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1.
Nat Genet ; 51(5): 793-803, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31043756

RESUMO

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10-4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10-8) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.


Assuntos
Transtorno Bipolar/genética , Loci Gênicos , Transtorno Bipolar/classificação , Estudos de Casos e Controles , Transtorno Depressivo Maior/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Transtornos Psicóticos/genética , Esquizofrenia/genética , Biologia de Sistemas
2.
Nucleic Acids Res ; 47(10): e59, 2019 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-30869147

RESUMO

Deletions in the 16.6 kb mitochondrial genome have been implicated in numerous disorders that often display muscular and/or neurological symptoms due to the high-energy demands of these tissues. We describe a catalogue of 4489 putative mitochondrial DNA (mtDNA) deletions, including their frequency and relative read rate, using a combinatorial approach of mitochondria-targeted PCR, next-generation sequencing, bioinformatics, post-hoc filtering, annotation, and validation steps. Our bioinformatics pipeline uses MapSplice, an RNA-seq splice junction detection algorithm, to detect and quantify mtDNA deletion breakpoints rather than mRNA splices. Analyses of 93 samples from postmortem brain and blood found (i) the 4977 bp 'common deletion' was neither the most frequent deletion nor the most abundant; (ii) brain contained significantly more deletions than blood; (iii) many high frequency deletions were previously reported in MitoBreak, suggesting they are present at low levels in metabolically active tissues and are not exclusive to individuals with diagnosed mitochondrial pathologies; (iv) many individual deletions (and cumulative metrics) had significant and positive correlations with age and (v) the highest deletion burdens were observed in major depressive disorder brain, at levels greater than Kearns-Sayre Syndrome muscle. Collectively, these data suggest the Splice-Break pipeline can detect and quantify mtDNA deletions at a high level of resolution.

3.
PLoS One ; 13(7): e0200003, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30016334

RESUMO

Psychiatric illness is unlikely to arise from pathology occurring uniformly across all cell types in affected brain regions. Despite this, transcriptomic analyses of the human brain have typically been conducted using macro-dissected tissue due to the difficulty of performing single-cell type analyses with donated post-mortem brains. To address this issue statistically, we compiled a database of several thousand transcripts that were specifically-enriched in one of 10 primary cortical cell types in previous publications. Using this database, we predicted the relative cell type content for 833 human cortical samples using microarray or RNA-Seq data from the Pritzker Consortium (GSE92538) or publicly-available databases (GSE53987, GSE21935, GSE21138, CommonMind Consortium). These predictions were generated by averaging normalized expression levels across transcripts specific to each cell type using our R-package BrainInABlender (validated and publicly-released on github). Using this method, we found that the principal components of variation in the datasets strongly correlated with the predicted neuronal/glial content of the samples. This variability was not simply due to dissection-the relative balance of brain cell types appeared to be influenced by a variety of demographic, pre- and post-mortem variables. Prolonged hypoxia around the time of death predicted increased astrocytic and endothelial gene expression, illustrating vascular upregulation. Aging was associated with decreased neuronal gene expression. Red blood cell gene expression was reduced in individuals who died following systemic blood loss. Subjects with Major Depressive Disorder had decreased astrocytic gene expression, mirroring previous morphometric observations. Subjects with Schizophrenia had reduced red blood cell gene expression, resembling the hypofrontality detected in fMRI experiments. Finally, in datasets containing samples with especially variable cell content, we found that controlling for predicted sample cell content while evaluating differential expression improved the detection of previously-identified psychiatric effects. We conclude that accounting for cell type can greatly improve the interpretability of transcriptomic data.

4.
Biol Psychiatry ; 84(8): 555-562, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29861095

RESUMO

BACKGROUND: While downregulation of several growth factors in major depressive disorder is well established, less attention has been paid to the upregulation of other growth factors. Yet, upregulated growth factors may offer better therapeutic targets. We show that connective tissue growth factor (CTGF) represents a target based on its upregulation in major depressive disorder and studies in animal models implicating it in negative affect. METHODS: CTGF gene expression was first evaluated in the postmortem human amygdala. The findings were followed up in outbred rats and in two rat lines that were selectively bred for differences in novelty-seeking and anxiety behavior (bred low responders and bred high responders). We studied the impact of social defeat and early-life treatment with fibroblast growth factor 2 on CTGF expression. Finally, we assessed the ability of an anti-CTGF antibody (FG-3019) to alter CTGF expression and emotionality. RESULTS: In the human amygdala, CTGF expression was significantly increased in major depressive disorder compared with control subjects. CTGF expression was also significantly increased in the dentate gyrus of adult bred low responders compared with bred high responders. Social defeat stress in bred low responders significantly increased CTGF expression in the dentate gyrus. Early-life fibroblast growth factor 2, a treatment that reduces anxiety-like behavior throughout life, decreased CTGF expression in the adult dentate gyrus. In outbred rats, CTGF administration increased depression-like behavior. Chronic treatment with FG-3019 decreased CTGF expression, and acute and chronic treatment was antidepressant. CONCLUSIONS: This study is the first to implicate CTGF as a prodepressant molecule that could serve as a target for the development of novel therapeutics.

5.
Mol Neuropsychiatry ; 3(3): 157-169, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29594135

RESUMO

Subjects with schizophrenia (SZ) and bipolar disorder (BD) show decreased protein and transcript levels for mitochondrial complex I. In vitro results suggest antipsychotic and antidepressant drugs may be responsible. We measured complex I activity in BD, SZ, and controls and presence of antipsychotic and antidepressant medications, mitochondrial DNA (mtDNA) copy number, and the mtDNA "common deletion" in the brain. Complex I activity in the prefrontal cortex was decreased by 45% in SZ compared to controls (p = 0.02), while no significant difference was found in BD. Complex I activity was significantly decreased (p = 0.01) in pooled cases (SZ and BD) that had detectable psychotropic medications and drugs compared to pooled cases with no detectable levels. Subjects with age at onset in their teens and psychotropic medications showed decreased (p < 0.05) complex I activity compared to subjects with an adult age at onset. Both SZ and BD groups displayed significant increases (p < 0.05) in mtDNA copy number compared to controls; however, common deletion burden was not altered. Complex I deficiency is found in SZ brain tissue, and psychotropic medications may play a role in mitochondrial dysfunction. Studies of medication-free first-episode psychosis patients are needed to elucidate whether mitochondrial pathophysiology occurs independent of medication effects.

6.
Genome Med ; 9(1): 72, 2017 07 28.
Artigo em Inglês | MEDLINE | ID: mdl-28754123

RESUMO

BACKGROUND: Psychiatric disorders are multigenic diseases with complex etiology that contribute significantly to human morbidity and mortality. Although clinically distinct, several disorders share many symptoms, suggesting common underlying molecular changes exist that may implicate important regulators of pathogenesis and provide new therapeutic targets. METHODS: We performed RNA sequencing on tissue from the anterior cingulate cortex, dorsolateral prefrontal cortex, and nucleus accumbens from three groups of 24 patients each diagnosed with schizophrenia, bipolar disorder, or major depressive disorder, and from 24 control subjects. We identified differentially expressed genes and validated the results in an independent cohort. Anterior cingulate cortex samples were also subjected to metabolomic analysis. ChIP-seq data were used to characterize binding of the transcription factor EGR1. RESULTS: We compared molecular signatures across the three brain regions and disorders in the transcriptomes of post-mortem human brain samples. The most significant disease-related differences were in the anterior cingulate cortex of schizophrenia samples compared to controls. Transcriptional changes were assessed in an independent cohort, revealing the transcription factor EGR1 as significantly down-regulated in both cohorts and as a potential regulator of broader transcription changes observed in schizophrenia patients. Additionally, broad down-regulation of genes specific to neurons and concordant up-regulation of genes specific to astrocytes was observed in schizophrenia and bipolar disorder patients relative to controls. Metabolomic profiling identified disruption of GABA levels in schizophrenia patients. CONCLUSIONS: We provide a comprehensive post-mortem transcriptome profile of three psychiatric disorders across three brain regions. We highlight a high-confidence set of independently validated genes differentially expressed between schizophrenia and control patients in the anterior cingulate cortex and integrate transcriptional changes with untargeted metabolite profiling.


Assuntos
Transtorno Bipolar/genética , Encéfalo/metabolismo , Transtorno Depressivo Maior/genética , Esquizofrenia/genética , Transcriptoma , Autopsia , Transtorno Bipolar/metabolismo , Imunoprecipitação da Cromatina , Transtorno Depressivo Maior/metabolismo , Proteína 1 de Resposta de Crescimento Precoce/metabolismo , Feminino , Humanos , Masculino , Metabolômica , Esquizofrenia/metabolismo , Análise de Sequência de RNA
7.
J Psychiatr Res ; 82: 58-67, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27468165

RESUMO

MicroRNAs (miRNAs) are small, non-coding RNAs acting as post-transcriptional regulators of gene expression. Though implicated in multiple CNS disorders, miRNAs have not been examined in any psychiatric disease state in anterior cingulate cortex (AnCg), a brain region centrally involved in regulating mood. We performed qPCR analyses of 29 miRNAs previously implicated in psychiatric illness (major depressive disorder (MDD), bipolar disorder (BP) and/or schizophrenia (SZ)) in AnCg of patients with MDD and BP versus controls. miR-132, miR-133a and miR-212 were initially identified as differentially expressed in BP, miR-184 in MDD and miR-34a in both MDD and BP (although none survived multiple correction testing and must be considered preliminary). In silico target prediction algorithms identified putative targets of differentially expressed miRNAs. Nuclear Co-Activator 1 (NCOA1), Nuclear Co-Repressor 2 (NCOR2) and Phosphodiesterase 4B (PDE4B) were selected based upon predicted targeting by miR-34a (with NCOR2 and PDE4B both targeted by miR-184) and published relevance to psychiatric illness. Luciferase assays identified PDE4B as a target of miR-34a and miR-184, while NCOA1 and NCOR2 were targeted by miR-34a and 184, respectively. qPCR analyses were performed to determine whether changes in miRNA levels correlated with mRNA levels of validated targets. NCOA1 showed an inverse correlation with miR-34a in BP, while NCOR2 demonstrated a positive correlation. In sum, this is the first study to demonstrate miRNA changes in AnCg in psychiatric illness and validate miR-34a as differentially expressed in CNS in MDD. These findings support a mechanistic role for miRNAs in the regulation of stress-responsive genes disrupted in psychiatric illness.


Assuntos
Transtorno Bipolar/patologia , Transtorno Depressivo Maior/patologia , Giro do Cíngulo/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Adulto , Idoso , Algoritmos , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/genética , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Feminino , Células HEK293 , Humanos , Masculino , Pessoa de Meia-Idade , Mutagênese , Coativador 1 de Receptor Nuclear/genética , Coativador 1 de Receptor Nuclear/metabolismo , Coativador 2 de Receptor Nuclear/genética , Coativador 2 de Receptor Nuclear/metabolismo , Mudanças Depois da Morte , RNA Mensageiro/metabolismo , Sirtuína 1/genética , Transfecção , Adulto Jovem
8.
Microarrays (Basel) ; 5(1)2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26998349

RESUMO

Genome-wide association studies of schizophrenia encompassing the major histocompatibility locus (MHC) were highly significant following genome-wide correction. This broad region implicates many genes including the MHC complex class II. Within this interval we examined the expression of two MHC II genes (HLA-DPA1 and HLA-DRB1) in brain from individual subjects with schizophrenia (SZ), bipolar disorder (BD), major depressive disorder (MDD), and controls by differential gene expression methods. A third MHC II mRNA, CD74, was studied outside of the MHC II locus, as it interacts within the same immune complex. Exon microarrays were performed in anterior cingulate cortex (ACC) in BD compared to controls, and both HLA-DPA1 and CD74 were decreased in expression in BD. The expression of HLA-DPA1 and CD74 were both reduced in hippocampus, amygdala, and dorsolateral prefrontal cortex regions in SZ and BD compared to controls by specific qPCR assay. We found several novel HLA-DPA1 mRNA variants spanning HLA-DPA1 exons 2-3-4 as suggested by exon microarrays. The intronic rs9277341 SNP was a significant cis expression quantitative trait locus (eQTL) that was associated with the total expression of HLA-DPA1 in five brain regions. A biomarker study of MHC II mRNAs was conducted in SZ, BD, MDD, and control lymphoblastic cell lines (LCL) by qPCR assay of 87 subjects. There was significantly decreased expression of HLA-DPA1 and CD74 in BD, and trends for reductions in SZ in LCLs. The discovery of multiple splicing variants in brain for HLA-DPA1 is important as the HLA-DPA1 gene is highly conserved, there are no reported splicing variants, and the functions in brain are unknown. Future work on the function and localization of MHC Class II proteins in brain will help to understand the role of alterations in neuropsychiatric disorders. The HLA-DPA1 eQTL is located within a large linkage disequilibrium block that has an irrefutable association with schizophrenia. Future tests in a larger cohort are needed to determine the significance of this eQTL association with schizophrenia. Our findings support the long-held hypothesis that alterations in immune function are associated with the pathophysiology of psychiatric disorders.

9.
Proc Natl Acad Sci U S A ; 112(38): 11953-8, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26351673

RESUMO

Both gene expression profiling in postmortem human brain and studies using animal models have implicated the fibroblast growth factor (FGF) family in affect regulation and suggest a potential role in the pathophysiology of major depressive disorder (MDD). FGF2, the most widely characterized family member, is down-regulated in the depressed brain and plays a protective role in rodent models of affective disorders. By contrast, using three microarray analyses followed by quantitative RT-PCR confirmation, we show that FGF9 expression is up-regulated in the hippocampus of individuals with MDD, and that FGF9 expression is inversely related to the expression of FGF2. Because little is known about FGF9's function in emotion regulation, we used animal models to shed light on its potential role in affective function. We found that chronic social defeat stress, an animal model recapitulating some aspects of MDD, leads to a significant increase in hippocampal FGF9 expression, paralleling the elevations seen in postmortem human brain tissue. Chronic intracerebroventricular administration of FGF9 increased both anxiety- and depression-like behaviors. In contrast, knocking down FGF9 expression in the dentate gyrus of the hippocampus using a lentiviral vector produced a decrease in FGF9 expression and ameliorated anxiety-like behavior. Collectively, these results suggest that high levels of hippocampal FGF9 play an important role in the development or expression of mood and anxiety disorders. We propose that the relative levels of FGF9 in relation to other members of the FGF family may prove key to understanding vulnerability or resilience in affective disorders.


Assuntos
Afeto , Fator 9 de Crescimento de Fibroblastos/metabolismo , Adulto , Afeto/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Animais , Ansiedade/complicações , Ansiedade/metabolismo , Aprendizagem da Esquiva/efeitos dos fármacos , Estudos de Casos e Controles , Demografia , Giro Denteado/efeitos dos fármacos , Giro Denteado/metabolismo , Transtorno Depressivo Maior/complicações , Transtorno Depressivo Maior/metabolismo , Feminino , Fator 9 de Crescimento de Fibroblastos/administração & dosagem , Fator 9 de Crescimento de Fibroblastos/genética , Fator 9 de Crescimento de Fibroblastos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Humanos , Lentivirus/metabolismo , Masculino , Microinjeções , Pessoa de Meia-Idade , Mudanças Depois da Morte , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Estresse Psicológico/complicações , Estresse Psicológico/genética , Adulto Jovem
10.
PLoS One ; 10(5): e0127280, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26011537

RESUMO

A considerable body of evidence supports the role of mitochondrial dysfunction in psychiatric disorders and mitochondrial DNA (mtDNA) mutations are known to alter brain energy metabolism, neurotransmission, and cause neurodegenerative disorders. Genetic studies focusing on common nuclear genome variants associated with these disorders have produced genome wide significant results but those studies have not directly studied mtDNA variants. The purpose of this study is to investigate, using next generation sequencing, the involvement of mtDNA variation in bipolar disorder, schizophrenia, major depressive disorder, and methamphetamine use. MtDNA extracted from multiple brain regions and blood were sequenced (121 mtDNA samples with an average of 8,800x coverage) and compared to an electronic database containing 26,850 mtDNA genomes. We confirmed novel and rare variants, and confirmed next generation sequencing error hotspots by traditional sequencing and genotyping methods. We observed a significant increase of non-synonymous mutations found in individuals with schizophrenia. Novel and rare non-synonymous mutations were found in psychiatric cases in mtDNA genes: ND6, ATP6, CYTB, and ND2. We also observed mtDNA heteroplasmy in brain at a locus previously associated with schizophrenia (T16519C). Large differences in heteroplasmy levels across brain regions within subjects suggest that somatic mutations accumulate differentially in brain regions. Finally, multiplasmy, a heteroplasmic measure of repeat length, was observed in brain from selective cases at a higher frequency than controls. These results offer support for increased rates of mtDNA substitutions in schizophrenia shown in our prior results. The variable levels of heteroplasmic/multiplasmic somatic mutations that occur in brain may be indicators of genetic instability in mtDNA.


Assuntos
DNA Mitocondrial/genética , Transtornos Mentais/genética , Mutação/genética , Adulto , Estudos de Casos e Controles , Análise Mutacional de DNA , Eletroforese em Gel de Ágar , Feminino , Loci Gênicos , Humanos , Masculino , Transtornos Mentais/sangue , Pessoa de Meia-Idade , Dados de Sequência Molecular , Córtex Pré-Frontal/patologia
11.
Ann N Y Acad Sci ; 1345: 1-15, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-26014447

RESUMO

Depression presents a wide canvas for considering some approaches, issues, and problems in the study of major categories of mental illness in the context of current behavioral and molecular neurobiology. The study of depression encompasses multiple interactions among psychiatry, neurology, and neuroscience, as well as interactions with a host of other disciplines. This paper considers issues from an American perspective and discusses topics including historical aspects of the ways humanity has struggled with depression; the growth of approaches, and the "wars" in psychiatry in the middle of the 20th century between different ideologies; the development of psychiatry as a behavioral science inclusive of many disciplines; current diagnostic systems such as the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) of the American Psychiatric Association, and the ICD-10 Classification of Mental and Behavioral Disorders of the World Health Organization; the efforts to delineate subtypes of depression; the search for new neurobiological and behavioral targets in the context of the National Institute of Mental Health's Research Domain Criteria framework; and examples of potential future discoveries and disciplines that may ultimately improve treatment.


Assuntos
Depressão , Depressão/classificação , Depressão/diagnóstico , Depressão/história , Depressão/terapia , Manual Diagnóstico e Estatístico de Transtornos Mentais , História do Século XVII , História do Século XVIII , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Neurociências/história , Neurociências/tendências , Psiquiatria/história , Psiquiatria/tendências , Estados Unidos
13.
Front Hum Neurosci ; 8: 238, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24795602

RESUMO

Given the emergent interest in biomarkers for mood disorders, we assessed gene expression in the choroid plexus (CP), the region that produces cerebrospinal fluid (CSF), in individuals with major depressive disorder (MDD). Genes that are expressed in the CP can be secreted into the CSF and may be potential biomarker candidates. Given that we have previously shown that fibroblast growth factor family members are differentially expressed in post-mortem brain of subjects with MDD and the CP is a known source of growth factors in the brain, we posed the question whether growth factor dysregulation would be found in the CP of subjects with MDD. We performed laser capture microscopy of the CP at the level of the hippocampus in subjects with MDD and psychiatrically normal controls. We then extracted, amplified, labeled, and hybridized the cRNA to Illumina BeadChips to assess gene expression. In controls, the most highly abundant known transcript was transthyretin. Moreover, half of the 14 most highly expressed transcripts in controls encode ribosomal proteins. Using BeadStudio software, we identified 169 transcripts differentially expressed (p < 0.05) between control and MDD samples. Using pathway analysis we noted that the top network altered in subjects with MDD included multiple members of the transforming growth factor-beta (TGFß) pathway. Quantitative real-time PCR (qRT-PCR) confirmed downregulation of several transcripts that interact with the extracellular matrix in subjects with MDD. These results suggest that there may be an altered cytoskeleton in the CP in MDD subjects that may lead to a disrupted blood-CSF-brain barrier.

14.
Nat Genet ; 45(9): 984-94, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23933821

RESUMO

Most psychiatric disorders are moderately to highly heritable. The degree to which genetic variation is unique to individual disorders or shared across disorders is unclear. To examine shared genetic etiology, we use genome-wide genotype data from the Psychiatric Genomics Consortium (PGC) for cases and controls in schizophrenia, bipolar disorder, major depressive disorder, autism spectrum disorders (ASD) and attention-deficit/hyperactivity disorder (ADHD). We apply univariate and bivariate methods for the estimation of genetic variation within and covariation between disorders. SNPs explained 17-29% of the variance in liability. The genetic correlation calculated using common SNPs was high between schizophrenia and bipolar disorder (0.68 ± 0.04 s.e.), moderate between schizophrenia and major depressive disorder (0.43 ± 0.06 s.e.), bipolar disorder and major depressive disorder (0.47 ± 0.06 s.e.), and ADHD and major depressive disorder (0.32 ± 0.07 s.e.), low between schizophrenia and ASD (0.16 ± 0.06 s.e.) and non-significant for other pairs of disorders as well as between psychiatric disorders and the negative control of Crohn's disease. This empirical evidence of shared genetic etiology for psychiatric disorders can inform nosology and encourages the investigation of common pathophysiologies for related disorders.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Transtornos Mentais/genética , Polimorfismo de Nucleotídeo Único , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno Bipolar/genética , Criança , Transtornos Globais do Desenvolvimento Infantil/genética , Doença de Crohn/genética , Transtorno Depressivo Maior/genética , Heterogeneidade Genética , Genoma Humano , Humanos , Padrões de Herança , Esquizofrenia/genética
15.
Proc Natl Acad Sci U S A ; 110(24): 9950-5, 2013 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-23671070

RESUMO

A cardinal symptom of major depressive disorder (MDD) is the disruption of circadian patterns. However, to date, there is no direct evidence of circadian clock dysregulation in the brains of patients who have MDD. Circadian rhythmicity of gene expression has been observed in animals and peripheral human tissues, but its presence and variability in the human brain were difficult to characterize. Here, we applied time-of-death analysis to gene expression data from high-quality postmortem brains, examining 24-h cyclic patterns in six cortical and limbic regions of 55 subjects with no history of psychiatric or neurological illnesses ("controls") and 34 patients with MDD. Our dataset covered ~12,000 transcripts in the dorsolateral prefrontal cortex, anterior cingulate cortex, hippocampus, amygdala, nucleus accumbens, and cerebellum. Several hundred transcripts in each region showed 24-h cyclic patterns in controls, and >100 transcripts exhibited consistent rhythmicity and phase synchrony across regions. Among the top-ranked rhythmic genes were the canonical clock genes BMAL1(ARNTL), PER1-2-3, NR1D1(REV-ERBa), DBP, BHLHE40 (DEC1), and BHLHE41(DEC2). The phasing of known circadian genes was consistent with data derived from other diurnal mammals. Cyclic patterns were much weaker in the brains of patients with MDD due to shifted peak timing and potentially disrupted phase relationships between individual circadian genes. This transcriptome-wide analysis of the human brain demonstrates a rhythmic rise and fall of gene expression in regions outside of the suprachiasmatic nucleus in control subjects. The description of its breakdown in MDD suggests potentially important molecular targets for treatment of mood disorders.


Assuntos
Encéfalo/metabolismo , Ritmo Circadiano/genética , Transtorno Depressivo Maior/genética , Perfilação da Expressão Gênica , Fatores de Transcrição ARNTL , Adulto , Idoso , Autopsia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Relógios Circadianos/genética , Feminino , Proteínas de Homeodomínio/genética , Humanos , Masculino , Pessoa de Meia-Idade , Membro 1 do Grupo D da Subfamília 1 de Receptores Nucleares/genética , Análise de Sequência com Séries de Oligonucleotídeos , Proteínas Circadianas Period/genética
16.
Front Genet ; 4: 297, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24391664

RESUMO

The G-protein linked signaling system (GPLS) comprises a large number of G-proteins, G protein-coupled receptors (GPCRs), GPCR ligands, and downstream effector molecules. G-proteins interact with both GPCRs and downstream effectors such as cyclic adenosine monophosphate (cAMP), phosphatidylinositols, and ion channels. The GPLS is implicated in the pathophysiology and pharmacology of both major depressive disorder (MDD) and bipolar disorder (BPD). This study evaluated whether GPLS is altered at the transcript level. The gene expression in the dorsolateral prefrontal (DLPFC) and anterior cingulate (ACC) were compared from MDD, BPD, and control subjects using Affymetrix Gene Chips and real time quantitative PCR. High quality brain tissue was used in the study to control for confounding effects of agonal events, tissue pH, RNA integrity, gender, and age. GPLS signaling transcripts were altered especially in the ACC of BPD and MDD subjects. Transcript levels of molecules which repress cAMP activity were increased in BPD and decreased in MDD. Two orphan GPCRs, GPRC5B and GPR37, showed significantly decreased expression levels in MDD, and significantly increased expression levels in BPD. Our results suggest opposite changes in BPD and MDD in the GPLS, "activated" cAMP signaling activity in BPD and "blunted" cAMP signaling activity in MDD. GPRC5B and GPR37 both appear to have behavioral effects, and are also candidate genes for neurodegenerative disorders. In the context of the opposite changes observed in BPD and MDD, these GPCRs warrant further study of their brain effects.

17.
Front Neurosci ; 6: 135, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23087602

RESUMO

Extensive evidence implicates dysfunction in serotonin (5-HT) signaling in the etiology of major depressive disorder (MDD). Dorsal raphe nucleus (DR) is a major source of serotonin in the brain, and previous studies have reported within it alterations in 5-HT-related gene expression, protein levels, receptor binding, and morphological organization in mood disorders. In the present study, we utilized in situ hybridization-guided laser capture microdissection to harvest tissue samples from the middle-caudal subregion of the human DR post-mortem from MDD patients and from psychiatrically normal comparison subjects. Extracted RNA was prepared for gene expression profiling, and subsequent confirmation of select targets with quantitative real-time PCR. Our data indicate expression changes in functional gene families that regulate: (1) cellular stress and energy balance, (2) intracellular signaling and transcriptional regulation, and (3) cell proliferation and connectivity. The greatest changes in expression were observed among transcriptional regulators, including downregulation in the expression of TOB1, EGR1, and NR4A2 and their downstream targets. Previous studies have implicated these gene products in the regulation of functional domains impacted by MDD, including cognitive function, affective regulation, and emotional memory formation. These observations indicate altered function of several transcriptional regulators and their downstream targets, which may lead to the dysregulation of multiple cellular functions that contribute to the pathophysiology of MDD. Future studies will require single cell analyses in the DR to determine potential impact of these changes on its cellular functions and related circuits.

18.
Ann N Y Acad Sci ; 1231: 1-16, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21884158

RESUMO

Sociophysiology was a term used early in the history of sociology and then again 25 years ago to describe interactions between the "social" and the "biological" worlds. Social scientists had largely viewed biology and the brain as a "black box" that was not an active aspect of their work or theories. A landmark, unpublished conference in 1986 brought together social scientists and biologists dedicated to the idea that bringing sociological conceptualizations and approaches together with those of physiology might create new ways to understand human behavior. The umbrella question for sociophysiology was dual: how do social processes impact the physiology of the organism, and how does that altered physiology affect future social behavior? This paper summarizes that conference with the goal of providing a glimpse into the early history of social neuroscience and to demonstrate the variety of individuals and interests that were present at the emergence of this new field. The late Patricia R. Barchas organized and chaired the conference.


Assuntos
Congressos como Assunto/história , Neurociências/história , Meio Social , Sociologia/história , História do Século XX , Humanos , Neurociências/métodos , Comportamento Social
19.
J Trauma Stress ; 24(3): 309-16, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21618288

RESUMO

The 2006 Lebanon War exposed children in the north of Israel to daily rocket attacks. To cope with the massive psychological needs, a teacher-delivered protocol focusing on enhancing personal resilience was implemented. Children were assessed for risk factors, symptoms, and adaptation before the 16-week program (Time 1; n = 983) and after its completion (Time 2; n = 563). At a 3-month follow-up (Time 3; n = 754) children were assessed together with a waiting-list comparison group (n = 1,152). Participating children showed a significant symptom decrease at Time 2 and significantly fewer symptoms than the control group at Time 3. Six or more risk factors were associated with greater symptoms and parental concern about the child's adaptive functioning. Teachers are valuable cost-effective providers for clinically informed interventions after mass trauma and disaster.


Assuntos
Docentes , Resiliência Psicológica , Transtornos de Estresse Pós-Traumáticos/terapia , Guerra , Adaptação Psicológica , Criança , Feminino , Humanos , Israel , Líbano , Masculino
20.
Ann N Y Acad Sci ; 1208: 1-9, 2010 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-20955319

RESUMO

The growing number of soldiers returning home with psychiatric and neurologic disorders, notably posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI), underscores the need for an interdisciplinary framework for understanding the emergent consequences of combat. Among the challenges facing the scientific community is the development of effective treatment strategies for TBI from blast and other injuries, given the confounding effects of comorbid psychological symptoms on accurate diagnoses. At the individual level, emerging technologies-including virtual reality, the use of genetic biomarkers to inform treatment response, and new brain imaging methodology-are playing an important role in the development of differential therapeutics to best address a soldier's particular clinical needs. At the macro level, new approaches toward understanding the political, cultural, and ideological contexts of mass conflict, the decision to join in violence, and ways of preventing genocide are discussed.


Assuntos
Distúrbios de Guerra/terapia , Guerra , Lesões Encefálicas/psicologia , Lesões Encefálicas/terapia , Distúrbios de Guerra/psicologia , Conflito (Psicologia) , Humanos , Militares/psicologia , Psiquiatria Militar , Transtornos de Estresse Pós-Traumáticos/psicologia , Transtornos de Estresse Pós-Traumáticos/terapia , Estados Unidos
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