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1.
Nat Commun ; 11(1): 3996, 2020 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-32778725

RESUMO

Psychomotor stimulants increase dopamine levels in the striatum and promote locomotion; however, their effects on striatal pathway function in vivo remain unclear. One model that has been proposed to account for these motor effects suggests that stimulants drive hyperactivity via activation and inhibition of direct and indirect pathway striatal neurons, respectively. Although this hypothesis is consistent with the cellular actions of dopamine receptors and received support from optogenetic and chemogenetic studies, it has been rarely tested with in vivo recordings. Here, we test this model and observe that cocaine increases the activity of both pathways in the striatum of awake mice. These changes are linked to a dopamine-dependent cocaine-induced strengthening of upstream orbitofrontal cortex (OFC) inputs to the dorsomedial striatum (DMS) in vivo. Finally, depressing OFC-DMS pathway with a high frequency stimulation protocol in awake mice over-powers the cocaine-induced potentiation of OFC-DMS pathway and attenuates the expression of locomotor sensitization, directly linking OFC-DMS potentiation to cocaine-induced hyperactivity.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cocaína/farmacologia , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/metabolismo , Hipercinese/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Animais , Comportamento Animal , Modelos Animais de Doenças , Dopamina , Feminino , Hipercinese/induzido quimicamente , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Optogenética
2.
PLoS One ; 15(8): e0237015, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32760098

RESUMO

Graves' orbitopathy (GO) is characterised in early stages by orbital fibroblast inflammation, which can be aggravated by oxidative stress and often leads to fibrosis. Protein tyrosine protein 1B (PTP1B) is a regulator of inflammation and a therapeutic target in diabetes. We investigated the role of PTP1B in the GO mechanism using orbital fibroblasts from GO and healthy non-GO subjects. After 24 hours of transfection with PTPN1 siRNA, the fibroblasts were exposed to interleukin (IL)-1ß, cigarette smoke extract (CSE), H2O2, and transforming growth factor (TGF)-ß stimulations. Inflammatory cytokines and fibrosis-related proteins were analysed using western blotting and/or enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) release was detected using an oxidant-sensitive fluorescent probe. IL-1ß, tumor necrosis factor (TNF)-α, bovine thyroid stimulating hormone (bTSH), high-affinity human stimulatory monoclonal antibody of TSH receptor (M22), and insulin-like growth factor-1 (IGF-1) significantly increased PTP1B protein production in GO and non-GO fibroblasts. PTPN1 silencing significantly blocked IL-1ß-induced inflammatory cytokine production, CSE- and H2O2-induced ROS synthesis, and TGF-ß-induced expression of collagen Iα, α-smooth muscle actin (SMA), and fibronectin in GO fibroblasts. Silencing PTPN1 also decreased phosphorylation levels of Akt, p38, and c-Jun N-terminal kinase (JNK) and endoplasmic reticulum (ER)-stress response proteins in GO cells. PTP1B may be a potential therapeutic target of anti-inflammatory, anti-oxidant and anti-fibrotic treatment of GO.


Assuntos
Oftalmopatia de Graves/enzimologia , Oftalmopatia de Graves/terapia , Proteína Tirosina Fosfatase não Receptora Tipo 1/antagonistas & inibidores , Adulto , Animais , Apoptose , Bovinos , Sobrevivência Celular , Citocinas/biossíntese , Estresse do Retículo Endoplasmático , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Inativação Gênica , Oftalmopatia de Graves/patologia , Humanos , Técnicas In Vitro , Mediadores da Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Proteína Tirosina Fosfatase não Receptora Tipo 1/genética , Proteína Tirosina Fosfatase não Receptora Tipo 1/metabolismo , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais
3.
PLoS One ; 15(6): e0234601, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32589693

RESUMO

Body weight is substantially determined by eating behaviors, which are themselves driven by biological factors interacting with the environment. Previous studies in young children suggest that genetic influences on dopamine function may confer differential susceptibility to the environment in such a way that increases behavioral obesity risk in a lower socioeconomic status (SES) environment but decreases it in a higher SES environment. We aimed to test if this pattern of effect could also be observed in adolescence, another critical period for development in brain and behavior, using a novel measure of predicted expression of the dopamine receptor 4 (DRD4) gene in prefrontal cortex. In a sample of 76 adolescents (37 boys and 39 girls from Baltimore, Maryland/US, aged 14-18y), we estimated individual levels of DRD4 gene expression (PredDRD4) in prefrontal cortex from individual genomic data using PrediXcan, and tested interactions with a composite SES score derived from their annual household income, maternal education, food insecurity, perceived resource availability, and receipt of public assistance. Primary outcomes were snack intake during a multi-item ad libitum meal test, and food-related impulsivity assessed using a food-adapted go/no-go task. A linear regression model adjusted for sex, BMI z-score, and genetic ethnicity demonstrated a PredDRD4 by composite SES score interaction for snack intake (p = 0.009), such that adolescents who had lower PredDRD4 levels exhibited greater snack intake in the lower SES group, but lesser snack intake in the higher SES group. Exploratory analysis revealed a similar pattern for scores on the Perceived Stress Scale (p = 0.001) such that the low PredDRD4 group reported higher stress in the lower SES group, but less stress in the higher SES group, suggesting that PredDRD4 may act in part by affecting perceptions of the environment. These results are consistent with a differential susceptibility model in which genes influencing environmental responsiveness interact with environments varying in obesogenicity to confer behavioral obesity risk in a less favorable environment, but behavioral obesity protection in a favorable one.


Assuntos
Comportamento Alimentar , Receptores de Dopamina D4/metabolismo , Lanches , Adolescente , Baltimore , Feminino , Humanos , Masculino , Obesidade , Córtex Pré-Frontal/metabolismo , Receptores Dopaminérgicos , Receptores de Dopamina D4/fisiologia , Fatores de Risco , Classe Social
4.
PLoS Genet ; 16(6): e1008756, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32520939

RESUMO

Paternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. Here we use mouse models to investigate mechanisms and impacts of paternal CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking is associated with changes in prefrontal cortex DNAme and gene expression patterns in offspring. Remarkably, the epigenetic and transcriptional effects of CS exposure that we observed in wild type mice are partially recapitulated in Nrf2-/- mice and their offspring, independent of smoking status. Nrf2 is a central regulator of antioxidant gene transcription, and mice lacking Nrf2 consequently display elevated oxidative stress, suggesting that oxidative stress may underlie CS-induced heritable epigenetic changes. Importantly, paternal sperm DNAme changes do not overlap with DNAme changes measured in offspring prefrontal cortex, indicating that the observed DNAme changes in sperm are not directly inherited. Additionally, the changes in sperm DNAme associated with CS exposure were not observed in sperm of unexposed offspring, suggesting the effects are likely not maintained across multiple generations.


Assuntos
Epigênese Genética , Fator 2 Relacionado a NF-E2/genética , Exposição Paterna , Poluição por Fumaça de Tabaco/efeitos adversos , Animais , Metilação de DNA , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/metabolismo , Espermatozoides/metabolismo
5.
PLoS One ; 15(6): e0235046, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32579566

RESUMO

Post-ictal emergence of slow wave EEG (electroencephalogram) activity and burst-suppression has been associated with the therapeutic effects of the electroconvulsive therapy (ECT), indicating that mere "cerebral silence" may elicit antidepressant actions. Indeed, brief exposures to burst-suppressing anesthesia has been reported to elicit antidepressant effects in a subset of patients, and produce behavioral and molecular alterations, such as increased expression of brain-derived neurotrophic factor (BDNF), connected with antidepressant responses in rodents. Here, we have further tested the cerebral silence hypothesis by determining whether repeated exposures to isoflurane anesthesia reduce depressive-like symptoms or influence BDNF expression in male Wistar outbred rats (Crl:WI(Han)) subjected to chronic mild stress (CMS), a model which is responsive to repeated electroconvulsive shocks (ECS, a model of ECT). Stress-susceptible, stress-resilient, and unstressed rats were exposed to 5 doses of isoflurane over a 15-day time period, with administrations occurring every third day. Isoflurane dosing is known to reliably produce rapid EEG burst-suppression (4% induction, 2% maintenance; 15 min). Antidepressant and anxiolytic effects of isoflurane were assessed after the first, third, and fifth drug exposure by measuring sucrose consumption, as well as performance on the open field and the elevated plus maze tasks. Tissue samples from the medial prefrontal cortex and hippocampus were collected, and levels of BDNF (brain-derived neurotrophic factor) protein were assessed. We find that isoflurane anesthesia had no impact on the behavior of stress-resilient or anhedonic rats in selected tests; findings which were consistent-perhaps inherently related-with unchanged levels of BDNF.


Assuntos
Antidepressivos/farmacologia , Transtorno Depressivo/prevenção & controle , Isoflurano/farmacologia , Estresse Psicológico/prevenção & controle , Anestésicos Inalatórios , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Transtorno Depressivo/etiologia , Transtorno Depressivo/fisiopatologia , Modelos Animais de Doenças , Eletroconvulsoterapia/métodos , Eletroencefalografia , Eletrochoque/efeitos adversos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Humanos , Isoflurano/administração & dosagem , Masculino , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Ratos Wistar , Estresse Psicológico/etiologia , Estresse Psicológico/fisiopatologia
6.
Nucleic Acids Res ; 48(11): e66, 2020 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-32383753

RESUMO

Multiplex single-molecule fluorescent in situ hybridization (smFISH) is a powerful method for validating RNA sequencing and emerging spatial transcriptomic data, but quantification remains a computational challenge. We present a framework for generating and analyzing smFISH data in complex tissues while overcoming autofluorescence and increasing multiplexing capacity. We developed dotdotdot (https://github.com/LieberInstitute/dotdotdot) as a corresponding software package to quantify RNA transcripts in single nuclei and perform differential expression analysis. We first demonstrate robustness of our platform in single mouse neurons by quantifying differential expression of activity-regulated genes. We then quantify spatial gene expression in human dorsolateral prefrontal cortex (DLPFC) using spectral imaging and dotdotdot to mask lipofuscin autofluorescence. We lastly apply machine learning to predict cell types and perform downstream cell type-specific expression analysis. In summary, we provide experimental workflows, imaging acquisition and analytic strategies for quantification and biological interpretation of smFISH data in complex tissues.


Assuntos
Automação , Hibridização in Situ Fluorescente/métodos , Imagem Individual de Molécula , Software , Adolescente , Adulto , Animais , Humanos , Processamento de Imagem Assistida por Computador , Lipofuscina/análise , Aprendizado de Máquina , Masculino , Camundongos , Neurônios/citologia , Neurônios/metabolismo , Especificidade de Órgãos , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , RNA Mensageiro/análise
7.
Nat Neurosci ; 23(6): 718-729, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32367065

RESUMO

DNA forms conformational states beyond the right-handed double helix; however, the functional relevance of these noncanonical structures in the brain remains unknown. Here we show that, in the prefrontal cortex of mice, the formation of one such structure, Z-DNA, is involved in the regulation of extinction memory. Z-DNA is formed during fear learning and reduced during extinction learning, which is mediated, in part, by a direct interaction between Z-DNA and the RNA-editing enzyme Adar1. Adar1 binds to Z-DNA during fear extinction learning, which leads to a reduction in Z-DNA at sites where Adar1 is recruited. Knockdown of Adar1 leads to an inability to modify a previously acquired fear memory and blocks activity-dependent changes in DNA structure and RNA state-effects that are fully rescued by the introduction of full-length Adar1. These findings suggest a new mechanism of learning-induced gene regulation that is dependent on proteins that recognize alternate DNA structure states, which are required for memory flexibility.


Assuntos
Adenosina Desaminase/metabolismo , Adenosina Desaminase/fisiologia , DNA Forma Z/fisiologia , Extinção Psicológica/fisiologia , Edição de RNA/fisiologia , Animais , DNA Forma Z/metabolismo , Medo , Aprendizagem/fisiologia , Camundongos , Córtex Pré-Frontal/metabolismo , RNA Interferente Pequeno/farmacologia
8.
Nat Neurosci ; 23(6): 696-700, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32424284

RESUMO

Cerebral atherosclerosis contributes to dementia via unclear processes. We performed proteomic sequencing of dorsolateral prefrontal cortex in 438 older individuals and found associations between cerebral atherosclerosis and reduced synaptic signaling and between RNA splicing and increased oligodendrocyte development and myelination. Consistently, single-cell RNA sequencing showed cerebral atherosclerosis associated with higher oligodendrocyte abundance. A subset of proteins and modules associated with cerebral atherosclerosis was also associated with Alzheimer's disease, suggesting shared mechanisms.


Assuntos
Envelhecimento/metabolismo , Doença de Alzheimer/metabolismo , Arteriosclerose Intracraniana/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Córtex Pré-Frontal/metabolismo , Proteômica , Doença de Alzheimer/complicações , Bases de Dados Factuais , Humanos , Arteriosclerose Intracraniana/complicações
9.
Nat Commun ; 11(1): 2301, 2020 05 08.
Artigo em Inglês | MEDLINE | ID: mdl-32385265

RESUMO

Depression is a leading cause of worldwide disability but there remains considerable uncertainty regarding its neural and behavioural associations. Here, using non-overlapping Psychiatric Genomics Consortium (PGC) datasets as a reference, we estimate polygenic risk scores for depression (depression-PRS) in a discovery (N = 10,674) and replication (N = 11,214) imaging sample from UK Biobank. We report 77 traits that are significantly associated with depression-PRS, in both discovery and replication analyses. Mendelian Randomisation analysis supports a potential causal effect of liability to depression on brain white matter microstructure (ß: 0.125 to 0.868, pFDR < 0.043). Several behavioural traits are also associated with depression-PRS (ß: 0.014 to 0.180, pFDR: 0.049 to 1.28 × 10-14) and we find a significant and positive interaction between depression-PRS and adverse environmental exposures on mental health outcomes. This study reveals replicable associations between depression-PRS and white matter microstructure. Our results indicate that white matter microstructure differences may be a causal consequence of liability to depression.


Assuntos
Depressão/genética , Córtex Pré-Frontal/metabolismo , Idoso , Bancos de Espécimes Biológicos , Depressão/metabolismo , Depressão/patologia , Feminino , Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Neuroimagem/métodos , Polimorfismo de Nucleotídeo Único/genética , Córtex Pré-Frontal/patologia , Fatores de Risco
10.
Hum Genet ; 139(10): 1285-1297, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32385526

RESUMO

During the past decade, genetic studies of schizophrenia have become one of the most exciting and fast-moving areas. Hundreds of genes implicated in schizophrenia have been identified by genetic, epigenetic, and gene expression studies. However, how to systematically and efficiently use these published data to pinpoint the causal genes becomes a major challenge in schizophrenia research. Here, we release an updated version of a comprehensive database for schizophrenia research, SZDB2.0 ( www.szdb.org ), which accompanies significant data expansion and feature improvements, as well as functionality optimization. Compared with the first version (SZDB), the current database has the following updates: (1) We added the newly published genome-wide association study (GWAS) of schizophrenia from CLOZUK + PGC, which is the largest GWAS for schizophrenia; (2) We included a polygenic risk score calculator; (3) In the refined "Gene" module of SZDB2.0, we collated genetic, gene expression, methylation, and integrative results of all available schizophrenia studies; (4) In the "CNV (copy number variation)" module, we collated the results of all 77 CNV publications about schizophrenia; (5) We also updated other data, including gene expression quantitative trait loci (eQTL), transcript QTL, methylation QTL, and protein-protein interaction data, based on the information from the latest literatures. We optimized the query interface of SZDB2.0 for a better visualization and data retrieval. The updated SZDB2.0 will advance the research of schizophrenia.


Assuntos
Bases de Dados Genéticas , Epigênese Genética , Predisposição Genética para Doença , Herança Multifatorial , Locos de Características Quantitativas , Esquizofrenia/genética , Variações do Número de Cópias de DNA , Metilação de DNA , Ontologia Genética , Estudo de Associação Genômica Ampla , Humanos , Armazenamento e Recuperação da Informação/métodos , Polimorfismo de Nucleotídeo Único , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Mapeamento de Interação de Proteínas , Risco , Esquizofrenia/diagnóstico , Esquizofrenia/fisiopatologia
11.
Psychopharmacology (Berl) ; 237(7): 1943-1957, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32399634

RESUMO

RATIONALE: The recreational use of naphyrone, a potent synthetic cathinone with a pyrovalerone structure, has raised questions about possible deleterious neurobehavioral consequences. OBJECTIVE: To investigate naphyrone-induced neurobehavioral effects and alterations in brain monoamines using two patterns of abuse, i.e., single and repeated (binge) use. METHODS: We studied naphyrone dose/induced locomotor activity relationship at 3, 10, 30, and 100 mg/kg in mice. We investigated the effects of single (30 mg/kg; acute injection) versus repeated (30 mg/kg ×3/day for 3 days; binge injection) intraperitoneal naphyrone administration on locomotor activity, anxiety-like behavior, spatial recognition memory, anhedonia, behavioral despair, and social interaction. We measured post-mortem prefrontal cortex levels of monoamines and modeled naphyrone pharmacokinetics and concentration/locomotor effect relationship. RESULTS: Both naphyrone administration patterns induced time-dependent increases in locomotor activity (p < 0.001 and p < 0.0001, respectively) and social interaction (p < 0.05 and p < 0.001, respectively) but did not alter spatial recognition memory or anhedonia. Acute naphyrone injection induced anxiety-like behavior (p < 0.01) and reduced resignation (p < 0.01) whereas binge administration induced non-anxiety-like behavior (p < 0.05) and did not alter behavioral despair. Both patterns increased the prefrontal cortex dopamine (p < 0.0001) and norepinephrine (p < 0.05 and p < 0.01, respectively) but not serotonin content. Naphyrone pharmacokinetics followed a two-compartment model with an overall elimination half-life of 0.3 h. The naphyrone concentration/locomotor effect relationship was described by an additive Emax model with an EC50 of 672 µg/L. CONCLUSIONS: Single naphyrone administration increases locomotor activity according to a direct concentration/effect relationship. The neurobehavioral effects after binge differs from those after single administration and are not explained by drug accumulation given the relatively fast elimination.


Assuntos
Drogas Desenhadas/farmacocinética , Drogas Ilícitas/farmacocinética , Locomoção/efeitos dos fármacos , Pentanonas/farmacocinética , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Pirrolidinas/farmacocinética , Animais , Relação Dose-Resposta a Droga , Locomoção/fisiologia , Masculino , Camundongos , Memória Espacial/efeitos dos fármacos , Memória Espacial/fisiologia
12.
Am J Chin Med ; 48(3): 559-577, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32345030

RESUMO

Depression is partially caused by inflammation in the central nervous system. Early study demonstrated that musk, glandular secretion from male musk deer, exerted an antidepressant-like effect. The aim of this study was to investigate if muscone, a bioactive ingredient in musk, could ameliorate neuroinflammation and depressive-like behaviors as well as explore the potential action mechanism. Mice were intraperitoneally (i.p.) injected with muscone for 2 weeks prior to administration of lipopolysaccharides (LPS, 1mg/kg, i.p.). Pre-treatment with muscone reversed the LPS-induced decrease in body weight within 24h and ameliorated depressive-like behaviors shown by sucrose preference, tail suspension test, and forced swimming test. LPS-induced activation of microglial cells and elevation in expression of inflammatory cytokines including IL-1ß, RANTES, and MCP-1 in the prefrontal cortex of mice were effectively abrogated by muscone, which significantly down-regulated expression of TLR4, MyD88, Caspase-1, NLRP3, renin, and Ang II. In addition, treatment of BV2 microglia cells with muscone markedly attenuated the LPS-induced rise in protein expression of TLR4, Ang II, and IL-1ß. This study revealed that muscone could ameliorate LPS-induced depressive-like behaviors by repressing neuroinflammation in the prefrontal cortex of mice caused by its suppression on microglia activation and production of inflammatory cytokines via acting on TLR4 pathway and RAS cascade.


Assuntos
Cicloparafinas/administração & dosagem , Cicloparafinas/farmacologia , Depressão/tratamento farmacológico , Lipopolissacarídeos/efeitos adversos , Animais , Peso Corporal/efeitos dos fármacos , Citocinas/metabolismo , Cervos , Depressão/induzido quimicamente , Mediadores da Inflamação/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos , Microglia/citologia , Microglia/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/metabolismo
13.
Chem Biol Interact ; 323: 109076, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32240654

RESUMO

A growing body of evidence indicates that exposure to nonylphenol (NP), a typical persistent organic pollutant (POP), in early life results in the impairment of the central nervous system (CNS), but the underlying mechanism still remains to be elucidated. High levels of pro-inflammatory cytokines in the brain have been implicated in the CNS damages. The animal model of exposure to NP in early life was established by maternal gavage during the pregnancy and lactation in the present study. We found that exposure to NP in early life increased the levels of pro-inflammatory cytokines in the rat prefrontal cortex. Interestingly, the levels of pro-inflammatory cytokines in the intestine as well as in the serum were also increased by NP exposure. Furthermore, the increased permeability of intestinal barrier and blood-brain barrier (BBB), two critical barriers in the gut to brain communication, was observed in the rats exposed to NP in early lives. The decreased expression of zonula occludens-1 (ZO-1) and claudin-1 (CLDN-1), tight junction proteins (TJs) that responsible for maintaining the permeability of intestinal barrier and BBB, was found, which may underlie these increases in permeability. Taken together, these results suggested that the disturbed gut-brain communication may contribute to the increased levels of pro-inflammatory cytokines in the prefrontal cortex caused by NP exposure in early life.


Assuntos
Citocinas/metabolismo , Trato Gastrointestinal/patologia , Mediadores da Inflamação/metabolismo , Fenóis/toxicidade , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Animais , Animais Recém-Nascidos , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Líquido Cefalorraquidiano/metabolismo , Claudina-1/metabolismo , Citocinas/sangue , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Mediadores da Inflamação/sangue , Intestinos/efeitos dos fármacos , Intestinos/patologia , Exposição Materna , Permeabilidade , Córtex Pré-Frontal/efeitos dos fármacos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Ratos Sprague-Dawley , Proteína da Zônula de Oclusão-1/metabolismo
14.
Nat Commun ; 11(1): 1797, 2020 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-32286273

RESUMO

Mutations that inactivate negative translation regulators cause autism spectrum disorders (ASD), which predominantly affect males and exhibit social interaction and communication deficits and repetitive behaviors. However, the cells that cause ASD through elevated protein synthesis resulting from these mutations remain unknown. Here we employ conditional overexpression of translation initiation factor eIF4E to increase protein synthesis in specific brain cells. We show that exaggerated translation in microglia, but not neurons or astrocytes, leads to autism-like behaviors in male mice. Although microglial eIF4E overexpression elevates translation in both sexes, it only increases microglial density and size in males, accompanied by microglial shift from homeostatic to a functional state with enhanced phagocytic capacity but reduced motility and synapse engulfment. Consequently, cortical neurons in the mice have higher synapse density, neuroligins, and excitation-to-inhibition ratio compared to control mice. We propose that functional perturbation of male microglia is an important cause for sex-biased ASD.


Assuntos
Transtorno Autístico/metabolismo , Comportamento Animal , Microglia/metabolismo , Biossíntese de Proteínas , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Movimento Celular , Feminino , Perfilação da Expressão Gênica , Genótipo , Homeostase , Masculino , Camundongos Knockout , Proteínas dos Microfilamentos/metabolismo , Neurônios/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Fagocitose , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/ultraestrutura , Comportamento Social , Sinapses/metabolismo
15.
Nat Commun ; 11(1): 1971, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32332754

RESUMO

We present Bisque, a tool for estimating cell type proportions in bulk expression. Bisque implements a regression-based approach that utilizes single-cell RNA-seq (scRNA-seq) or single-nucleus RNA-seq (snRNA-seq) data to generate a reference expression profile and learn gene-specific bulk expression transformations to robustly decompose RNA-seq data. These transformations significantly improve decomposition performance compared to existing methods when there is significant technical variation in the generation of the reference profile and observed bulk expression. Importantly, compared to existing methods, our approach is extremely efficient, making it suitable for the analysis of large genomic datasets that are becoming ubiquitous. When applied to subcutaneous adipose and dorsolateral prefrontal cortex expression datasets with both bulk RNA-seq and snRNA-seq data, Bisque replicates previously reported associations between cell type proportions and measured phenotypes across abundant and rare cell types. We further propose an additional mode of operation that merely requires a set of known marker genes.


Assuntos
Biologia Computacional/métodos , RNA-Seq/métodos , Análise de Célula Única/métodos , Tecido Adiposo/metabolismo , Algoritmos , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Genômica , Humanos , Córtex Pré-Frontal/metabolismo , RNA Citoplasmático Pequeno , Software , Transcriptoma
16.
Brain ; 143(4): 1261-1277, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32236540

RESUMO

Frontotemporal dysconnectivity is a key pathology in schizophrenia. The specific nature of this dysconnectivity is unknown, but animal models imply dysfunctional theta phase coupling between hippocampus and medial prefrontal cortex (mPFC). We tested this hypothesis by examining neural dynamics in 18 participants with a schizophrenia diagnosis, both medicated and unmedicated; and 26 age, sex and IQ matched control subjects. All participants completed two tasks known to elicit hippocampal-prefrontal theta coupling: a spatial memory task (during magnetoencephalography) and a memory integration task. In addition, an overlapping group of 33 schizophrenia and 29 control subjects underwent PET to measure the availability of GABAARs expressing the α5 subunit (concentrated on hippocampal somatostatin interneurons). We demonstrate-in the spatial memory task, during memory recall-that theta power increases in left medial temporal lobe (mTL) are impaired in schizophrenia, as is theta phase coupling between mPFC and mTL. Importantly, the latter cannot be explained by theta power changes, head movement, antipsychotics, cannabis use, or IQ, and is not found in other frequency bands. Moreover, mPFC-mTL theta coupling correlated strongly with performance in controls, but not in subjects with schizophrenia, who were mildly impaired at the spatial memory task and no better than chance on the memory integration task. Finally, mTL regions showing reduced phase coupling in schizophrenia magnetoencephalography participants overlapped substantially with areas of diminished α5-GABAAR availability in the wider schizophrenia PET sample. These results indicate that mPFC-mTL dysconnectivity in schizophrenia is due to a loss of theta phase coupling, and imply α5-GABAARs (and the cells that express them) have a role in this process.


Assuntos
Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , Esquizofrenia/fisiopatologia , Lobo Temporal/fisiopatologia , Ritmo Teta/fisiologia , Adulto , Feminino , Humanos , Magnetoencefalografia , Masculino , Vias Neurais/metabolismo , Tomografia por Emissão de Pósitrons , Córtex Pré-Frontal/metabolismo , Receptores de GABA-A/metabolismo , Esquizofrenia/metabolismo , Lobo Temporal/metabolismo
17.
Nat Neurosci ; 23(6): 771-781, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341540

RESUMO

Major depressive disorder (MDD) has an enormous impact on global disease burden, affecting millions of people worldwide and ranking as a leading cause of disability for almost three decades. Past molecular studies of MDD employed bulk homogenates of postmortem brain tissue, which obscures gene expression changes within individual cell types. Here we used single-nucleus transcriptomics to examine ~80,000 nuclei from the dorsolateral prefrontal cortex of male individuals with MDD (n = 17) and of healthy controls (n = 17). We identified 26 cellular clusters, and over 60% of these showed differential gene expression between groups. We found that the greatest dysregulation occurred in deep layer excitatory neurons and immature oligodendrocyte precursor cells (OPCs), and these contributed almost half (47%) of all changes in gene expression. These results highlight the importance of dissecting cell-type-specific contributions to the disease and offer opportunities to identify new avenues of research and novel targets for treatment.


Assuntos
Transtorno Depressivo Maior/metabolismo , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Neurônios/metabolismo , Células Precursoras de Oligodendrócitos/metabolismo , Córtex Pré-Frontal/metabolismo , Transcriptoma , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
18.
Neuron ; 106(6): 992-1008.e9, 2020 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-32320644

RESUMO

Astrocytes play essential roles in brain function by supporting synaptic connectivity and associated circuits. How these roles are regulated by transcription factors is unknown. Moreover, there is emerging evidence that astrocytes exhibit regional heterogeneity, and the mechanisms controlling this diversity remain nascent. Here, we show that conditional deletion of the transcription factor nuclear factor I-A (NFIA) in astrocytes in the adult brain results in region-specific alterations in morphology and physiology that are mediated by selective DNA binding. Disruptions in astrocyte function following loss of NFIA are most pronounced in the hippocampus, manifested by impaired interactions with neurons, coupled with diminution of learning and memory behaviors. These changes in hippocampal astrocytes did not affect basal neuronal properties but specifically inhibited synaptic plasticity, which is regulated by NFIA in astrocytes through calcium-dependent mechanisms. Together, our studies reveal region-specific transcriptional dependencies for astrocytes and identify astrocytic NFIA as a key transcriptional regulator of hippocampal circuits.


Assuntos
Astrócitos/metabolismo , Encéfalo/metabolismo , Cálcio/metabolismo , Regulação da Expressão Gênica , Aprendizagem/fisiologia , Fatores de Transcrição NFI/genética , Animais , Astrócitos/fisiologia , Encéfalo/citologia , Encéfalo/fisiopatologia , Tronco Encefálico/citologia , Tronco Encefálico/metabolismo , Tronco Encefálico/fisiopatologia , Região CA1 Hipocampal/citologia , Região CA1 Hipocampal/metabolismo , Região CA1 Hipocampal/fisiopatologia , Hipocampo/citologia , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Potenciação de Longa Duração/fisiologia , Memória/fisiologia , Camundongos , Camundongos Knockout , Vias Neurais , Plasticidade Neuronal , Neurônios , Bulbo Olfatório/citologia , Bulbo Olfatório/metabolismo , Bulbo Olfatório/fisiopatologia , Técnicas de Patch-Clamp , Córtex Pré-Frontal/citologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/fisiopatologia , Memória Espacial/fisiologia
20.
J Neurosci ; 40(20): 4033-4041, 2020 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-32284336

RESUMO

Cytoskeletal proteins and post-translational modifications play a role in mood disorders. Post-translational modifications of tubulin also alter microtubule dynamics. Furthermore, tubulin interacts closely with Gαs, the G-protein responsible for activation of adenylyl cyclase. Postmortem tissue derived from depressed suicide brain showed increased Gαs in lipid-raft domains compared with normal subjects. Gαs, when ensconced in lipid rafts, couples less effectively with adenylyl cyclase to produce cAMP, and this is reversed by antidepressant treatment. A recent in vitro study demonstrated that tubulin anchors Gαs to lipid rafts and that increased tubulin acetylation (due to HDAC6 inhibition) and antidepressant treatment decreased the proportion of Gαs complexed with tubulin. This suggested that deacetylated-tubulin might be more prevalent in depression. This study examined tubulin acetylation in whole-tissue homogenate, plasma membrane, and lipid-raft membrane domains in tissue from normal control subjects, depressed suicides, and depressed nonsuicides (human males/females). While tissue homogenate showed no changes in tubulin acetylation between control, depressed suicides, and depressed nonsuicides, plasma membrane-associated tubulin showed significant decreases in acetylation from depressed suicides and depressed nonsuicides compared with controls. No change was seen in expression of the enzymes responsible for tubulin acetylation or deacetylation. These data suggest that, during depression, membrane-localized tubulin maintains a lower acetylation state, permitting increased sequestration of Gαs in lipid-raft domains, where it is less likely to couple to adenylyl cyclase for cAMP production. Thus, membrane tubulin may play a role in mood disorders, which could be exploited for diagnosis and treatment.SIGNIFICANCE STATEMENT There is little understanding about the molecular mechanisms involved in the development of depression and, in severe cases, suicide. Evidence for the role of microtubule modifications in progression of depressive disorders is emerging. These postmortem data provide strong evidence for membrane tubulin modification leading to reduced efficacy of the G protein, Gαs, in depression. This study reveals a direct link between decreased tubulin acetylation in human depression and the increased localization of Gαs in lipid-raft domains responsible for attenuated cAMP signaling. The evidence presented here suggest a novel diagnostic and therapeutic locus for depression.


Assuntos
Citoesqueleto/metabolismo , Depressão/metabolismo , Desacetilase 6 de Histona/metabolismo , Córtex Pré-Frontal/metabolismo , Tubulina (Proteína)/metabolismo , Acetilação , Adenilil Ciclases/metabolismo , Adolescente , Adulto , Idoso , Membrana Celular/metabolismo , AMP Cíclico/biossíntese , Feminino , Humanos , Masculino , Microdomínios da Membrana/metabolismo , Pessoa de Meia-Idade , Mudanças Depois da Morte , Suicídio , Adulto Jovem
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