scholarly journals SUN-722 Liver Leptin Receptor Gene Network Moderates the Effects of Early Life Adversity on Anxiety and Depression Problems in Children and Adolescents

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Randriely Merscher Sobreira de Lima ◽  
Barbara Barth ◽  
Danusa Mar Arcego ◽  
Euclides José de Mendonça Filho ◽  
Sachin Patel ◽  
...  
Keyword(s):  
Early Life ◽  
Gene Network ◽  
Child Behavior Checklist ◽  
Cholesterol Metabolism ◽  
Emotional Behavior ◽  
Anterior Cingulate ◽  
Polygenic Risk Score ◽  
Emotional Symptoms ◽  
Early Life Adversity ◽  
Lepr Gene

Abstract Leptin is a hormone involved in the regulation of food intake, with receptors largely expressed centrally and peripherally, in structures like the hypothalamus and the liver. Beyond its well-known actions as an energy-balance regulator, leptin is linked to psychiatric disorders. Considering that the association between genetic and early environmental factors contributes to psychopathology, disruptions of leptin signaling could be a key mechanism in this interaction. To investigate this possibility, we created an expression-based polygenic risk score (ePRS) reflecting variations in the function of the LepR gene network in the liver and hypothalamus, and investigated its interaction with postnatal adversity on Child Behavior Checklist in 4 years old children (main cohort: MAVAN, N=137) and 17 years old teenagers (Replication Cohort: ALSPAC, N=2630). There is an interaction effect between adversity exposure and liver-based LepR-ePRS, increasing depressive and anxiety problems on the MAVAN cohort (β=78.16, p=0.02, β=83.77, p=0.01). In ALSPAC, the results were replicated, showing an interaction between adversity exposure and liver-based LepR-ePRS, increasing the depression score and somatic symptoms (β=24.65, p=0.005; β=33.51, p=0.009). No significant interactions were found using the hypothalamus-based LepR-ePRS (p>0.05), suggesting specificity for the liver LepR gene network to predict these behavioral outcomes. A parallel-independent component analysis showed relationships between the SNPs from the liver ePRS-LepR and gray matter density in cortical areas involved in emotion regulation (middle frontal gyrus, inferior parietal lobule and anterior cingulate). Finally, the relationship between gene and MRI components in this analysis is moderated by the history of early life adversity exposure. Enrichment analysis of the liver LepR co-expression network shows that these genes are related to biological processes including regulation of glucose transport, cholesterol metabolism and cellular glucose homeostasis, which indicates possible underlying mechanisms linking peripheral metabolism-related gene expression and the development of emotional symptoms. Our data supports the hypothesis that exposure to early adversity affects emotional behavior, and the liver LepR gene network is an important moderator of these effects. Further studies on development of emotional symptoms should consider metabolic markers to understand these complex phenotypes.

scholarly journals MON-722 Cross-Species Glucocorticoid-Sensitive Posterior Dentate Gyrus Gene Network: Developing a Polygenic Score Associated to Susceptibility to Depression After Early Life Adversity Exposure in Humans

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Danusa Mar Arcego ◽  
Nick O’Toole ◽  
Jan-Paul Buschdorf ◽  
Nirmala Arul Rayan ◽  
Barbara Barth ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dentate Gyrus ◽  
Early Life ◽  
Gene Network ◽  
Female Rats ◽  
Early Adversity ◽  
Polygenic Risk Score ◽  
Adult Women ◽  
Early Life Adversity ◽  
Polygenic Score

Abstract Exposure to stress during the life-course has consistently been associated with neuropsychological disorders, but the precise role of stress released glucocorticoids remains unclear in this context. We aimed at using hippocampal gene expression data from macaques to identify clusters of genes sensible to glucocorticoid exposure and create a biologically relevant polygenic score to investigate emotional disorders in a child and adult humans exposed to early adversity. RNA-sequencing data from the posterior dentate gyrus (pDG) of adult Macaca fascicularis females treated with Betamethasone (glucocorticoid) or saline injections for 8 consecutive days were analyzed from two cohorts: Singapore (reference) and Vietnam (replication) with N=12/each. Weighted gene co-expression network analysis (WGCNA) was used to identify clusters (modules) of co-expressed genes associated with betamethasone. In Singaporean animals, genes were clustered in 52 modules, in which 5 were associated with betamethasone. Two modules were preserved in a replication dataset (Vietnam) and in data from female rats treated with corticosterone for 6 weeks, being the black module (557 genes, P=0.01, r=0.7) the one having the highest correlation with glucocorticoid exposure. Gene ontology analysis (FDR<0.05, Metacore®) revealed that this module is associated with transcription processes. The SNPs derived from genes within the module were used to calculate an expression-based polygenic risk score (ePRS) in the human samples, weighing each SNP by the slope of the association between genotype and gene expression (GTex). Linear regression analysis showed a significant interaction between ePRS and early adversity on the Dominique - major depressive disorder domain (β=1304; P=0.003; N=65) in girls aged 6 years (MAVAN), in which a higher ePRS was associated with more symptoms as the adversity scores increases (simple slope analysis,P=0.004). A comparable interaction between the ePRS and postnatal adversity was also observed in adult women (UK Biobank), in which there was an increased risk for early depression onset (β= -424.3, P=0.04; N=13899). In the adult cohort, whole brain gray matter volume was also associated with differences in the expression of the genes that composed the ePRS-black network (main ePRS effect, β=1865776, P=0.03, N=10902). Glucocorticoid exposure affects a specific group of genes in pDG of adult female macaques and rats, influencing transcriptional processes. Variations in the expression of this gene network sensible to glucocorticoids were associated with susceptibility for the development of depression in girls and adult women exposed to early life adversity. These show the importance of glucocorticoids on the development of depressive symptoms. The gene network affected by glucocorticoids can guide future pharmacological or mechanistic studies in other samples or species.

scholarly journals Association of BDNF Val66Met Polymorphism and Brain BDNF levels with Major Depression and Suicide

2017 ◽  
Author(s):  
Mariam M. Youssef ◽  
Mark D. Underwood ◽  
Yung-Yu Huang ◽  
Shu-chi Hsiung ◽  
Yan Liu ◽  
...  
Keyword(s):  
Major Depression ◽  
Early Life ◽  
Childhood Adversity ◽  
Anterior Cingulate ◽  
Bdnf Expression ◽  
Early Life Adversity ◽  
Val66met Polymorphism ◽  
Protein Levels ◽  
Dorsolateral Prefrontal ◽  
Bdnf Val66met Polymorphism

ABSTRACTBrain-derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depressive disorder (MDD) and suicide. Both are partly caused by early life adversity (ELA) and ELA reduces both BDNF protein and gene expression. This study examines the association of BDNF Val66Met polymorphism and brain BDNF levels with depression and suicide. We hypothesized that both MDD and ELA would be associated with the Met allele and lower brain BDNF levels. Such an association would be consistent with low BDNF mediating the effect of ELA on adulthood suicide and MDD. BDNF Val66Met polymorphism was genotyped in postmortem brains of 37 suicide decedents and 53 non-suicides. Additionally, BDNF protein levels were determined by Western blot in dorsolateral prefrontal cortex (Brodmann area 9; BA9), anterior cingulate cortex (ACC; BA24), caudal brainstem and rostral brainstem. The relationships between these measures and major depression, death by suicide and reported childhood adversity were examined. Depressed subjects had an excess of the Met allele and lower BDNF levels in ACC and caudal brainstem compared with non-depressed subjects. No effect of history of suicide death or early life adversity was observed with genotype, but lower BDNF levels in ACC were found in subjects who had been exposed to early life adversity and/or died by suicide compared to nonsuicide decedents and no reported childhood adversity. This study provides further evidence for low BDNF in major depression related to the BDNF met risk allele. Future studies should seek to determine how altered BDNF expression contributes to MDD and suicide.

scholarly journals Less NMDA Receptor Binding in Dorsolateral Prefrontal Cortex and Anterior Cingulate Cortex Associated With Reported Early-Life Adversity but Not Suicide

2020 ◽  
Vol 23 (5) ◽  
pp. 311-318 ◽  
Author(s):  
Mark D Underwood ◽  
Mihran J Bakalian ◽  
Virginia L Johnson ◽  
Suham A Kassir ◽  
Steven P Ellis ◽  
...  
Keyword(s):  
Nmda Receptor ◽  
Receptor Binding ◽  
Early Life ◽  
Anterior Cingulate ◽  
Major Depression Disorder ◽  
Early Life Adversity ◽  
Mk 801 ◽  
Dorsolateral Prefrontal ◽  
Depression Disorder ◽  
Nmda Receptor Binding

Abstract Background Glutamate is an excitatory neurotransmitter binding to 3 classes of receptors, including the N-methyl, D-aspartate (NMDA) receptor. NMDA receptor binding is lower in major depression disorder and suicide. NMDA receptor blocking with ketamine can have antidepressant and anti-suicide effects. Early-life adversity (ELA) may cause glutamate-mediated excitotoxicity and is more common with major depression disorder and in suicide decedents. We sought to determine whether NMDA-receptor binding is altered with suicide and ELA. Methods A total 52 postmortem cases were organized as 13 quadruplets of suicide and non-suicide decedents matched for age, sex, and postmortem interval, with or without reported ELA (≤16 years). Tissue blocks containing dorsal prefrontal (BA8), dorsolateral prefrontal (BA9), or anterior cingulate (BA24) cortex were collected at autopsy. Psychiatrically healthy controls and suicide decedents underwent psychological autopsy to determine psychiatric diagnoses and details of childhood adversity. NMDA receptor binding was determined by quantitative autoradiography of [3H]MK-801 binding (displaced by unlabeled MK-801) in 20-µm-thick sections. Results [3H]MK-801 binding was not associated with suicide in BA8, BA9, or BA24. However, [3H]MK-801 binding with ELA was less in BA8, BA9, and BA24 independent of suicide (P < .05). [3H]MK-801 binding was not associated with age or postmortem interval in any brain region or group. Conclusions Less NMDA receptor binding with ELA is consistent with the hypothesis that stress can cause excitotoxicity via excessive glutamate, causing either NMDA receptor downregulation or less receptor binding due to neuron loss consequent to the excitotoxicity.

scholarly journals The roles of early-life adversity and rumination in neural response to emotional faces amongst anxious and depressed adults

2018 ◽  
Vol 49 (13) ◽  
pp. 2267-2278 ◽  
Author(s):  
Amy T. Peters ◽  
Katie L. Burkhouse ◽  
Kerry L. Kinney ◽  
K. Luan Phan
Keyword(s):  
Early Life ◽  
Emotion Processing ◽  
Brain Regions ◽  
Anterior Cingulate ◽  
Matching Task ◽  
Parameter Estimates ◽  
Early Life Adversity ◽  
Emotional Faces ◽  
Regulatory Strategies ◽  
Emotional Face

AbstractBackgroundEarly-life adversity (ELA) is a risk factor for internalizing psychopathology (IP). ELA is also linked to alterations in neural phenotypes of emotion processing and maladaptive emotion regulatory strategies, such as ruminative brooding, in adulthood. We therefore expected that ELA would predict cortical brain activation to emotional faces in transdiagnostic IP and in turn, mediate the extent of rumination amongst patients with IPs and ELA (IP + ELA).MethodOne hundred and thirty-two individuals, including 102 treatment-seeking adults with heterogeneous IPs and 30 healthy controls (HCs) performed an Emotional Face-Matching Task during functional magnetic resonance imaging. Whole-brain analyses compared HC (n = 30), IP (n = 52), and IP + ELA (n = 50) neural responses to emotional (angry, fearful, happy, and sad) faces v. shapes, controlling for depression and anxiety symptoms. Parameter estimates of activation were extracted for significant between-group differences and tested as a mediator of ruminative brooding in IP + ELA.ResultsIP + ELA demonstrated increased activation in the superior frontal gyrus and anterior cingulate cortex (fear), superior parietal lobule, precuneus, posterior cingulate, and inferior temporal gyrus (fear only), and cuneus (fear and angry). These regions were preferentially correlated with ruminative brooding in IP + ELA, many of which mediated the link between IP + ELA and ruminative brooding.ConclusionsResults provide evidence that ELA history amongst IP patients augments engagement of brain regions involved in emotion processing, above and beyond what is accounted for by current symptoms. Though longitudinal designs are needed, alterations in the neural correlates of maladaptive processing of socio-emotional information may be a common pathway by which ELA poses risk for psychopathology.

scholarly journals Cumulative prenatal exposure to adversity reveals associations with a broad range of neurodevelopmental outcomes that are moderated by a novel, biologically informed polygenetic score based on the serotonin transporter solute carrier family C6, member 4 (SLC6A4) gene expression

2017 ◽  
Vol 29 (5) ◽  
pp. 1601-1617 ◽  
Author(s):  
Patrícia P. Silveira ◽  
Irina Pokhvisneva ◽  
Carine Parent ◽  
Shirong Cai ◽  
Anu Sathyan Sathyapalan Rema ◽  
...  
Keyword(s):  
Serotonin Transporter ◽  
Early Life ◽  
Child Behavior Checklist ◽  
Birth Cohorts ◽  
Neurodevelopmental Outcomes ◽  
Genetic Score ◽  
Cumulative Impact ◽  
Early Life Adversity ◽  
Developmental Problems ◽  
Wide Range

AbstractWhile many studies focus on the association between early life adversity and the later risk for psychopathology, few simultaneously explore diverse forms of environmental adversity. Moreover, those studies that examined the cumulative impact of early life adversity focus uniquely on postnatal influences. The objective of this study was to focus on the fetal period of development to construct and validate a cumulative prenatal adversity score in relation to a wide range of neurodevelopmental outcomes. We also examined the interaction of this adversity score with a biologically informed genetic score based on the serotonin transporter gene. Prenatal adversities were computed in two community birth cohorts using information on health during pregnancy, birth weight, gestational age, income, domestic violence/sexual abuse, marital strain, as well as maternal smoking, anxiety, and depression. A genetic score based on genes coexpressed with the serotonin transporter in the amygdala, hippocampus, and prefrontal cortex during prenatal life was constructed with an emphasis on functionally relevant single nucleotide polymorphisms, that is, expression quantitative trait loci. Prenatal adversities predicted a wide range of developmental and behavioral alterations in children as young as 2 years of age in both cohorts. There were interactions between the genetic score and adversities for several domains of the Child Behavior Checklist (CBCL), with pervasive developmental problems remaining significant adjustment for multiple comparisons. Scores combining different prenatal adverse exposures predict childhood behavior and interact with the genetic background to influence the risk for psychopathology.

scholarly journals Serotonin deficiency induced after brain maturation rescues consequences of early life adversity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
B. Aboagye ◽  
T. Weber ◽  
H. L. Merdian ◽  
D. Bartsch ◽  
K. P. Lesch ◽  
...  
Keyword(s):  
Early Life ◽  
Depressive Disorders ◽  
Maternal Separation ◽  
Tryptophan Hydroxylase ◽  
Escape Behavior ◽  
Emotional Behavior ◽  
Brain Maturation ◽  
Marker Genes ◽  
Early Life Adversity ◽  
The Impact

AbstractBrain serotonin (5-HT) system dysfunction is implicated in depressive disorders and acute depletion of 5-HT precursor tryptophan has frequently been used to model the influence of 5-HT deficiency on emotion regulation. Tamoxifen (TAM)-induced Cre/loxP-mediated inactivation of the tryptophan hydroxylase-2 gene (Tph2) was used to investigate the effects of provoked 5-HT deficiency in adult mice (Tph2 icKO) previously subjected to maternal separation (MS). The efficiency of Tph2 inactivation was validated by immunohistochemistry and HPLC. The impact of Tph2 icKO in interaction with MS stress (Tph2 icKO × MS) on physiological parameters, emotional behavior and expression of 5-HT system-related marker genes were assessed. Tph2 icKO mice displayed a significant reduction in 5-HT immunoreactive cells and 5-HT concentrations in the rostral raphe region within four weeks following TAM treatment. Tph2 icKO and MS differentially affected food and water intake, locomotor activity as well as panic-like escape behavior. Tph2 icKO prevented the adverse effects of MS stress and altered the expression of the genes previously linked to stress and emotionality. In conclusion, an experimental model was established to study the behavioral and neurobiological consequences of 5-HT deficiency in adulthood in interaction with early-life adversity potentially affecting brain development and the pathogenesis of depressive disorders.

scholarly journals Early Life Adversity, but not suicide, is associated with less prefrontal cortex gray matter in adulthood

2019 ◽  
Author(s):  
Mark D. Underwood ◽  
Mihran J. Bakalian ◽  
Teresa Escobar ◽  
Suham Kassir ◽  
J. John Mann ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Early Life ◽  
Suicide Risk ◽  
Anterior Cingulate ◽  
Psychological Autopsy ◽  
Cell Nuclei ◽  
Early Life Adversity ◽  
Neuron Density ◽  
Dorsolateral Prefrontal

AbstractBackgroundSuicide and major depression (MDD) are more prevalent in individuals reporting early life adversity (ELA). Prefrontal cortex volume is reduced by stress acutely and progressively in vivo, and changes in neuron and glia density are reported in depressed suicide decedents. We previously found reduced levels of the neurotrophic factor BDNF in suicide decedents and with ELA, and in the present study we sought to determine whether cortex thickness, neuron density or glia density in the dorsolateral prefrontal (BA9) and anterior cingulate (BA24) cortex are associated with ELA or suicide.MethodsA total of 52 brains, constituting 13 quadruplets of nonpsychiatric nonsuicide controls and MDD suicide decedents with and without ELA (n=13/group), all with psychological autopsy, were matched for age, sex and postmortem interval. Brains were collected at autopsy and frozen and blocks containing BA9 and BA24 were later dissected, post-fixed and sectioned. Sections were immunostained for NeuN to label neurons and counterstained with thionin to stain glial cell nuclei. Cortex thickness, neuron and glial density and neuron volume were measured by stereology.ResultsCortical thickness was 6% less with an ELA history in BA9 and 12% less in BA24 (p<0.05), but not in depressed suicide decedents in either BA9 or BA24. Neuron density was not different in ELA or in suicide decedents, but glial density was 17% greater with ELA history in BA9 and 15% greater in BA24, but not in suicides. Neuron volume was not different with ELA or suicide.DiscussionReported ELA, but not the stress associated with suicide, is associated with thinner prefrontal cortex and greater glia density in adulthood. ELA may alter normal neurodevelopment and contribute to suicide risk.

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