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1.
Life Sci ; 234: 116778, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31430454

RESUMO

AIMS: To clarify the role of the gut-brain axis in depression. MAIN METHODS: We used the iTRAQ technique to identify differential proteins in the intestine of the rat model of chronic unpredictable mild stress (CUMS)-induced depression. Significant differential proteins were subjected to Gene Ontology (GO) functional annotations and KEGG pathway enrichment analysis. Key proteins were validated at the mRNA and protein levels. The levels of cytokines in the intestine, serum and hypothalamus were examined by ELISA. HPLC-UV was used to detect the levels of amino acids. KEY FINDINGS: In the rat intestine, 349 differential proteins (209 downregulated, 140 upregulated) were identified. GO analysis indicated that "protein complex assembly" was the first-ranked biological process. SNARE complex components, including SNAP23, VAMP3 and VAMP8, were increased at the mRNA levels, while only VAMP3 and VAMP8 were also upregulated at the protein level. TNFα, IL6 and IL1ß were upregulated in the CUMS rat intestine, while TNFα was decreased in the serum and hypothalamus. IL1ß was decreased in the serum. "Protein digestion and absorption" was the most significantly enriched KEGG pathway, involving 5 differential proteins: SLC9A3, ANPEP, LAT1, ASCT2 and B0AT1. Glutamine, glycine and aspartic acid were perturbed in the CUMS rat intestine. SIGNIFICANCE: Our findings suggest that CUMS enhances the adaptive immune response in the intestine through ER-phagosome pathway mediated by SNARE complex and disturb absorption of amino acids. It advances our understanding of the role of gut-brain axis in depression and provides a potential therapeutic target for the disease.


Assuntos
Aminoácidos/análise , Citocinas/análise , Depressão/patologia , Mucosa Intestinal/metabolismo , Intestinos/patologia , Proteínas SNARE/análise , Aminoácidos/metabolismo , Animais , Citocinas/genética , Depressão/etiologia , Depressão/genética , Modelos Animais de Doenças , Regulação da Expressão Gênica , Absorção Intestinal , Masculino , Proteômica , Ratos , Ratos Sprague-Dawley , Proteínas SNARE/genética , Estresse Psicológico/complicações
2.
DNA Cell Biol ; 38(8): 808-813, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31335167

RESUMO

This study aims to investigate whether a relationship exists between the C3435T polymorphism of ABCB1 gene and poststroke depression (PSD). A total of 82 PSD patients and 115 nondepression patient (NPSD) controls were included in this study. All patients were evaluated using the Hamilton Rating Scale for Depression to determine the severity of depression and complete the packet. PSD patients were diagnosed in accordance with the DSM-V criteria. The C3435T polymorphism of ABCB1 was genotyped through fluorescence in situ hybridization and chromosome karyotype analysis system. The PSD (n = 82) and NPSD groups (n = 115) had a total prevalence rate of 41.6%. The prevalence of PSD in men was 58.5%, whereas that in women was 41.5%, and no statistically significant difference existed between the two groups (χ2 = 1.009; p = 0.315). The CC, CT, and TT frequencies of the PSD group were 26.8%, 47.6%, and 25.6%, respectively, whereas those of the NPSD group were 42.6%, 45.2%, and 12.2%, respectively. Based on the CC genotype, the relative risk of homozygous mutant TT was 3.341 (χ2 = 7.869; p = 0.005; OR = 3.341), and the T allele frequency in the PSD group was 49.4% higher than that in the NPSD group. The locus gene frequency was 34.8%, and the relative risk of allele T relative to allele C was 1.830 (χ2 = 8.381; p = 0.004; OR = 1.830). A certain correlation exists between the C3435T gene polymorphism and PSD in the Han population in South Anhui Province, China, and further studies are needed to confirm our findings.


Assuntos
Depressão/genética , Polimorfismo Genético , Acidente Vascular Cerebral/psicologia , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Grupo com Ancestrais do Continente Asiático/genética , China , Depressão/etiologia , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Acidente Vascular Cerebral/complicações
4.
Gastroenterology ; 157(2): 507-521.e4, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31071306

RESUMO

BACKGROUND & AIMS: Mood disorders and constipation are often comorbid, yet their shared etiologies have rarely been explored. The neurotransmitter serotonin (5-HT) regulates central nervous system and enteric nervous system (ENS) development and long-term functions, including gastrointestinal (GI) motility and mood. Therefore, defects in neuron production of 5-HT might result in brain and intestinal dysfunction. Tryptophan hydroxylase 2 (TPH2) is the rate-limiting enzyme in 5-HT biosynthesis. A variant of TPH2 that encodes the R441H substitution (TPH2-R441H) was identified in individuals with severe depression. We studied mice with an analogous mutation (TPH2-R439H), which results in a 60%-80% decrease in levels of 5-HT in the central nervous system and behaviors associated with depression in humans. Feeding chow that contains 5-HTP slow release (5-HTP SR) to TPH2-R439H mice restores levels of 5-HT in the central nervous system and reduces depressive-like behaviors. METHODS: We compared the effects of feeding chow, with or without 5-HTP SR, to mice with the TPH2-R439H mutation and without this mutation (control mice). Myenteric and submucosal plexuses were isolated from all 4 groups of mice, and immunocytochemistry was used to quantify total enteric neurons, serotonergic neurons, and 5-HT-dependent subsets of neurons. We performed calcium imaging experiments to evaluate responses of enteric neurons to tryptamine-evoked release of endogenous 5-HT. In live mice, we measured total GI transit, gastric emptying, small intestinal transit, and propulsive colorectal motility. To measure colonic migrating motor complexes (CMMCs), we isolated colons and constructed spatiotemporal maps along the proximodistal length to quantify the frequency, velocity, and length of CMMCs. We measured villus height, crypt perimeter, and relative densities of enterochromaffin and enteroendocrine cells in small intestinal tissue. RESULTS: Levels of 5-HT were significantly lower in enteric neurons from TPH2-R439H mice than from control mice. TPH2-R439H mice had abnormalities in ENS development and ENS-mediated GI functions, including reduced motility and intestinal epithelial growth. Total GI transit and propulsive colorectal motility were slower in TPH2-R439H mice than controls, and CMMCs were slower and less frequent. Villus height and crypt perimeter were significantly decreased in colon tissues from TPH2-R439H mice compared with controls. Administration of 5-HTP SR to adult TPH2-R439H mice restored 5-HT to enteric neurons and reversed these abnormalities. Adult TPH2-R439H mice given oral 5-HTP SR had normalized numbers of enteric neurons, total GI transit, and colonic motility. Intestinal tissue from these mice had normal measures of CMMCs and enteric epithelial growth CONCLUSIONS: In studies of TPH2-R439H mice, we found evidence for reduced release of 5-HT from enteric neurons that results in defects in ENS development and GI motility. Our findings indicate that neuron production of 5-HT links constipation with mood dysfunction. Administration of 5-HTP SR to mice restored 5-HT to the ENS and normalized GI motility and growth of the enteric epithelium. 5-HTP SR might be used to treat patients with intestinal dysfunction associated with low levels of 5-HT.


Assuntos
5-Hidroxitriptofano/administração & dosagem , Constipação Intestinal/tratamento farmacológico , Depressão/tratamento farmacológico , Trato Gastrointestinal/fisiopatologia , Serotonina/metabolismo , Animais , Constipação Intestinal/etiologia , Constipação Intestinal/fisiopatologia , Preparações de Ação Retardada/administração & dosagem , Depressão/complicações , Depressão/genética , Depressão/fisiopatologia , Modelos Animais de Doenças , Sistema Nervoso Entérico/efeitos dos fármacos , Sistema Nervoso Entérico/fisiopatologia , Feminino , Motilidade Gastrointestinal/efeitos dos fármacos , Motilidade Gastrointestinal/fisiologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/inervação , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mutação , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Resultado do Tratamento , Triptofano Hidroxilase/genética , Triptofano Hidroxilase/metabolismo
5.
Nord J Psychiatry ; 73(4-5): 257-263, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31070508

RESUMO

Background: Prenatal maternal stress increases the risk of offspring developmental and psychological difficulties. The biological mechanisms behind these associations are mostly unknown. One explanation suggests that exposure of the fetus to maternal stress may influence DNA methylation. However, this hypothesis is largely based on animal studies, and human studies of candidate genes from single timepoints. Aim: The aim of this study was to investigate if prenatal maternal stress, in the form of maternal depressive symptoms, was associated with variation in genome-wide DNA methylation at two timepoints. Methods: One-hundred and eighty-four mother-child dyads were selected from a population of pregnant women in the Little-in-Norway study. The Edinburgh Postnatal Depression Scale (EPDS) measured maternal depressive symptoms. It was completed by the pregnant mothers between weeks 17 and 32 of gestation. DNA was obtained from infant saliva cells at two timepoints (age 6 weeks and 12 months). DNA methylation was measured in 274 samples from 6 weeks (n = 146) and 12 months (n = 128) using the Illumina Infinium HumanMethylation 450 BeadChip. Linear regression analyses of prenatal maternal depressive symptoms and infant methylation were performed at 6 weeks and 12 months separately, and for both timepoints together using a mixed model. Results: The analyses revealed no significant genome-wide association between maternal depressive symptoms and infant DNA methylation in the separate analyses and for both timepoints together. Conclusions: This sample of pregnant women and their infants living in Norway did not reveal associations between maternal depressive symptoms and infant DNA methylation.


Assuntos
Metilação de DNA/fisiologia , Depressão/psicologia , Epigenômica/métodos , Complicações na Gravidez/psicologia , Efeitos Tardios da Exposição Pré-Natal/psicologia , Adulto , Animais , Depressão/epidemiologia , Depressão/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Recém-Nascido , Estudos Longitudinais , Mães/psicologia , Noruega/epidemiologia , Gravidez , Complicações na Gravidez/epidemiologia , Complicações na Gravidez/genética , Efeitos Tardios da Exposição Pré-Natal/epidemiologia , Efeitos Tardios da Exposição Pré-Natal/genética , Adulto Jovem
6.
Depress Anxiety ; 36(6): 565-575, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30958913

RESUMO

BACKGROUND: Telomeres cap and protect DNA but shorten with each somatic cell division. Aging and environmental and lifestyle factors contribute to the speed of telomere attrition. Current evidence suggests a link between relative telomere length (RTL) and depression but the directionality of the relationship remains unclear. We prospectively examined associations between RTL and subsequent depressive symptom trajectories. METHODS: Among 8,801 women of the Nurses' Health Study, depressive symptoms were measured every 4 years from 1992 to 2012; group-based trajectories of symptoms were identified using latent class growth-curve analysis. Multinomial logistic models were used to relate midlife RTLs to the probabilities of assignment to subsequent depressive symptom trajectory groups. RESULTS: We identified four depressive symptom trajectory groups: minimal depressive symptoms (62%), worsening depressive symptoms (14%), improving depressive symptoms (19%), and persistent-severe depressive symptoms (5%). Longer midlife RTLs were related to significantly lower odds of being in the worsening symptoms trajectory versus minimal trajectory but not to other trajectories. In comparison with being in the minimal symptoms group, the multivariable-adjusted odds ratio of being in the worsening depressive symptoms group was 0.78 (95% confidence interval, 0.62-0.97; p = 0.02), for every standard deviation increase in baseline RTL. CONCLUSIONS: In this large prospective study of generally healthy women, longer telomeres at midlife were associated with significantly lower risk of a subsequent trajectory of worsening mood symptoms over 20 years. The results raise the possibility of telomere shortening as a novel contributing factor to late-life depression.


Assuntos
Envelhecimento/genética , Envelhecimento/psicologia , Depressão/diagnóstico , Depressão/genética , Encurtamento do Telômero/fisiologia , Telômero/metabolismo , Adulto , Transtorno Depressivo/diagnóstico , Transtorno Depressivo/genética , Feminino , Humanos , Modelos Logísticos , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Telômero/genética , Encurtamento do Telômero/genética
7.
Depress Anxiety ; 36(6): 480-489, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31017373

RESUMO

BACKGROUND: The serotonin system and hypothalamic pituitary-adrenal (HPA)-axis are each implicated in the pathway to depression; human and animal research support these systems' cross-talk. Our work implicates a 5-variant additive serotoninergic multilocus genetic profile score (MGPS) and separately the cortisol awakening response (CAR) in the prospective prediction of depression; other work has shown that the serotonin transporter polymorphism 5HTTLPR predicts CAR and interacts with the CAR to predict depression. METHODS: We tested the hypothesis that a 6-variant MGPS (original plus 5HTTLPR) would interact with CAR to predict prospective depressive episode onsets in 201 emerging adults using four annual follow-up interviews. We also tested whether MGPS predicted CAR. We attempted replication of significant findings in a sample of 77 early adolescents predicting depression symptoms. RESULTS: In sample 1, MGPS did not significantly predict CAR. MGPS interacted with CAR to predict depressive episodes; CAR slopes for depression steepened as MGPS increased, for risk or protection. No single variant accounted for results, though CAR's interactions with 5HTTLPR and the original MGPS were both significant. In sample 2, the 6-variant MGPS significantly interacted with CAR to predict depression symptoms. CONCLUSIONS: Higher serotonergic MGPS appears to sensitize individuals to CAR level-for better and worse-in predicting depression.


Assuntos
Distinções e Prêmios , Depressão/genética , Depressão/metabolismo , Transtorno Depressivo/genética , Transtorno Depressivo/metabolismo , Hidrocortisona/metabolismo , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Serotonina/metabolismo , Adolescente , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Sistema Hipófise-Suprarrenal/metabolismo , Polimorfismo Genético , Estudos Prospectivos , Fatores de Risco , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo
9.
Nat Commun ; 10(1): 1776, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30992449

RESUMO

Polygenic risk scores (PRS) have shown promise in predicting human complex traits and diseases. Here, we present PRS-CS, a polygenic prediction method that infers posterior effect sizes of single nucleotide polymorphisms (SNPs) using genome-wide association summary statistics and an external linkage disequilibrium (LD) reference panel. PRS-CS utilizes a high-dimensional Bayesian regression framework, and is distinct from previous work by placing a continuous shrinkage (CS) prior on SNP effect sizes, which is robust to varying genetic architectures, provides substantial computational advantages, and enables multivariate modeling of local LD patterns. Simulation studies using data from the UK Biobank show that PRS-CS outperforms existing methods across a wide range of genetic architectures, especially when the training sample size is large. We apply PRS-CS to predict six common complex diseases and six quantitative traits in the Partners HealthCare Biobank, and further demonstrate the improvement of PRS-CS in prediction accuracy over alternative methods.


Assuntos
Predisposição Genética para Doença , Modelos Genéticos , Herança Multifatorial/genética , Característica Quantitativa Herdável , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/genética , Teorema de Bayes , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Simulação por Computador , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/genética , Bases de Dados Genéticas/estatística & dados numéricos , Depressão/diagnóstico , Depressão/genética , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/genética , Feminino , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genética , Desequilíbrio de Ligação/genética , Masculino , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
10.
Psychopharmacology (Berl) ; 236(7): 2119-2142, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30900007

RESUMO

OBJECTIVES: Major depressive disorder characterized as recurrent negative mood is one of the prevalent psychiatric diseases. Chronic stress plus lack of reward may induce long-term imbalance between reward and penalty circuits in the brain, leading to persistent negative mood. Numerous individuals demonstrate resilience to chronic mild stress. Molecular mechanisms for major depression and resilience in the brain remain unclear. METHODS: After juvenile mice were treated by the chronic unpredictable mild stress (CUMS) for 4 weeks, they were screened by sucrose preference, Y-maze and forced swimming tests to examine whether their behaviors were depression-like or not. mRNA and miRNA profiles were quantified by high-throughput sequencing in amygdala tissues harvested from control, CUMS-susceptible, and CUMS-resilience mice. RESULTS: 1.5-fold ratio in reads per kilo-base per million reads was set to be the threshold to judge the involvement of mRNAs and miRNAs in the CUMS, major depression, or resilience. In the amygdala from CUMS-susceptible mice, the expression of genes relevant to GABAergic, cholinergic, glutamatergic, dopaminergic, and serotonergic synapses was changed, as well as the expression of genes that encoded signal pathways of PI3K-Akt, calcium, cAMP, MAPK, and drug addiction was imbalanced. The expression of these genes in the amygdala form CUMS-resilience mice was less changed. CONCLUSIONS: The downregulation of genes relevant to synaptic functions and the imbalance of intra-signaling pathway in the amygdala are associated with major depression. Consistent results through sequencing mRNA and miRNA and using different methods validate our finding and conclusion.


Assuntos
Depressão/genética , MicroRNAs/genética , RNA Mensageiro/genética , Resiliência Psicológica , Estresse Psicológico/genética , Transcriptoma/genética , Fatores Etários , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/metabolismo , Depressão/tratamento farmacológico , Redes Reguladoras de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/biossíntese , RNA Mensageiro/biossíntese , Transdução de Sinais/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Natação/fisiologia , Natação/psicologia
11.
Molecules ; 24(5)2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30823679

RESUMO

Suppressive effects of ginsenoside Rh2 (Rh2), (24R)-pseudo-ginsenoside HQ (R-PHQ), and (24S)-pseudo-ginsenoside HQ (S-PHQ) against lipopolysaccharide (LPS)-induced depression-like behavior were evaluated using the forced swimming test (FST) and tail suspension test (TST) in mice. Pretreatment with Rh2, R-PHQ, and S-PHQ significantly decreased immobility time in FST and TST with clear dose-dependence, and significantly downregulated levels of serum tumor necrosis factor-α and interleukin-6, and upregulated superoxide dismutase activity in the hippocampus of LPS-challenged mice. Furthermore, R-PHQ and S-PHQ significantly increased the expression of the brain-derived neurotrophic factor (BDNF), tropomyosin-related kinase B (TrkB), sirtuin type 1 (Sirt1), and nuclear-related factor 2, and inhibited the phosphorylation of inhibitor of κB-α and nuclear factor-κB (NF-κB) in the hippocampus of LPS-challenged mice. Additionally, the antidepressant-like effect of R-PHQ was found related to the dopaminergic (DA), γ-aminobutyric acid (GABA)ergic, and noradrenaline systems, while the antidepressive effect of S-PHQ was involved in the DA and GABAergic systems. Taken together, these results suggested that Rh2, R-PHQ, and S-PHQ produced significant antidepressant-like effects, which may be related to the BDNF/TrkB and Sirt1/NF-κB signaling pathways.


Assuntos
Antidepressivos/administração & dosagem , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Ginsenosídeos/administração & dosagem , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Depressão/induzido quimicamente , Depressão/genética , Depressão/fisiopatologia , Modelos Animais de Doenças , Regulação da Expressão Gênica/efeitos dos fármacos , Elevação dos Membros Posteriores , Humanos , Interleucina-6/genética , Lipopolissacarídeos/toxicidade , Camundongos , NF-kappa B/genética , Transdução de Sinais/efeitos dos fármacos , Natação , Triterpenos/administração & dosagem , Fator de Necrose Tumoral alfa/genética
12.
Mol Med Rep ; 19(5): 3411-3420, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30864711

RESUMO

The prevalence of mental health disorders such as depression is high. Depression is a multifactorial disorder and its underlying mechanisms remain unclear. Competing endogenous RNA (ceRNA) regulation has been reported to serve important roles in human disease. In the present study, ceRNA networks for depression and the corresponding normal physiological states were constructed. Further analysis of the ceRNA networks revealed that ceRNA regulation may be important for depression. Hub ceRNAs including high mobility group nucleosomal binding domain 3, peroxisome proliferator­activated receptor­Î³ coactivator 1ß and leukemia inhibitory factor receptor­α were associated with depression. A common core ceRNA network was identified by comparison analysis. Functional analysis suggested that these ceRNAs may be implicated in depression. Differential expression analysis revealed that ceRNAs in the obtained ceRNA interaction networks were significantly enriched with significantly differentially expressed genes. A total of 8 key functional modules for depression were identified, and small target molecules were screened. ceRNA protocadherin­α subfamily C2 in module 1 and ceRNA Cyclin­dependent kinase 6 in module 3 were reported to be implicated in the occurrence and development of depressive disorders. Thus, the present analysis may provide insight into the pathogenesis of depression and improve its treatment.


Assuntos
Biologia Computacional , Depressão/genética , Redes Reguladoras de Genes , Predisposição Genética para Doença , Modelos Biológicos , Interferência de RNA , RNA/genética , Análise por Conglomerados , Biologia Computacional/métodos , Descoberta de Drogas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Transcriptoma
13.
Dev Psychopathol ; 31(2): 443-456, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837010

RESUMO

This study used a structural equation mixture model to examine associations between child maltreatment, polygenic risk, and indices of adaptive functioning. Children aged 6 to 13 years (N = 1,004), half maltreated, half nonmaltreated, were recruited to attend a research day camp. Multi-informant indicators of prosocial behavior, antisocial behavior, withdrawn behavior, and depression were collected and used in a latent class analysis. Four classes emerged, characterizing "well-adjusted," "externalizing," "internalizing," and "socially dominant" groups. Twelve genetic variants, previously reported in the Gene × Environment literature, were modeled as one weighted polygenic risk score. Large main effects between maltreatment and adaptive functioning were observed (Wald = 35.3, df = 3, p < .0001), along with evidence of a small Gene × Environment effect (Wald = 13.5, df = 3, p = .004), adjusting for sex, age, and covariate interaction effects.


Assuntos
Maus-Tratos Infantis/psicologia , Mecanismos de Defesa , Depressão/psicologia , Comportamento Problema/psicologia , Ajustamento Social , Adolescente , Criança , Depressão/genética , Feminino , Humanos , Masculino , Herança Multifatorial
14.
Psychopharmacology (Berl) ; 236(6): 1917-1929, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30796492

RESUMO

RATIONALE: The ventral tegmental area (VTA) is implicated in the pathophysiology of depression and addictive disorders and is subject to the detrimental effects of stress. Chronic stress may differentially alter the activity pattern of its different subregions along the rostrocaudal and dorsoventral axes, which may relate to the variable behavioral sensitivity to stress mediated by these subregions. OBJECTIVES: Here, chronic stress-exposed rats were tested for depressive-like reactivity. In situ hybridization for zif268 as a marker of neuronal activation was combined with in vivo single-unit recording of dopaminergic neurons to assess modifications in the activity of the rostral VTA (rVTA) and caudal VTA (cVTA). Changes in the expression of stress-responsive glucocorticoid receptors (GR) and brain-derived neurotrophic factor (BDNF) were also assessed. RESULTS: Stress-induced anhedonia-like, hyper-anxious, and passive-like responding were associated with reductions in dopaminergic burst activity in the cVTA and an increase in local GABAergic activity, particularly in GABAA receptor sensitivity. On the other hand, stress increased single-spiking activity, burst activity, and zif268 mRNA levels in the rVTA, which were associated with increased glutamatergic tonus and enhanced GR and AMPA receptor (AMPAR) expression. rVTA and cVTA activity differentially correlated with sucrose preference and passivity measures. CONCLUSIONS: These data demonstrate that the rVTA and cVTA respond differently to stress and suggest that while cVTA activity may be related to passivity-like states, the activity of both subregions appears to be related to anhedonia and the processing of incentive value. These region-dependent abnormalities indicate the multi-modular composition of the VTA, which could provide multiple substrates for different symptom features.


Assuntos
Anedonia/fisiologia , Estresse Psicológico/metabolismo , Estresse Psicológico/psicologia , Área Tegmentar Ventral/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doença Crônica , Depressão/genética , Depressão/metabolismo , Depressão/psicologia , Dopamina/metabolismo , Neurônios Dopaminérgicos/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Proteína 1 de Resposta de Crescimento Precoce/genética , Masculino , Ratos , Ratos Endogâmicos F344 , Estresse Psicológico/genética
15.
Nat Neurosci ; 22(3): 343-352, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30718901

RESUMO

Major depression is a debilitating psychiatric illness that is typically associated with low mood and anhedonia. Depression has a heritable component that has remained difficult to elucidate with current sample sizes due to the polygenic nature of the disorder. To maximize sample size, we meta-analyzed data on 807,553 individuals (246,363 cases and 561,190 controls) from the three largest genome-wide association studies of depression. We identified 102 independent variants, 269 genes, and 15 genesets associated with depression, including both genes and gene pathways associated with synaptic structure and neurotransmission. An enrichment analysis provided further evidence of the importance of prefrontal brain regions. In an independent replication sample of 1,306,354 individuals (414,055 cases and 892,299 controls), 87 of the 102 associated variants were significant after multiple testing correction. These findings advance our understanding of the complex genetic architecture of depression and provide several future avenues for understanding etiology and developing new treatment approaches.


Assuntos
Depressão/genética , Transtorno Depressivo Maior/genética , Córtex Pré-Frontal/metabolismo , Estudos de Coortes , Feminino , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Herança Multifatorial , Polimorfismo de Nucleotídeo Único
16.
Transl Psychiatry ; 9(1): 68, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718449

RESUMO

There has been a limited number of systematic reviews conducted to summarize the overview of the relationship between DNA methylation and depression, and to critically appraise the roles of major study characteristics in the accuracy of study findings. This systematic review aims to critically appraise the impact of study characteristics on the association between DNA methylation and depression, and summarize the overview of this association. Electronic databases and gray literatures until December 2017 were searched for English-language studies with standard diagnostic criteria of depression. A total of 67 studies were included in this review along with a summary of their study characteristics. We grouped the findings into etiological and treatment studies. Majority of these selected studies were recently published and from developed countries. Whole blood samples were the most studied common tissues. Bisulfite conversion, along with pyrosequencing, was widely used to test the DNA methylation level across all the studies. High heterogeneity existed among the studies in terms of experimental and statistical methodologies and study designs. As recommended by the Cochrane guideline, a systematic review without meta-analysis should be undertaken. This review has, in general, found that DNA methylation modifications were associated with depression. Subgroup analyses showed that most studies found BDNF and SLC6A4 hypermethylations to be associated with MDD or depression in general. In contrast, studies on NR3C1, OXTR, and other genes, which were tested by only few studies, reported mixed findings. More longitudinal studies using standardized experimental and laboratory methodologies are needed in future studies to enable more systematical comparisons and quantitative synthesis.


Assuntos
Metilação de DNA , Depressão/metabolismo , Transtorno Depressivo/metabolismo , Depressão/genética , Transtorno Depressivo/genética , Humanos
17.
Int J Mol Sci ; 20(3)2019 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-30708948

RESUMO

Impaired sleep is both a risk factor and a symptom of depression. Objective sleep is assessed using the sleep electroencephalogram (EEG). Characteristic sleep-EEG changes in patients with depression include disinhibition of rapid eye movement (REM) sleep, changes of sleep continuity, and impaired non-REM sleep. Most antidepressants suppress REM sleep both in healthy volunteers and depressed patients. Various sleep-EEG variables may be suitable as biomarkers for diagnosis, prognosis, and prediction of therapy response in depression. In family studies of depression, enhanced REM density, a measure for frequency of rapid eye movements, is characteristic for an endophenotype. Cordance is an EEG measure distinctly correlated with regional brain perfusion. Prefrontal theta cordance, derived from REM sleep, appears to be a biomarker of antidepressant treatment response. Some predictive sleep-EEG markers of depression appear to be related to hypothalamo-pituitary-adrenocortical system activity.


Assuntos
Antidepressivos/uso terapêutico , Depressão/tratamento farmacológico , Transtornos do Sono-Vigília/diagnóstico , Antidepressivos/farmacologia , Depressão/complicações , Depressão/etiologia , Depressão/genética , Eletroencefalografia , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Transtornos do Sono-Vigília/complicações , Transtornos do Sono-Vigília/etiologia , Transtornos do Sono-Vigília/prevenção & controle , Sono REM/efeitos dos fármacos
18.
Transl Psychiatry ; 9(1): 14, 2019 02 04.
Artigo em Inglês | MEDLINE | ID: mdl-30718454

RESUMO

Stress is associated with poorer physical and mental health. To improve our understanding of this link, we performed genome-wide association studies (GWAS) of depressive symptoms and genome-wide by environment interaction studies (GWEIS) of depressive symptoms and stressful life events (SLE) in two UK population-based cohorts (Generation Scotland and UK Biobank). No SNP was individually significant in either GWAS, but gene-based tests identified six genes associated with depressive symptoms in UK Biobank (DCC, ACSS3, DRD2, STAG1, FOXP2 and KYNU; p < 2.77 × 10-6). Two SNPs with genome-wide significant GxE effects were identified by GWEIS in Generation Scotland: rs12789145 (53-kb downstream PIWIL4; p = 4.95 × 10-9; total SLE) and rs17070072 (intronic to ZCCHC2; p = 1.46 × 10-8; dependent SLE). A third locus upstream CYLC2 (rs12000047 and rs12005200, p < 2.00 × 10-8; dependent SLE) when the joint effect of the SNP main and GxE effects was considered. GWEIS gene-based tests identified: MTNR1B with GxE effect with dependent SLE in Generation Scotland; and PHF2 with the joint effect in UK Biobank (p < 2.77 × 10-6). Polygenic risk scores (PRSs) analyses incorporating GxE effects improved the prediction of depressive symptom scores, when using weights derived from either the UK Biobank GWAS of depressive symptoms (p = 0.01) or the PGC GWAS of major depressive disorder (p = 5.91 × 10-3). Using an independent sample, PRS derived using GWEIS GxE effects provided evidence of shared aetiologies between depressive symptoms and schizotypal personality, heart disease and COPD. Further such studies are required and may result in improved treatments for depression and other stress-related conditions.


Assuntos
Depressão/genética , Transtorno Depressivo Maior/genética , Acontecimentos que Mudam a Vida , Herança Multifatorial , Polimorfismo de Nucleotídeo Único , Bancos de Espécimes Biológicos , Estudos de Coortes , Depressão/etiologia , Transtorno Depressivo Maior/etiologia , Feminino , Interação Gene-Ambiente , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise de Regressão , Escócia , Reino Unido
19.
PLoS One ; 14(1): e0207353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30605476

RESUMO

BACKGROUND: Human endogenous retroviruses (HERV) comprise 8% of the human genome and can be classified into at least 31 families. Increased levels of transcripts from the W and H families of HERV have been observed in association with human diseases, such as multiple sclerosis and schizophrenia. Although HERV transcripts have been detected in many tissues and cell-types based on microarray and PCR studies, the extent of HERV expression in different cell-types and diseases state has been less comprehensively studied. RESULTS: We examined overall transcription of HERV, and particularly of HERV-W and HERV-H elements in human postmortem brain samples obtained from individuals with psychiatric diagnoses (n = 111) and healthy controls (n = 51) by analyzing publicly available RNA sequencing datasets. Sequence reads were aligned to prototypical sequences representing HERV, downloaded from Repbase. We reported a consistent expression (0.1~0.2% of mappable reads) of different HERV families across three regions of human brains. Spearman correlations revealed highly correlated expression levels between three brain regionsacross 475 consensus sequences. By mapping sequences that aligned to the consensus sequences of HERV-W and HERV-H families to individual loci on chromosome 7, more than 60 loci from each family were identified, part of which are being transcribed. The ERVWE1, locus located at chr7q21.2, exhibited high levels of transcription across the three datasets. Notably, we demonstrated a trend of increased expression of overall HERV, as well as HERV-W family in samples from both schizophrenia and bipolar disorder patients. CONCLUSIONS: The current analyses indicate that RNA sequencing is a useful approach for investigating global expression of repetitive elements, such as HERV, in the human genome. HERV-W/H with the tendency of transcription up-regulation in patients suggests potential implication of HERV-W/H in psychiatric diseases.


Assuntos
Encéfalo/metabolismo , Encéfalo/virologia , Retrovirus Endógenos/genética , Análise de Sequência de RNA , Transcrição Genética , Transtorno Bipolar/genética , Transtorno Bipolar/virologia , Cromossomos Humanos Par 7/genética , Depressão/genética , Depressão/virologia , Regulação Viral da Expressão Gênica , Loci Gênicos , Genoma Humano , Humanos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sequências Repetitivas de Ácido Nucleico/genética , Esquizofrenia/genética , Esquizofrenia/virologia , Estatísticas não Paramétricas
20.
J Affect Disord ; 246: 738-744, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30616163

RESUMO

BACKGROUND: The mechanisms underlying the relationship between life events and psychological distress are unclear. However, evidence of genetic involvement, including the neuropeptide S receptor gene (NPSR1), exists. METHODS: A total of 600 Chinese adults were enrolled in this cross-sectional study using random cluster sampling. Demographic information, measures of life events and psychiatric symptoms, and fasting blood samples were collected. RESULTS: Significant correlations were observed among life-event scores, somatization, and psychological distress (i.e., anxiety and depressive symptoms). Regression revealed life-event scores and somatization predicted anxiety, depressive symptoms, and psychological distress, while controlling for sex, age, income, education, and marital status. Structural equation modeling indicated that somatization mediated the association between life-event scores and psychological distress. Moreover, the mediating effect was influenced by the NPSR1 gene, suggesting that the NPSR1 polymorphisms rs324981, rs6947841, and rs6972158 influenced the association between life-event scores and somatization (ps < 0.05). The NPSR1 polymorphisms rs12673132 significantly affected the relationship of somatization with psychological distress (p < 0.05). CONCLUSIONS: In conclusion, somatization mediated the association between life-event scores and psychological distress. The current study is the first to demonstrate this relationship with a Chinese sample, whereby the NPSR1 gene affects the mediating effect of somatization on the association between life-event scores and psychological distress.


Assuntos
Acontecimentos que Mudam a Vida , Polimorfismo Genético , Receptores Acoplados a Proteínas-G/sangue , Transtornos Somatoformes/genética , Estresse Psicológico/genética , Adulto , Ansiedade/genética , Ansiedade/psicologia , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/psicologia , China , Análise por Conglomerados , Estudos Transversais , Depressão/genética , Depressão/psicologia , Feminino , Humanos , Análise de Classes Latentes , Masculino , Pessoa de Meia-Idade , Análise de Regressão , Transtornos Somatoformes/psicologia , Estresse Psicológico/psicologia
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