Telomere length as a predictor of emotional processing in the brain.
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ABSTRACT:
SUBMITTER: Powell TR
PROVIDER: S-EPMC6492163 | biostudies-literature | 2019 Apr
REPOSITORIES: biostudies-literature
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Project description:Several studies have reported association between leukocyte telomere length (LTL) and neuropsychiatric disorders. Although telomere length is affected by environmental factors, genetic variants in certain loci are strongly associated with LTL. Thus, we aimed to identify the genomic relationship between genetic variants of LTL with brain-based regulatory changes and brain volume. We tested genetic colocalization of seven and nine LTL loci in two ancestry groups, European (EUR) and East-Asian (EAS), respectively, with brain morphology measures for 101 T1-magnetic resonance imaging-based region of interests (n = 21 821). The posterior probability (>90%) was observed for 'fourth ventricle', 'gray matter' and 'cerebellar vermal lobules I-IV' volumes. We then tested causal relationship using LTL loci for gene and methylation expression. We found causal pleiotropy for gene (EAS = four genes; EUR = five genes) and methylation expression (EUR = 17 probes; EAS = 4 probes) of brain tissues (P ≤ 2.47 × 10-6). Integrating chromatin profiles with LTL-single nucleotide polymorphisms identified 45 genes (EUR) and 79 genes (EAS) (P ≤ 9.78×10-7). We found additional 38 LTL-genes using chromatin-based gene mapping for EUR ancestry population. Gene variants in three LTL-genes-GPR37, OBFC1 and RTEL1/RTEL1-TNFRSF6B-show convergent evidence of pleiotropy with brain morphology, gene and methylation expression and chromatin association. Mapping gene functions to drug-gene interactions, we identified process 'transmission across chemical synapses' (P < 2.78 × 10-4). This study provides evidence that genetic variants of LTL have pleiotropic roles with brain-based effects that could explain the phenotypic association of LTL with several neuropsychiatric traits.
| S-EPMC8255129 | biostudies-literature
Project description:BackgroundSex, emotion, and reproduction are fundamental and tightly entwined aspects of human behavior. At a population level in humans, both the desire for sexual stimulation and the desire to bond with a partner are important precursors to reproduction. However, the relationships between these processes are incompletely understood. The limbic brain system has key roles in sexual and emotional behaviors, and is a likely candidate system for the integration of behavior with the hormonal reproductive axis. We investigated the effects of kisspeptin, a recently identified key reproductive hormone, on limbic brain activity and behavior.MethodsUsing a combination of functional neuroimaging and hormonal and psychometric analyses, we compared the effects of kisspeptin versus vehicle administration in 29 healthy heterosexual young men.ResultsWe demonstrated that kisspeptin administration enhanced limbic brain activity specifically in response to sexual and couple-bonding stimuli. Furthermore, kisspeptin's enhancement of limbic brain structures correlated with psychometric measures of reward, drive, mood, and sexual aversion, providing functional significance. In addition, kisspeptin administration attenuated negative mood.ConclusionsCollectively, our data provide evidence of an undescribed role for kisspeptin in integrating sexual and emotional brain processing with reproduction in humans. These results have important implications for our understanding of reproductive biology and are highly relevant to the current pharmacological development of kisspeptin as a potential therapeutic agent for patients with common disorders of reproductive function.FundingNational Institute for Health Research (NIHR), Wellcome Trust (Ref 080268), and the Medical Research Council (MRC).
| S-EPMC5272173 | biostudies-literature
Project description:The Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) initiative has formed with the expressed intent of identifying constructs and paradigms that would identify biomarkers of psychosis. The manipulation of these biomarkers would serve as targets for treatment interventions. The second phase of CNTRICS consisted of critical discussions evaluating brain mapping (functional neuroimaging and brain electrical activity) paradigms as biomarkers to measure specific constructs. Among the constructs identified in, CNTRICS I was socio-emotional processing, specifically focused on affect recognition. Here, we provide a critical appraisal of the ability of candidate socio-emotional tasks to identify putative biomarkers and recommendations for future directions in this rapidly moving research domain.
| S-EPMC3245598 | biostudies-literature
Project description:BackgroundTelomere length (TL) is considered a biological marker of aging and may indicate age-related disease susceptibility. Adults and children show a fixed ranking and tracking of TL over time. However, the contribution of an individual's initial birth TL to their later life TL is unknown. We evaluated change and tracking of TL from birth to child- and adulthood.MethodsTelomere length at birth was measured using qPCR in two independent prospective birth cohorts. After a median follow-up period of 4 years in ENVIRONAGE (n = 273) we assessed leukocyte telomere length (LTL) and after 23 years in EFPTS (n = 164) buccal TL was assessed. Correlations and multivariable regression models were applied to study telomere tracking and determinants of TL change from birth onwards.FindingsIn children, LTL at the age of 4 correlates with TL at the start of life both in cord blood (r = 0.71, P < 0.0001;) and placenta (r = 0.60, P < 0.0001) and was -11.2% and -33.1% shorter, respectively. In adulthood, buccal TL at the age of 23 correlates with placental TL (r = 0.46, P < 0.0001) and was -35.9% shorter. TL attrition was higher in individuals with longer birth TL. However, based on TL ranking, individuals do not tend to change dramatically from TL rank after 4 or 23 years of follow-up. Finally, longer maternal TL associates with lower telomere attrition in the next generation.InterpretationThe high prediction of newborn TL for later life TL, and stable TL ranking from birth onwards underscores the importance of understanding the initial setting of newborn TL and its significance for later life.FundingEuropean Research Council (ERC-StG310898) and Flemish Scientific Fund (12X9620N).
| S-EPMC7808927 | biostudies-literature
Project description:Telomeres play important roles in genome stability and cell proliferation. Telomere lengths are heterogeneous and because just a few abnormal telomeres are sufficient to trigger significant cellular response, it is informative to have accurate assays that reveal not only average telomere lengths, but also the distribution of the longest and shortest telomeres in a given sample. Herein we report for the first time, the development of single telomere length analysis (STELA) - a PCR-based assay that amplifies multiple, individual telomeres - for Ustilago maydis, a basidiomycete fungus. Compared to the standard telomere Southern technique, STELA revealed a broader distribution of telomere size as well as the existence of relatively short telomeres in wild type cells. When applied to blm?, a mutant thought to be defective in telomere replication, STELA revealed preferential loss of long telomeres, whose maintenance may thus be especially dependent upon efficient replication. In comparison to blm?, the trt1? (telomerase null) mutant exhibited greater erosion of short telomeres, consistent with a special role for telomerase in re-lengthening extra-short telomeres. We also used STELA to characterize the 5' ends of telomere C-strand, and found that in U. maydis, they terminate preferentially at selected nucleotide positions within the telomere repeat. Deleting trt1 altered the 5'-end distributions, suggesting that telomerase may directly or indirectly modulate C-strand 5' end formation. These findings illustrate the utility of STELA as well as the strengths of U. maydis as a model system for telomere research.
| S-EPMC6167521 | biostudies-literature
Project description:Meta-analytic techniques for mining the neuroimaging literature continue to exert an impact on our conceptualization of functional brain networks contributing to human emotion and cognition. Traditional theories regarding the neurobiological substrates contributing to affective processing are shifting from regional- towards more network-based heuristic frameworks. To elucidate differential brain network involvement linked to distinct aspects of emotion processing, we applied an emergent meta-analytic clustering approach to the extensive body of affective neuroimaging results archived in the BrainMap database. Specifically, we performed hierarchical clustering on the modeled activation maps from 1,747 experiments in the affective processing domain, resulting in five meta-analytic groupings of experiments demonstrating whole-brain recruitment. Behavioral inference analyses conducted for each of these groupings suggested dissociable networks supporting: (1) visual perception within primary and associative visual cortices, (2) auditory perception within primary auditory cortices, (3) attention to emotionally salient information within insular, anterior cingulate, and subcortical regions, (4) appraisal and prediction of emotional events within medial prefrontal and posterior cingulate cortices, and (5) induction of emotional responses within amygdala and fusiform gyri. These meta-analytic outcomes are consistent with a contemporary psychological model of affective processing in which emotionally salient information from perceived stimuli are integrated with previous experiences to engender a subjective affective response. This study highlights the utility of using emergent meta-analytic methods to inform and extend psychological theories and suggests that emotions are manifest as the eventual consequence of interactions between large-scale brain networks.
| S-EPMC5951754 | biostudies-literature
Project description:The number of (TTAGGG)n repeats at the ends of chromosomes is highly variable between individual chromosomes, between different cells and between species. Progressive loss of telomere repeats limits the proliferation of pre-malignant human cells but also contributes to aging by inducing apoptosis and senescence in normal cells. Despite enormous progress in understanding distinct pathways that result in loss and gain of telomeric DNA in different cell types, many questions remain. Further studies are needed to delineate the role of damage to telomeric DNA, replication errors, chromatin structure, liquid-liquid phase transition, telomeric transcripts (TERRA) and secondary DNA structures such as guanine quadruplex structures, R-loops and T-loops in inducing gains and losses of telomere repeats in different cell types. Limitations of current telomere length measurements techniques and differences in telomere biology between species and different cell types complicate generalizations about the role of telomeres in aging and cancer. Here some of the factors regulating the telomere length in embryonic and adult cells in mammals are discussed from a mechanistic and evolutionary perspective.
| S-EPMC9289283 | biostudies-literature
Project description:Neuropeptide Y (NPY) has been associated with stress reactivity in affective disorders and is most densely expressed in the amygdala. An important stressor associated with affective disorders is the experience of childhood emotional maltreatment (CEM). We investigated whether the interaction of NPY risk genotype and CEM would affect brain activation. From The Netherlands Study of Depression and Anxiety, 33 healthy controls and 85 patients with affective disorders were scanned with functional magnetic resonance imaging while making gender decisions of emotional facial expressions. Results showed interactions between genotype and CEM, within carriers of the risk genotype, CEM was associated with higher amygdala activation, whereas CEM did not influence activation in non-risk carriers. In the posterior cingulate cortex (PCC), less activation was seen in those with CEM and the risk genotype, whereas genotype did not influence PCC activation in those without CEM. In addition, those carrying the risk genotype and with experience of CEM made a faster gender decision than those without CEM. Thus, the combined effect of carrying NPY risk genotype and a history of CEM affected amygdala and PCC reactivity, areas related to emotion, self-relevance processing and autobiographical memory. These results are consistent with the notion that the combination of risk genotype and CEM may cause hypervigilance.
| S-EPMC4014098 | biostudies-literature
Project description:We studied peripheral leukocyte telomere length (LTL) as a predictor of antidepressant response to PPAR-γ agonist in patients with unremitted depression. In addition we examined correlation between LTL and the insulin resistance (IR) status in these subjects. Forty-two medically stable men and women ages 23-71 with non-remitted depression participated in double-blind placebo-controlled add-on of Pioglitazone to treatment-as-usual. Oral glucose tolerance tests were administered at baseline and at 12 weeks. Diagnostic evaluation of psychiatric disorders was performed at baseline and mood severity was followed weekly throughout the duration of the trial. At baseline, no differences in LTL were detected by depression severity, duration or chronicity. LTL was also not significantly different between insulin-resistant and insulin-sensitive subjects at baseline. Subjects with longer telomeres exhibited greater declines in depression severity in the active arm, but not in a placebo arm, P=0.005, r=-0.63, 95% confidence interval (95% CI)=(-0.84,-0.21). In addition, LTL predicted improvement in insulin sensitivity in the group overall and did not differ between intervention arms, P=0.036, r=-0.44, 95% CI=(-0.74,0.02) for the active arm, and P=0.026, r=-0.50, 95% CI=(-0.78,-0.03) for the placebo arm. LTL may emerge as a viable predictor of antidepressant response. An association between insulin sensitization and LTL regardless of the baseline IR status points to potential role of LTL as a non-specific moderator of metabolic improvement in these patients.
| S-EPMC5068869 | biostudies-literature
Project description:IntroductionTelomeres, are composed of tandem repeat sequences located at the ends of chromosomes and are required to maintain genomic stability. Telomeres can become shorter due to cell division and specific lifestyle factors. Critically shortened telomeres are linked to cellular dysfunction, senescence and aging. A number of studies have used low resolution techniques to assess telomere length in the placenta. In this study, we applied Single Telomere Length Analysis (STELA) which provides high-resolution chromosome specific telomere length profiles to ask whether we could obtain more detailed information on the length of individual telomeres in the placenta.MethodsTerm placentas (37-42 weeks) were collected from women delivering at University Hospital of Wales or Royal Gwent Hospital within 2 h of delivery. Multiple telomere-length distributions were determined using STELA. Intraplacental variation of telomere length was analysed (N = 5). Telomere length distributions were compared between labouring (N = 10) and non-labouring (N = 11) participants. Finally, telomere length was compared between female (N = 17) and male (N = 20) placenta.ResultsThere were no significant influences of sampling site, mode of delivery or foetal sex on the telomere-length distributions obtained. The mean telomere length was 7.7 kb ranging from 5.0 kb to 11.7 kb across all samples (N = 42) and longer compared with other human tissues at birth. STELA also revealed considerable telomere length heterogeneity within samples.ConclusionsWe have shown that STELA can be used to study telomere length homeostasis in the placenta regardless of sampling site, mode of delivery and foetal sex. Moreover, as each amplicon is derived from a single telomeric molecule, from a single cell, STELA can reveal the full detail of telomere-length distributions, including telomeres within the length ranges observed in senescent cells. STELA thus provides a new tool to interrogate the relationship between telomere length and pregnancy complications linked to placental dysfunction.
| S-EPMC5687939 | biostudies-literature