate after the split between anthozoans and hydrozoans. Comparison of Shaker family gene complements from diverse metazoan species reveals frequent, large scale duplication has produced highly unique sets of Shaker channels in the major metazoan lineages.
The study objective was to inform patient-centered care for adolescent insomnia by describing adolescents' perspectives on insomnia. Specific constructs of interest included: 1) factors that ...contributed to insomnia development or maintenance, 2) impact of insomnia on day-to-day life, 3) recommended research priorities, and 4) overall experience living with insomnia.
A convenience sample of adolescents (ages 13-18 years) self-identifying with insomnia symptoms was recruited through social media. Respondents (
= 3,014) completed an online survey. Responses to an open-ended item assessing patient experience were coded using thematic analysis.
Participants identified as 70.8% White non-Hispanic, 77.0% female, and lived in one of five English-speaking countries (United States, United Kingdom, Canada, Australia, or New Zealand). Most (87.5%) met DSM-V diagnostic criteria for insomnia. The most common contributory factors to insomnia endorsed were stress (72.1%) and depressed mood (63.6%), while common impact areas were mood (72.2%), focus (61.0%), and pain (49.7%). Patient-centered research priorities were identifying insomnia causes (66.4%) and early detection (66.1%). Common adolescent experiences included high distress levels, feelings of invalidation, and helplessness about their insomnia.
Adolescents with insomnia offer a unique perspective that should inform patient-centered research and care. There is a need for heightened screening and awareness about insomnia as a condition that causes significant distress and impairment for adolescents. To provide validating care, providers should recognize the multifaceted causes of insomnia.
Swi-independent 3a and 3b (Sin3a and Sin3b) are paralogous transcriptional coregulators that direct cellular differentiation, survival, and function. Here, we report that mouse Sin3a and Sin3b are ...coproduced in most pancreatic cells during embryogenesis but become much more enriched in endocrine cells in adults, implying continued essential roles in mature endocrine cell function. Mice with loss of Sin3a in endocrine progenitors were normal during early postnatal stages but gradually developed diabetes before weaning. These physiological defects were preceded by the compromised survival, insulin-vesicle packaging, insulin secretion, and nutrient-induced Ca2+ influx of Sin3a-deficient β-cells. RNA sequencing coupled with candidate chromatin immunoprecipitation assays revealed several genes that could be directly regulated by Sin3a in β-cells, which modulate Ca2+/ion transport, cell survival, vesicle/membrane trafficking, glucose metabolism, and stress responses. Finally, mice with loss of both Sin3a and Sin3b in multipotent embryonic pancreatic progenitors had significantly reduced islet cell mass at birth, caused by decreased endocrine progenitor production and increased β-cell death. These findings highlight the stage-specific requirements for the presumed "general" coregulators Sin3a and Sin3b in islet β-cells, with Sin3a being dispensable for differentiation but required for postnatal function and survival.
Abstract In spite of intense interest in how altered epigenetic processes including DNA methylation may contribute to psychiatric and neurodevelopmental disorders, there is a limited understanding of ...how methylation processes change during early postnatal brain development. The present study used in situ hybridization to assess mRNA expression for the three major DNA methyltranserases (DNMTs) – DNMT1, DNMT3a and DNMT3b – in the developing rat brain at seven developmental timepoints: postnatal days (P) 1, 4, 7, 10, 14, 21, and 75. We also assessed 5-methylcytosine levels (an indicator of global DNA methylation) in selected brain regions during the first three postnatal weeks. DNMT1, DNMT3a and DNMT3b mRNAs are widely expressed throughout the adult and postnatal developing rat brain. Overall, DNMT mRNA levels reached their highest point in the first week of life and gradually decreased over the first three postnatal weeks within the hippocampus, amygdala, striatum, cingulate and lateral septum. Global DNA methylation levels did not follow this developmental pattern; methylation levels gradually increased over the first three postnatal weeks in the hippocampus, and remained stable in the developing amygdala and prefrontal cortex. Our results contribute to a growing understanding of how DNA methylation markers unfold in the developing brain, and highlight how these developmental processes may differ within distinct brain regions.
Picoeukaryotes are a taxonomically diverse group of organisms less than 2 micrometers in diameter. Photosynthetic marine picoeukaryotes in the genus Micromonas thrive in ecosystems ranging from ...tropical to polar and could serve as sentinel organisms for biogeochemical fluxes of modern oceans during climate change. These broadly distributed primary producers belong to an anciently diverged sister clade to land plants. Although Micromonas isolates have high 18S ribosomal RNA gene identity, we found that genomes from two isolates shared only 90% of their predicted genes. Their independent evolutionary paths were emphasized by distinct riboswitch arrangements as well as the discovery of intronic repeat elements in one isolate, and in metagenomic data, but not in other genomes. Divergence appears to have been facilitated by selection and acquisition processes that actively shape the repertoire of genes that are mutually exclusive between the two isolates differently than the core genes. Analyses of the Micromonas genomes offer valuable insights into ecological differentiation and the dynamic nature of early plant evolution.
Small cell lung cancer (SCLC) tumors comprise heterogeneous mixtures of cell states, categorized into neuroendocrine (NE) and non-neuroendocrine (non-NE) transcriptional subtypes. NE to non-NE state ...transitions, fueled by plasticity, likely underlie adaptability to treatment and dismal survival rates. Here, we apply an archetypal analysis to model plasticity by recasting SCLC phenotypic heterogeneity through multi-task evolutionary theory. Cell line and tumor transcriptomics data fit well in a five-dimensional convex polytope whose vertices optimize tasks reminiscent of pulmonary NE cells, the SCLC normal counterparts. These tasks, supported by knowledge and experimental data, include proliferation, slithering, metabolism, secretion, and injury repair, reflecting cancer hallmarks. SCLC subtypes, either at the population or single-cell level, can be positioned in archetypal space by bulk or single-cell transcriptomics, respectively, and characterized as task specialists or multi-task generalists by the distance from archetype vertex signatures. In the archetype space, modeling single-cell plasticity as a Markovian process along an underlying state manifold indicates that task trade-offs, in response to microenvironmental perturbations or treatment, may drive cell plasticity. Stifling phenotypic transitions and plasticity may provide new targets for much-needed translational advances in SCLC. A record of this paper's Transparent Peer Review process is included in the supplemental information.
Assessing amniotic fluid volume is an integral part of obstetric practice. Data are sparse on at-risk pregnancy and amniotic fluid volumes. The aim of our study was to determine if there is a ...difference in perinatal outcomes based on complications of pregnancy and amniotic fluid volumes. We hypothesized that at-risk pregnancies with abnormal amniotic fluid volumes would have worse perinatal outcomes than normal pregnancies with abnormal amniotic fluid volumes.
This retrospective cohort study evaluated both normal and at-risk singleton pregnancies with intact membranes on admission for delivery. Amniotic fluid volumes were estimated using both the amniotic fluid index (AFI) and single deepest pocket (SDP) techniques. All sonograms were performed by trained ultrasound technicians or obstetrician/gynecologists. We placed 3365 women into 6 separate groups (at-risk versus normal, then further stratified by oligohydramnios by SDP, normal fluid, or polyhydramnios by AFI).
At-risk pregnancies with normal fluid and at-risk pregnancies with polyhydramnios have significantly increased risk of neonatal intensive care unit (NICU) admission OR 2.06 (95% CI 1.63,2.60), OR 2.74 (95% CI 1.54, 4.87). Birthweight is significantly higher in at-risk and normal pregnancies with polyhydramnios than those with normal pregnancies and normal fluid (p<0.0001). Birthweight is significantly lower in at-risk pregnancies with oligohydramnios (p<0.0001). There were no significant differences in need for amnioinfusion in labor, variables or lates influencing delivery, meconium staining, or umbilical artery pH <7.1.
Our study attempted to further define risk of adverse pregnancy outcomes by defining the pregnancy as normal or at-risk and amniotic fluid volumes. Contrary to our hypothesis, we did not find an increased risk of many of the adverse perinatal outcomes we studied amongst at-risk pregnancies with abnormal fluid. There was an increased risk of NICU admission associated with polyhydramnios in normal and at-risk pregnancies.
All organisms exhibit a wide range of emotional behaviors and interact with the environment in different ways. Some individuals may be more quiet and shy whereas others are more outgoing and ...adventurous. These temperamental and personality differences can predispose individuals to certain psychopathologies which may be influenced by genetic vulnerability and/or early life experiences. Rodent models can be used to recapitulate emotional reactivity differences, and these models can, in turn, be used to examine potential neurobiological underpinnings of these traits. The present study utilizes two strains of rats that were selectively bred for differences in novelty seeking. High Novelty-Responding (bHR) rats are very active in response to novelty, exhibit exaggerated risk-taking, aggression, impulsivity, and show increased behavioral response to cocaine. Low Novelty-Responding (bLR) rats show increased anxiety, depressive behavior and vulnerability to chronic stress. One way in which the bHR versus bLR behavioral phenotypes may differ is through epigenetic modification of DNA. DNA can be modified through processes such as acetylation or methylation to either enhance or subdue gene expression. This study examines putative differences in methylation levels in the hippocampus and amygdala of developing bHR-bLR rats. Previous research observed widespread gene expression differences in the bLR developing hippocampus, and the current study aims to begin to examine potential epigenetic factors that may contribute to those gene differences. The amygdala was chosen because it is involved in emotional processes, in part through its connections with the hippocampus. Therefore, the present study used in situ hybridization to assess the expression of DNA methyltransferase-1 (DNMT1) mRNA in the hippocampus, amygdala and several other brain areas of bHR and bLR pups at three developmental time points: postnatal days (P) 7, 14, and 21. We focused on the first 3 postnatal weeks, in part to parallel our early microarray gene expression work, and because this represents a critical period of brain development, which shapes individuals' lifelong emotional and stress reactivity. We found significant differences in dentate gyrus and CA3 regions of the hippocampus at P7 with no differences seen at P14 or P21. Interestingly, we also found significant bHR-bLR DNMT1 differences at P7 within the lateral, basolateral and medial nuclei of the amygdala, with no difference at P14 and P21, suggesting that the first postnatal week is a critical period for DNA methylation during brain development.
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