RESUMO
We have previously demonstrated functional and molecular changes in hippocampal subfields in individuals with schizophrenia (SZ) psychosis associated with hippocampal excitability. In this study, we use RNA-seq and assess global transcriptome changes in the hippocampal subfields, DG, CA3, and CA1 from individuals with SZ psychosis and controls to elucidate subfield-relevant molecular changes. We also examine changes in gene expression due to antipsychotic medication in the hippocampal subfields from our SZ ON- and OFF-antipsychotic medication cohort. We identify unique subfield-specific molecular profiles in schizophrenia postmortem samples compared with controls, implicating astrocytes in DG, immune mechanisms in CA3, and synaptic scaling in CA1. We show a unique pattern of subfield-specific effects by antipsychotic medication on gene expression levels with scant overlap of genes differentially expressed by SZ disease effect versus medication effect. These hippocampal subfield changes serve to confirm and extend our previous model of SZ and can explain the lack of full efficacy of conventional antipsychotic medication on SZ symptomatology. With future characterization using single-cell studies, the identified distinct molecular profiles of the DG, CA3, and CA1 in SZ psychosis may serve to identify further potential hippocampal-based therapeutic targets.
Assuntos
Transtornos Psicóticos , Esquizofrenia , Perfilação da Expressão Gênica , Hipocampo , Humanos , Imageamento por Ressonância Magnética , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/genética , Esquizofrenia/genéticaRESUMO
ß-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice ß-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide ß-catenin enrichment mapping, we identify Dicer1-important in small RNA (for example, microRNA) biogenesis--as a ß-catenin target gene that mediates resilience. Small RNA profiling after excising ß-catenin from nucleus accumbens in the context of chronic stress reveals ß-catenin-dependent microRNA regulation associated with resilience. Together, these findings establish ß-catenin as a critical regulator in the development of behavioural resilience, activating a network that includes Dicer1 and downstream microRNAs. We thus present a foundation for the development of novel therapeutic targets to promote stress resilience.
Assuntos
RNA Helicases DEAD-box/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Resiliência Psicológica , Ribonuclease III/genética , Estresse Fisiológico/genética , beta Catenina/metabolismo , Adaptação Fisiológica/genética , Animais , RNA Helicases DEAD-box/metabolismo , Depressão/fisiopatologia , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Neurônios/metabolismo , Ribonuclease III/metabolismo , Transdução de Sinais , beta Catenina/genéticaRESUMO
RAD51, a multifunctional protein, plays a central role in DNA replication and homologous recombination repair, and is known to be involved in cancer development. We identified a novel role for RAD51 in innate immune response signaling. Defects in RAD51 lead to the accumulation of self-DNA in the cytoplasm, triggering a STING-mediated innate immune response after replication stress and DNA damage. In the absence of RAD51, the unprotected newly replicated genome is degraded by the exonuclease activity of MRE11, and the fragmented nascent DNA accumulates in the cytosol, initiating an innate immune response. Our data suggest that in addition to playing roles in homologous recombination-mediated DNA double-strand break repair and replication fork processing, RAD51 is also implicated in the suppression of innate immunity. Thus, our study reveals a previously uncharacterized role of RAD51 in initiating immune signaling, placing it at the hub of new interconnections between DNA replication, DNA repair, and immunity.
Assuntos
Replicação do DNA , Proteínas de Ligação a DNA/genética , DNA/genética , Proteínas de Membrana/genética , Rad51 Recombinase/genética , Reparo de DNA por Recombinação/genética , Linhagem Celular Tumoral , DNA/imunologia , Quebras de DNA de Cadeia Dupla/efeitos dos fármacos , Proteínas de Ligação a DNA/imunologia , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/imunologia , Fibroblastos/citologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/imunologia , Genes Reporter , Humanos , Ácidos Hidroxâmicos/farmacologia , Imunidade Inata , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Proteína Homóloga a MRE11 , Proteínas de Membrana/imunologia , Pirimidinonas/farmacologia , Rad51 Recombinase/deficiência , Rad51 Recombinase/imunologia , Reparo de DNA por Recombinação/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Tionas/farmacologia , Vorinostat , Proteína Vermelha FluorescenteRESUMO
BACKGROUND: The use of cannabis has garnered more attention recently with ongoing efforts at marijuana legalization. The consequences of cannabis use are not clearly understood and remain a concern. OBJECTIVES: To review the acute and persistent effects of cannabis use and associations with psychiatric disorders. METHODS: Using Pubmed and PsychInfo, we conducted a narrative review of the literature on cannabis and psychiatric comorbidity using the keywords cannab*, marijuana, schizo*, psychosis, mood, depression, mania, bipolar, and anxiety. RESULTS: There is substantial evidence of cannabis use leading to other illicit drug use and of an association between cannabis use and psychosis. A few reports suggest an association with bipolar disorder while the association with depression and anxiety disorders is mixed. CONCLUSIONS: Whenever an association is observed between cannabis use and psychiatric disorders, the relationship is generally an adverse one. Age at the time of cannabis use appears to be an important factor with stronger associations observed between adolescent onset cannabis use and later onset of psychiatric disorders. Additional studies taking into account potential confounds (such as withdrawal symptoms, periods of abstinence, and other substance use) and moderators (such as age of initiation of cannabis use, the amount and frequency of drug use, prior history of childhood maltreatment, and gender) are needed to better understand the psychiatric consequences of cannabis use.
Assuntos
Abuso de Maconha/complicações , Fumar Maconha/epidemiologia , Transtornos Mentais/epidemiologia , Adolescente , Fatores Etários , Idade de Início , Diagnóstico Duplo (Psiquiatria) , Humanos , Abuso de Maconha/epidemiologia , Fumar Maconha/efeitos adversos , Transtornos Mentais/fisiopatologia , Transtornos Relacionados ao Uso de Substâncias/epidemiologiaRESUMO
Regulator of G protein signaling 4 (Rgs4) is a signal transduction protein that controls the function of monoamine, opiate, muscarinic, and other G protein-coupled receptors via interactions with Gα subunits. Rgs4 is expressed in several brain regions involved in mood, movement, cognition, and addiction and is regulated by psychotropic drugs, stress, and corticosteroids. In this study, we use genetic mouse models and viral-mediated gene transfer to examine the role of Rgs4 in the actions of antidepressant medications. We first analyzed human postmortem brain tissue and found robust up-regulation of RGS4 expression in the nucleus accumbens (NAc) of subjects receiving standard antidepressant medications that target monoamine systems. Behavioral studies of mice lacking Rgs4, including specific knockdowns in NAc, demonstrate that Rgs4 in this brain region acts as a positive modulator of the antidepressant-like and antiallodynic-like actions of several monoamine-directed antidepressant drugs, including tricyclic antidepressants, selective serotonin reuptake inhibitors, and norepinephrine reuptake inhibitors. Studies using viral-mediated increases in Rgs4 activity in NAc further support this hypothesis. Interestingly, in prefrontal cortex, Rgs4 acts as a negative modulator of the actions of nonmonoamine-directed drugs that are purported to act as antidepressants: the N-methyl-D-aspartate glutamate receptor antagonist ketamine and the delta opioid agonist (+)-4-[(αR)-α-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide. Together, these data reveal a unique modulatory role of Rgs4 in the brain region-specific actions of a wide range of antidepressant drugs and indicate that pharmacological interventions at the level of RGS4 activity may enhance the actions of such drugs used for the treatment of depression and neuropathic pain.
Assuntos
Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Proteínas de Ligação ao GTP/metabolismo , Regulação da Expressão Gênica , Neuralgia/tratamento farmacológico , Proteínas RGS/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Comportamento Animal , Encéfalo/patologia , Desipramina/farmacologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Transtornos do Humor/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos , Adulto JovemRESUMO
Based on earlier gene expression and chromatin array data, we identified the protein, dishevelled (DVL)-2, as being regulated in the nucleus accumbens (NAc), a key brain reward region, in the mouse social defeat model of depression. Here, we validate these findings by showing that DVL2 mRNA and protein levels are downregulated in NAc of mice susceptible to social defeat stress, effects not seen in resilient mice. Other DVL isoforms, DVL1 and DVL3, show similar patterns of regulation. Downregulation of DVL was also demonstrated in the NAc of depressed humans examined postmortem. Interestingly, several members of the WNT (Wingless)-DVL signaling cascade, including phospho-GSK3ß (glycogen synthase kinase-3ß), also show significant downregulation in the NAc of susceptible, but not resilient, mice, demonstrating concerted regulation of this pathway in the NAc due to social defeat stress. By using viral-mediated gene transfer to overexpress a dominant-negative mutant of DVL in NAc, or by using a pharmacological inhibitor of DVL administered into this brain region, we show that blockade of DVL function renders mice more susceptible to social defeat stress and promotes depression-like behavior in other assays. Similar prodepression-like effects were induced upon overexpressing GSK3ß in the NAc, while overexpressing a dominant-negative mutant of GSK3ß promoted resilience to social defeat stress. These findings are consistent with the knowledge that downregulation of DVL and phospho-GSK3ß reflects an increase in GSK3ß activity. These studies reveal a novel role for the DVL-GSK3ß signaling pathway, acting within the brain's reward circuitry, in regulating susceptibility to chronic stress.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Depressão/metabolismo , Modelos Animais de Doenças , Quinase 3 da Glicogênio Sintase/metabolismo , Núcleo Accumbens/metabolismo , Fosfoproteínas/metabolismo , Transdução de Sinais , Proteínas Wnt/metabolismo , Animais , Depressão/etiologia , Proteínas Desgrenhadas , Dominação-Subordinação , Glicogênio Sintase Quinase 3 beta , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Psicológico/complicações , Estresse Psicológico/metabolismoRESUMO
The concentration of glycine (Gly) was measured in gray matter (GM) and white matter (WM) in the human brain using single-voxel localized (1)H MRS at 7 T. A point-resolved spectroscopy sequence with echo time = 150 ms was used for measuring Gly levels in various regions of the frontal and occipital lobes in 11 healthy volunteers and one subject with a glioblastoma. The point-resolved spectroscopy spectra were analyzed with LCModel using basis functions generated from density matrix simulations that included the effects of volume localized radio-frequency and gradient pulses. The fraction of GM and white matter within the voxels was obtained from T(1)-weighted image segmentation. The metabolite concentrations within the voxels, estimated with respect to the GM + WM water concentrations, were fitted to a linear function of fractional GM content. The Gly concentrations in pure GM and white matter were estimated to be 1.1 and 0.1 mM, with 95% confidence intervals 1.0-1.2 and 0.0-0.2, respectively.
Assuntos
Encéfalo/metabolismo , Glicina/análise , Fibras Nervosas Mielinizadas/metabolismo , Neurônios/metabolismo , Adulto , Encéfalo/anatomia & histologia , Feminino , Humanos , Masculino , Prótons , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Distribuição TecidualRESUMO
The molecular mechanisms underlying stress- and drug-induced neuronal adaptations are incompletely understood. One molecule implicated in such adaptations is ΔFosB, a transcription factor that accumulates in the rodent nucleus accumbens (NAc), a key brain reward region, in response to either chronic stress or repeated exposure to drugs of abuse. The upstream transcriptional mechanisms controlling ΔFosB induction by these environmental stimuli remain elusive. Here, we identify the activity-dependent transcription factor, serum response factor (SRF), as a novel upstream mediator of stress-, but not cocaine-, induced ΔFosB. SRF is downregulated in NAc of both depressed human patients and in mice chronically exposed to social defeat stress. This downregulation of SRF is absent in resilient animals. Through the use of inducible mutagenesis, we show that stress-mediated induction of ΔFosB, which occurs predominantly in resilient mice, is dependent on SRF expression in this brain region. Furthermore, NAc-specific genetic deletion of SRF promotes a variety of prodepressant- and proanxiety-like phenotypes and renders animals more sensitive to the deleterious effects of chronic stress. In contrast, we demonstrate that SRF does not play a role in ΔFosB accumulation in NAc in response to chronic cocaine exposure. Furthermore, NAc-specific knock-out of SRF has no effect on cocaine-induced behaviors, indicating that chronic social defeat stress and repeated cocaine exposure regulate ΔFosB accumulation and behavioral sensitivity through independent mechanisms.
Assuntos
Proteínas Proto-Oncogênicas c-fos/fisiologia , Resiliência Psicológica/efeitos dos fármacos , Fator de Resposta Sérica/fisiologia , Meio Social , Estresse Psicológico/psicologia , Adulto , Idoso , Animais , Antidepressivos/sangue , Ansiedade/metabolismo , Ansiedade/psicologia , Western Blotting , Cocaína/farmacologia , Depressão/metabolismo , Depressão/psicologia , Feminino , Desamparo Aprendido , Humanos , Imunoprecipitação , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Proteínas Proto-Oncogênicas c-fos/biossíntese , Proteínas Proto-Oncogênicas c-fos/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator de Resposta Sérica/genética , Comportamento SocialRESUMO
Brain stimulation and imaging studies in humans have highlighted a key role for the prefrontal cortex in clinical depression; however, it remains unknown whether excitation or inhibition of prefrontal cortical neuronal activity is associated with antidepressant responses. Here, we examined cellular indicators of functional activity, including the immediate early genes (IEGs) zif268 (egr1), c-fos, and arc, in the prefrontal cortex of clinically depressed humans obtained postmortem. We also examined these genes in the ventral portion of the medial prefrontal cortex (mPFC) of mice after chronic social defeat stress, a mouse model of depression. In addition, we used viral vectors to overexpress channel rhodopsin 2 (a light-activated cation channel) in mouse mPFC to optogenetically drive "burst" patterns of cortical firing in vivo and examine the behavioral consequences. Prefrontal cortical tissue derived from clinically depressed humans displayed significant reductions in IEG expression, consistent with a deficit in neuronal activity within this brain region. Mice subjected to chronic social defeat stress exhibited similar reductions in levels of IEG expression in mPFC. Interestingly, some of these changes were not observed in defeated mice that escape the deleterious consequences of the stress, i.e., resilient animals. In those mice that expressed a strong depressive-like phenotype, i.e., susceptible animals, optogenetic stimulation of mPFC exerted potent antidepressant-like effects, without affecting general locomotor activity, anxiety-like behaviors, or social memory. These results indicate that the activity of the mPFC is a key determinant of depression-like behavior, as well as antidepressant responses.
Assuntos
Transtorno Depressivo/genética , Transtorno Depressivo/terapia , Genes Precoces/fisiologia , Córtex Pré-Frontal/fisiologia , Animais , Channelrhodopsins , Transtorno Depressivo/patologia , Proteína 1 de Resposta de Crescimento Precoce/biossíntese , Regulação da Expressão Gênica , Humanos , Relações Interpessoais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Córtex Pré-Frontal/patologiaRESUMO
Persistent symptoms of depression suggest the involvement of stable molecular adaptations in brain, which may be reflected at the level of chromatin remodeling. We find that chronic social defeat stress in mice causes a transient decrease, followed by a persistent increase, in levels of acetylated histone H3 in the nucleus accumbens, an important limbic brain region. This persistent increase in H3 acetylation is associated with decreased levels of histone deacetylase 2 (HDAC2) in the nucleus accumbens. Similar effects were observed in the nucleus accumbens of depressed humans studied postmortem. These changes in H3 acetylation and HDAC2 expression mediate long-lasting positive neuronal adaptations, since infusion of HDAC inhibitors into the nucleus accumbens, which increases histone acetylation, exerts robust antidepressant-like effects in the social defeat paradigm and other behavioral assays. HDAC inhibitor [N-(2-aminophenyl)-4-[N-(pyridine-3-ylmethoxy-carbonyl)aminomethyl]benzamide (MS-275)] infusion also reverses the effects of chronic defeat stress on global patterns of gene expression in the nucleus accumbens, as determined by microarray analysis, with striking similarities to the effects of the standard antidepressant fluoxetine. Stress-regulated genes whose expression is normalized selectively by MS-275 may provide promising targets for the future development of novel antidepressant treatments. Together, these findings provide new insight into the underlying molecular mechanisms of depression and antidepressant action, and support the antidepressant potential of HDAC inhibitors and perhaps other agents that act at the level of chromatin structure.
Assuntos
Antidepressivos/farmacologia , Comportamento Animal/efeitos dos fármacos , Benzamidas/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Inibidores de Histona Desacetilases , Núcleo Accumbens/enzimologia , Piridinas/farmacologia , Proteínas Repressoras/antagonistas & inibidores , Análise de Variância , Animais , Depressão/tratamento farmacológico , Depressão/enzimologia , Depressão/patologia , Modelos Animais de Doenças , Dominação-Subordinação , Relação Dose-Resposta a Droga , Fluoxetina/farmacologia , Preferências Alimentares/efeitos dos fármacos , Perfilação da Expressão Gênica/métodos , Regulação Enzimológica da Expressão Gênica/fisiologia , Histona Desacetilase 2 , Histona Desacetilases/genética , Histona Desacetilases/metabolismo , Histonas/genética , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos , Relações Interpessoais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Biológicos , Núcleo Accumbens/efeitos dos fármacos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Mudanças Depois da Morte , RNA Mensageiro/metabolismo , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Sacarose/farmacologia , Edulcorantes/farmacologia , VorinostatRESUMO
N-Acetylaspartylglutamate in human brain has been measured with difference editing at 7 T. The CH(2) proton resonances (â¼ 2.5 ppm) of the aspartyl groups of N-acetylaspartylglutamate and N-acetylaspartate were difference edited (MEGA) using 20-msec gaussian radiofrequency pulses for selective 180 ° rotations of the coupling partners at 4.61 and 4.38 ppm, respectively. The echo time of the editing sequence, 108 msec, was obtained in phantom tests. Single-voxel localized in vivo measurements were conducted in the medial prefrontal and right frontal cortices of five healthy volunteers. The gray and white matter fractions within the voxels were obtained from T(1)-weighted image segmentation. Using linear regression of the metabolite concentration vs. fractional white matter contents within the voxels, the N-acetylaspartylglutamate-to-N-acetylaspartate concentration ratios in gray and white matter were estimated to be 0.13 and 0.28 by difference editing (95% confidence intervals 0.07-0.19 and 0.22-0.34), respectively, assuming identical relaxation effects between the metabolites.
Assuntos
Algoritmos , Dipeptídeos/análise , Lobo Frontal/química , Espectroscopia de Ressonância Magnética/métodos , Adulto , Feminino , Humanos , Masculino , PrótonsRESUMO
Previous research has shown that cAMP response element (CRE) binding protein (CREB) in the nucleus accumbens gates behavioral responses to emotional stimuli. For example, overexpression of CREB decreases anxiety, sucrose preference, and sensitivity to drugs of abuse and increases depression-like behavior, whereas blocking CREB via overexpression of inducible cAMP early repressor (ICER) or other dominant-negative inhibitors of CRE-mediated transcription has the opposite effects. However, CREB and ICER are but two members of a larger family of leucine zipper-containing transcription factors composed of multiple products of the creb, crem (cAMP response element modulator), and atf (activating transcription factor) genes. We demonstrate here that ATF2, ATF3, and ATF4 are each robustly induced in the nucleus accumbens and dorsal striatum by restraint stress or by amphetamine administration. In contrast, little induction is seen for ATF1 or CREM. Using viral-mediated gene transfer, we show that ATF2 overexpression in nucleus accumbens produces increases in emotional reactivity and antidepressant-like responses, a behavioral phenotype similar to that caused by dominant-negative antagonists of CREB. In contrast, ATF3 or ATF4 overexpression in nucleus accumbens decreases emotional reactivity and increases depression-like behavior, consistent with the behavioral phenotype induced by CREB. Because amphetamine and stress induce ATF2, ATF3, and ATF4 in nucleus accumbens, and overexpression of these transcription factors in this brain region in turn alters behavioral responsiveness to amphetamine and stress, our findings support novel roles for these ATF family members in regulating emotional behavior.
Assuntos
Fator 2 Ativador da Transcrição/metabolismo , Fator 3 Ativador da Transcrição/metabolismo , Fator 4 Ativador da Transcrição/metabolismo , Regulação da Expressão Gênica/fisiologia , Núcleo Accumbens/metabolismo , Estresse Psicológico/patologia , Fator 2 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/genética , Fator 4 Ativador da Transcrição/genética , Anfetamina/farmacologia , Animais , Comportamento Animal , Estimulantes do Sistema Nervoso Central/farmacologia , Preferências Alimentares/efeitos dos fármacos , Preferências Alimentares/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Técnicas de Transferência de Genes , Vetores Genéticos/fisiologia , Proteínas de Fluorescência Verde/biossíntese , Masculino , Aprendizagem em Labirinto/fisiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Núcleo Accumbens/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Estresse Psicológico/metabolismo , Natação , Fatores de TempoRESUMO
A single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) filtering strategy for in vivo detection of serine (Ser) in human brain at 7T is proposed. Spectral difference of coupled resonances arising from different subecho times of triple refocusing at a constant total echo time (TE) was utilized to detect the Ser multiplet and cancel the overlapping creatine (Cr) 3.92-ppm singlet via difference editing. Dependence of the Ser signal on subecho times was investigated using density-matrix simulation incorporating the slice-selective radio frequency (RF) pulses. The simulation indicated that the difference-edited Ser CH(2) multiplet at approximately 3.96 ppm is maximized with (TE(1), TE(2), TE(3)) = (54, 78, 78) and (36, 152, 22) ms. The edited Ser peak amplitude was estimated, with both numerical and phantom analyses of the performance, as 83% with respect to 90 degrees acquisition for a localized volume, ignoring relaxation effects. From the area ratio of the edited Ser and unedited Cr 3.03-ppm peaks, assuming identical T(1) and T(2) between Ser and Cr, the Ser-to-Cr concentration ratio for the frontal cortex of healthy adults was estimated to be 0.8 +/- 0.2 (mean +/- SD; N = 6).
Assuntos
Algoritmos , Química Encefálica , Espectroscopia de Ressonância Magnética/métodos , Serina/análise , Adulto , Feminino , Humanos , Masculino , Prótons , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
Group II metabotropic glutamate receptors (mGluR2 and mGluR3) are implicated in schizophrenia. We characterized mGluR2 and 3 mRNA in the human prefrontal cortex (PFC) and mesencephalon, and then compared cases with schizophrenia to matched controls. In the human brain, both receptors were expressed in the PFC and, unlike the rodent, in dopaminergic (DA) cell groups. In schizophrenia, we found significantly higher levels of mGluR2 mRNA in the PFC white matter. The expression of mGluR2, 3 in DA cells provide a mechanism for glutamate to modulate dopamine release in the human brain and this species-specific difference may be critical to understanding rodent models in schizophrenia.
Assuntos
Dopamina/metabolismo , Ácido Glutâmico/metabolismo , Mesencéfalo/metabolismo , Córtex Pré-Frontal/metabolismo , Receptores de Glutamato Metabotrópico/genética , Esquizofrenia/genética , Esquizofrenia/metabolismo , Adolescente , Adulto , Idoso , Corpo Estriado/metabolismo , Corpo Estriado/fisiopatologia , Feminino , Regulação da Expressão Gênica/genética , Humanos , Masculino , Mesencéfalo/fisiopatologia , Pessoa de Meia-Idade , Vias Neurais/metabolismo , Vias Neurais/fisiopatologia , Córtex Pré-Frontal/fisiopatologia , RNA Mensageiro/metabolismo , Esquizofrenia/fisiopatologia , Substância Negra/metabolismo , Substância Negra/fisiopatologia , Área Tegmentar Ventral/metabolismo , Área Tegmentar Ventral/fisiopatologia , Adulto JovemRESUMO
INTRODUCTION: Hospital emergency departments (EDs) around the country are being challenged by an ever-increasing volume of patients seeking psychiatric services. This manuscript describes a study performed to identify internal and external factors contributing to repeated psychiatric patient admissions to the hospital main ED. METHODS: Data from ED visits of patients who were admitted to the Parkland Memorial Hospital ED (the community hospital for Dallas County, TX, USA) with a psychiatric complaint more than once within a 30-day period were evaluated (n=202). A 50-item readmission survey was used to collect information on demographic and clinical factors associated with 30-day readmission, as well as to identify quality improvement opportunities by assessing related moderating factors. An analysis of acute readmission visits (occurring within 3 days of previous discharge) was also performed. RESULTS: Patients readmitted to the ED commonly present with a combination of acute psychiatric symptoms, substance use (especially in the case of acute readmission), and violent or suicidal behavior. The vast majority of cases reviewed found that readmitted patients had difficulties coordinating care outside the ED. A number of moderating factors were identified and targeted for quality improvement including additional support for filling prescriptions, transportation, communication with family and outside providers, drug and alcohol treatment, intensive case management, and housing. CONCLUSION: Many of the resources necessary to reduce psychiatric patient visits to hospital EDs are available within the community. There is no formal method of integrating and insuring the continuity of community services that may reduce the demand for psychiatric and related services in the ED. While agreements between community service providers may be challenging and require considerable vigilance to maintain equitable agreements between parties, this route of improving efficiency may be the only available method, given the current and projected patient care needs.
RESUMO
Associations between cannabis use and psychotic disorders suggest that cannabis may be a contributory risk factor in the neurobiology of psychosis. In this study, we examined brain structure characteristics, total and regional gray matter density (GMD), using Voxel Based Morphometry, in psychotic individuals, stratified by history of cannabis use (total nâ¯=â¯109). We also contrasted GMD estimates in individual diagnostic groups (schizophrenia/bipolar I disorder) with and without history of adolescent cannabis use (ACU). Individuals with psychosis as a whole, both with and without history of ACU, had lower total and regional GMD, compared to healthy controls. ACU was associated with attenuated GMD reductions, compared to non-users, especially in the schizophrenia cases, who showed robust GMD reductions in fronto-temporal and parietal cortex, as well as subcortical regions. Notably, total and regional GMD estimates in individuals with psychosis and ACU were not different from controls with no ACU. These data indicate that the history of ACU in psychotic individuals is associated with attenuated GMD abnormalities. Future investigations targeting potential unique etiological and risk factors associated with psychosis in individuals with ACU may help in understanding of the neurobiology of psychotic disorders and novel treatment options for these individuals.
Assuntos
Transtorno Bipolar/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Substância Cinzenta/diagnóstico por imagem , Uso da Maconha/epidemiologia , Transtornos Psicóticos/diagnóstico por imagem , Esquizofrenia/diagnóstico por imagem , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Adulto JovemRESUMO
UNLABELLED: The present study estimated radiation-absorbed doses of the dopamine D(1) receptor radioligand [(11)C]((+)-8-chloro-5-(7-benzofuranyl)-7-hydroxy-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine) (NNC 112) in humans, based on dynamic whole-body PET in healthy subjects. METHODS: Whole-body PET was performed on 7 subjects after injection of 710 +/- 85 MBq of (11)C-NNC 112. Fourteen frames were acquired for a total of 120 min in 7 segments of the body. Regions of interest were drawn on compressed planar images of source organs that could be identified. Radiation dose estimates were calculated from organ residence times using the OLINDA 1.0 program. RESULTS: The organs with the highest radiation-absorbed doses were the gallbladder, liver, lungs, kidneys, and urinary bladder wall. Biexponential fitting of mean bladder activity demonstrated that 15% of activity was excreted via the urine. With a 2.4-h voiding interval, the effective dose was 5.7 microSv/MBq (21.1 mrem/mCi). CONCLUSION: (11)C-NNC 112 displays a favorable radiation dose profile in humans and would allow multiple PET examinations per year to be performed on the same subject.
Assuntos
Benzazepinas/farmacocinética , Benzofuranos/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Receptores de Dopamina D1/metabolismo , Imagem Corporal Total/métodos , Contagem Corporal Total/métodos , Adulto , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Especificidade de Órgãos , Doses de Radiação , Ensaio Radioligante , Compostos Radiofarmacêuticos/farmacocinética , Distribuição TecidualRESUMO
Postmortem human brain tissue is used for the study of many different brain diseases. A key factor in conducting postmortem research is the quality of the tissue. Unlike animal tissue, whose condition at death can be controlled and influenced, human tissue can only be collected naturalistically. This introduces potential confounds, based both on pre- and postmortem conditions, that may influence the quality of tissue and its ability to yield accurate results. The traditionally recognized confounds that reduce tissue quality are agonal factors (e.g., coma, hypoxia, hyperpyrexia at the time of death), and long postmortem interval (PMI). We measured tissue quality parameters in over 100 postmortem cases collected from different sources and correlated them with RNA quality (as indicated by the RNA Integrity Number (RIN)) and with protein quality (as measured by the level of representative proteins). Our results show that the most sensible indicator of tissue quality is RIN and that there is a good correlation between RIN and the pH. No correlation developed between protein levels and the aforementioned factors. Moreover, even when RNA was degraded, the protein levels remained stable. However, these correlations did not prove true under all circumstances (e.g., thawed tissue, surgical tissue), that yielded unexpected quality indicators. These data also suggest that cases whose source was a Medical Examiner's office represent high tissue quality.
Assuntos
Encéfalo/metabolismo , Neurônios/metabolismo , Mudanças Depois da Morte , RNA/metabolismo , Manejo de Espécimes/normas , Adulto , Idoso , Análise de Variância , Autopsia/normas , Biomarcadores/metabolismo , Encéfalo/citologia , Química Encefálica , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/metabolismo , Neuroglia/metabolismo , Controle de Qualidade , RNA/análise , Estabilidade de RNA , Fatores de TempoRESUMO
Prior cannabis use, compared to nonuse, is reported to be associated with less cognitive impairment in schizophrenia. The age of cannabis use and the persistent influence of cannabis use on cognitive function has not been examined across the psychosis dimension. Ninety-seven volunteers with psychosis (schizophrenia, schizoaffective, or bipolar psychosis) and 64 controls were recruited at the Dallas site of the Bipolar-Schizophrenia Network on Intermediate Phenotypes consortium. Cannabis use history obtained in a semi-structured manner was used to categorize subjects into nonusers, adolescent-onset users, and late-onset users. The a priori hypothesis tested was that individuals with psychosis and a history of adolescent cannabis use (ACU) would have better global neuropsychological performance, as measured by the Brief Assessment of Cognition in Schizophrenia (BACS) battery, compared to those with psychosis and no cannabis use history. BACS Composite scores were significantly higher in individuals with psychosis with ACU compared to individuals with psychosis and no prior cannabis use. In subgroup analyses, ACU influenced global cognition in the schizophrenia/schizoaffective (SCZ) subgroup but not the bipolar psychosis subgroup. Exploratory analyses within the SCZ group, suggest that ACU was associated with better performance in specific domains compared to non-ACU groups. There are distinct associations between age of cannabis use and neuropsychological function across psychotic illnesses. Specifically, ACU is associated with better cognitive function in SCZ but not bipolar psychosis. This age-dependent and diagnosis-specific influence of cannabis may need to be factored into the design of future cognitive studies in SCZ.
Assuntos
Transtornos Psicóticos Afetivos/complicações , Cannabis , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/prevenção & controle , Fármacos Neuroprotetores/farmacologia , Transtornos Psicóticos/complicações , Esquizofrenia/complicações , Adolescente , Comportamento do Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
The single nucleotide val158met polymorphism in catechol o-methyltransferase (COMT) influences prefrontal cortex function. Working memory, dependent on the dorsolateral prefrontal cortex (DLPFC), has been repeatedly shown to be influenced by this COMT polymorphism. The high activity COMT val isoform is associated with lower synaptic dopamine levels. Altered synaptic dopamine levels are expected to lead to molecular adaptations within the synapse and within DLPFC neural circuitry. In this human post mortem study using high quality DLPFC tissue, we first examined the influence of the COMT val158met polymorphism on markers of dopamine neurotransmission, N-methyl-d-aspartate (NMDA) receptor subunits and glutamatic acid decarboxylase 67 (GAD67), all known to be critical to DLPFC circuitry and function. Next, we compared target gene expression profiles in a cohort of control and schizophrenia cases, each characterized by COMT genotype. We find that the COMT val allele in control subjects is associated with significant upregulation of GluN2A and GAD67 mRNA levels compared to met carriers. Comparisons between control and schizophrenia groups reveal that GluN2A, GAD67 and DRD2 are differentially regulated between diagnostic groups in a genotype specific manner. Chronic antipsychotic treatment in rodents did not explain these differences. These data demonstrate an association between COMTval158met genotype and gene expression profile in the DLPFC of controls, possibly adaptations to maintain DLPFC function. In schizophrenia val homozygotes, these adaptations are not seen and could reflect pathophysiologic mechanisms related to the known poorer performance of these subjects on DLPFC-dependent tasks.