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1.
Proc Natl Acad Sci U S A ; 113(34): 9623-8, 2016 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-27506785

RESUMO

Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanisms-such as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.


Assuntos
Proteínas de Transporte/genética , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Cocaína/administração & dosagem , Histonas/metabolismo , Núcleo Accumbens/metabolismo , Processamento de Proteína Pós-Traducional , Acetilação , Animais , Proteínas de Transporte/metabolismo , Transtornos Relacionados ao Uso de Cocaína/genética , Transtornos Relacionados ao Uso de Cocaína/patologia , Histonas/genética , Humanos , Masculino , Metilação , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismo , Neurônios/patologia , Núcleo Accumbens/patologia , Proteína-Arginina N-Metiltransferases/genética , Proteína-Arginina N-Metiltransferases/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D1/genética , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo
2.
J Neurosci ; 36(14): 3954-61, 2016 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-27053203

RESUMO

ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins. SIGNIFICANCE STATEMENT: We show that BAZ1B, a component of chromatin remodeling complexes, in the nucleus accumbens regulates reward-related behaviors in response to chronic exposure to both rewarding and aversive stimuli by regulating largely distinct subsets of genes.


Assuntos
Comportamento Animal/fisiologia , Emoções/fisiologia , Núcleo Accumbens/fisiologia , Recompensa , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia , Adenosina Trifosfatases/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Cromatina/genética , Proteínas Cromossômicas não Histona/metabolismo , Cocaína/farmacologia , Epigênese Genética/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos , Ratos Sprague-Dawley , Autoadministração , Meio Social , Estresse Psicológico
3.
Nature ; 472(7344): 466-70, 2011 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-21460835

RESUMO

Adult hippocampal neurogenesis is a unique form of neural circuit plasticity that results in the generation of new neurons in the dentate gyrus throughout life. Neurons that arise in adults (adult-born neurons) show heightened synaptic plasticity during their maturation and can account for up to ten per cent of the entire granule cell population. Moreover, levels of adult hippocampal neurogenesis are increased by interventions that are associated with beneficial effects on cognition and mood, such as learning, environmental enrichment, exercise and chronic treatment with antidepressants. Together, these properties of adult neurogenesis indicate that this process could be harnessed to improve hippocampal functions. However, despite a substantial number of studies demonstrating that adult-born neurons are necessary for mediating specific cognitive functions, as well as some of the behavioural effects of antidepressants, it is unknown whether an increase in adult hippocampal neurogenesis is sufficient to improve cognition and mood. Here we show that inducible genetic expansion of the population of adult-born neurons through enhancing their survival improves performance in a specific cognitive task in which two similar contexts need to be distinguished. Mice with increased adult hippocampal neurogenesis show normal object recognition, spatial learning, contextual fear conditioning and extinction learning but are more efficient in differentiating between overlapping contextual representations, which is indicative of enhanced pattern separation. Furthermore, stimulation of adult hippocampal neurogenesis, when combined with an intervention such as voluntary exercise, produces a robust increase in exploratory behaviour. However, increasing adult hippocampal neurogenesis alone does not produce a behavioural response like that induced by anxiolytic agents or antidepressants. Together, our findings suggest that strategies that are designed to increase adult hippocampal neurogenesis specifically, by targeting the cell death of adult-born neurons or by other mechanisms, may have therapeutic potential for reversing impairments in pattern separation and dentate gyrus dysfunction such as those seen during normal ageing.


Assuntos
Afeto/fisiologia , Envelhecimento/fisiologia , Cognição/fisiologia , Hipocampo/citologia , Hipocampo/fisiologia , Modelos Neurológicos , Neurogênese/fisiologia , Envelhecimento/efeitos dos fármacos , Envelhecimento/patologia , Animais , Antidepressivos/farmacologia , Ansiedade/fisiopatologia , Ansiedade/terapia , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cognição/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Clássico/fisiologia , Giro Denteado/citologia , Giro Denteado/patologia , Giro Denteado/fisiologia , Giro Denteado/fisiopatologia , Comportamento Exploratório/efeitos dos fármacos , Comportamento Exploratório/fisiologia , Extinção Psicológica/efeitos dos fármacos , Extinção Psicológica/fisiologia , Medo/fisiologia , Medo/psicologia , Feminino , Hipocampo/patologia , Hipocampo/fisiopatologia , Aprendizagem/efeitos dos fármacos , Aprendizagem/fisiologia , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Células-Tronco Neurais/citologia , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Condicionamento Físico Animal/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Proteína X Associada a bcl-2/deficiência , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismo
4.
Proc Natl Acad Sci U S A ; 111(5): 2005-10, 2014 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-24449909

RESUMO

Many of the long-term effects of cocaine on the brain's reward circuitry have been shown to be mediated by alterations in gene expression. Several chromatin modifications, including histone acetylation and methylation, have been implicated in this regulation, but the effect of other histone modifications remains poorly understood. Poly(ADP-ribose) polymerase-1 (PARP-1), a ubiquitous and abundant nuclear protein, catalyzes the synthesis of a negatively charged polymer called poly(ADP-ribose) or PAR on histones and other substrate proteins and forms transcriptional regulatory complexes with several other chromatin proteins. Here, we identify an essential role for PARP-1 in cocaine-induced molecular, neural, and behavioral plasticity. Repeated cocaine administration, including self-administration, increased global levels of PARP-1 and its mark PAR in mouse nucleus accumbens (NAc), a key brain reward region. Using PARP-1 inhibitors and viral-mediated gene transfer, we established that PARP-1 induction in NAc mediates enhanced behavioral responses to cocaine, including increased self-administration of the drug. Using chromatin immunoprecipitation sequencing, we demonstrated a global, genome-wide enrichment of PARP-1 in NAc of cocaine-exposed mice and identified several PARP-1 target genes that could contribute to the lasting effects of cocaine. Specifically, we identified sidekick-1--important for synaptic connections during development--as a critical PARP-1 target gene involved in cocaine's behavioral effects as well as in its ability to induce dendritic spines on NAc neurons. These findings establish the involvement of PARP-1 and PARylation in the long-term actions of cocaine.


Assuntos
Cocaína/farmacologia , Poli Adenosina Difosfato Ribose/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Imunoprecipitação da Cromatina , Cocaína/administração & dosagem , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Genoma/genética , Imunoglobulina G/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/enzimologia , Poli(ADP-Ribose) Polimerases/genética , Poli(ADP-Ribose) Polimerases/metabolismo , Ligação Proteica/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Especificidade por Substrato/efeitos dos fármacos , Transcrição Gênica/efeitos dos fármacos
5.
J Neurosci ; 32(22): 7577-84, 2012 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-22649236

RESUMO

The molecular mechanism underlying induction by cocaine of ΔFosB, a transcription factor important for addiction, remains unknown. Here, we demonstrate a necessary role for two transcription factors, cAMP response element binding protein (CREB) and serum response factor (SRF), in mediating this induction within the mouse nucleus accumbens (NAc), a key brain reward region. CREB and SRF are both activated in NAc by cocaine and bind to the fosB gene promoter. Using viral-mediated Cre recombinase expression in the NAc of single- or double-floxed mice, we show that deletion of both transcription factors from this brain region completely blocks cocaine induction of ΔFosB in NAc, whereas deletion of either factor alone has no effect. Furthermore, deletion of both SRF and CREB from NAc renders animals less sensitive to the rewarding effects of moderate doses of cocaine when tested in the conditioned place preference (CPP) procedure and also blocks locomotor sensitization to higher doses of cocaine. Deletion of CREB alone has the opposite effect and enhances both cocaine CPP and locomotor sensitization. In contrast to ΔFosB induction by cocaine, ΔFosB induction in NAc by chronic social stress, which we have shown previously requires activation of SRF, is unaffected by the deletion of CREB alone. These surprising findings demonstrate the involvement of distinct transcriptional mechanisms in mediating ΔFosB induction within this same brain region by cocaine versus stress. Our results also establish a complex mode of regulation of ΔFosB induction in response to cocaine, which requires the concerted activities of both SRF and CREB.


Assuntos
Proteína de Ligação a CREB/metabolismo , Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Fator de Resposta Sérica/metabolismo , Análise de Variância , Animais , Proteína de Ligação a CREB/deficiência , Imunoprecipitação da Cromatina , Condicionamento Operante/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Núcleo Accumbens/metabolismo , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Proteínas Proto-Oncogênicas c-fos/genética , RNA Mensageiro/metabolismo , Fator de Resposta Sérica/deficiência , Estresse Psicológico/genética , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Transdução Genética
6.
J Neurosci ; 32(48): 17454-64, 2012 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-23197736

RESUMO

Dysregulation of histone modifying enzymes has been associated with numerous psychiatric disorders. Alterations in G9a (Ehmt2), a histone methyltransferase that catalyzes the euchromatic dimethylation of histone H3 at lysine 9 (H3K9me2), has been implicated recently in mediating neural and behavioral plasticity in response to chronic cocaine administration. Here, we show that chronic morphine, like cocaine, decreases G9a expression, and global levels of H3K9me2, in mouse nucleus accumbens (NAc), a key brain reward region. In contrast, levels of other histone methyltransferases or demethylases, or of other methylated histone marks, were not affected in NAc by chronic morphine. Through viral-mediated gene transfer and conditional mutagenesis, we found that overexpression of G9a in NAc opposes morphine reward and locomotor sensitization and concomitantly promotes analgesic tolerance and naloxone-precipitated withdrawal, whereas downregulation of G9a in NAc enhances locomotor sensitization and delays the development of analgesic tolerance. We identified downstream targets of G9a by providing a comprehensive chromatin immunoprecipitation followed by massively parallel sequencing analysis of H3K9me2 distribution in NAc in the absence and presence of chronic morphine. These data provide novel insight into the epigenomic regulation of H3K9me2 by chronic morphine and suggest novel chromatin-based mechanisms through which morphine-induced addictive-like behaviors arise.


Assuntos
Comportamento Animal/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Histonas/genética , Morfina/farmacologia , Entorpecentes/farmacologia , Núcleo Accumbens/efeitos dos fármacos , Animais , Metilação de DNA/efeitos dos fármacos , Técnicas de Transferência de Genes , Histonas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Morfina/efeitos adversos , Atividade Motora/efeitos dos fármacos , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Entorpecentes/efeitos adversos , Núcleo Accumbens/metabolismo , Síndrome de Abstinência a Substâncias/metabolismo
7.
J Neurosci ; 32(30): 10267-72, 2012 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-22836260

RESUMO

ΔFosB, a Fosb gene product, is induced in nucleus accumbens (NAc) and caudate-putamen (CPu) by repeated exposure to drugs of abuse such as cocaine. This induction contributes to aberrant patterns of gene expression and behavioral abnormalities seen with repeated drug exposure. Here, we assessed whether a remote history of cocaine exposure in rats might alter inducibility of the Fosb gene elicited by subsequent drug exposure. We show that prior chronic cocaine administration, followed by extended withdrawal, increases inducibility of Fosb in NAc, as evidenced by greater acute induction of ΔFosB mRNA and faster accumulation of ΔFosB protein after repeated cocaine reexposure. No such primed Fosb induction was observed in CPu; in fact, subsequent acute induction of ΔFosB mRNA was suppressed in CPu. These abnormal patterns of Fosb expression are associated with chromatin modifications at the Fosb gene promoter. Prior chronic cocaine administration induces a long-lasting increase in RNA polymerase II (Pol II) binding at the Fosb promoter in NAc only, suggesting that Pol II "stalling" primes Fosb for induction in this region upon reexposure to cocaine. A cocaine challenge then triggers the release of Pol II from the gene promoter, allowing for more rapid Fosb transcription. A cocaine challenge also decreases repressive histone modifications at the Fosb promoter in NAc, but increases such repressive marks and decreases activating marks in CPu. These results provide new insight into the chromatin dynamics at the Fosb promoter and reveal a novel mechanism for primed Fosb induction in NAc upon reexposure to cocaine.


Assuntos
Cocaína/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Epigênese Genética/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/genética , Animais , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Expressão Gênica/efeitos dos fármacos , Masculino , Atividade Motora/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Regiões Promotoras Genéticas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Ratos , Ratos Sprague-Dawley
8.
J Neurosci ; 29(31): 9875-87, 2009 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-19657039

RESUMO

The dentate gyrus (DG) is modified throughout life by integration of new adult-born neurons. Similarities in neuronal maturation during DG development and adult hippocampal neurogenesis suggest that genetically encoded intrinsic regulatory mechanisms underlying these temporally distinct processes are conserved and reused. Here, we identify a novel transcriptional regulator of dentate granule neuron maturation, Krüppel-like factor 9 (Klf-9). We show that Klf-9 expression is induced by neuronal activity and as dentate granule neurons functionally integrate in the developing and adult DG. During development, dentate granule neurons lacking Klf-9 show delayed maturation as reflected by altered expression of early-phase markers, dendritic spine formation, and electrophysiological properties. Adult Klf-9-null mice exhibit normal stem cell proliferation and cell fate specification in the DG but show impaired differentiation of adult-born neurons and decreased neurogenesis-dependent synaptic plasticity. Behavioral analysis of Klf-9-null mice revealed a subtle increase in anxiety-like behavior and an impairment in contextual fear discrimination learning. Thus, Klf-9 is necessary for late-phase maturation of dentate granule neurons both in DG development and during adult hippocampal neurogenesis. Klf-9-dependent neuronal maturation may therefore represent a candidate regulatory mechanism underlying these temporally distinct processes.


Assuntos
Giro Denteado/crescimento & desenvolvimento , Hipocampo/fisiologia , Fatores de Transcrição Kruppel-Like/metabolismo , Neurogênese/fisiologia , Neurônios/fisiologia , Células-Tronco Adultas/fisiologia , Animais , Animais Recém-Nascidos , Ansiedade/genética , Ansiedade/metabolismo , Espinhas Dendríticas/fisiologia , Giro Denteado/citologia , Giro Denteado/fisiologia , Medo , Hipocampo/citologia , Fatores de Transcrição Kruppel-Like/genética , Aprendizagem/fisiologia , Deficiências da Aprendizagem/genética , Deficiências da Aprendizagem/metabolismo , Camundongos , Camundongos Knockout , Plasticidade Neuronal/fisiologia , Neurônios/citologia , Sinapses/fisiologia
9.
Cell Rep ; 23(11): 3183-3196, 2018 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-29898391

RESUMO

Stress exposure is associated with the pathogenesis of psychiatric disorders, including post-traumatic stress disorder (PTSD) and major depressive disorder (MDD). Here, we show in rodents that chronic stress exposure rapidly and transiently elevates hippocampal expression of Kruppel-like factor 9 (Klf9). Inducible genetic silencing of Klf9 expression in excitatory forebrain neurons in adulthood prior to, but not after, onset of stressor prevented chronic restraint stress (CRS)-induced potentiation of contextual fear acquisition in female mice and chronic corticosterone (CORT) exposure-induced fear generalization in male mice. Klf9 silencing prevented chronic CORT and CRS induced enlargement of dendritic spines in the ventral hippocampus of male and female mice, respectively. KLF9 mRNA density was increased in the anterior dentate gyrus of women, but not men, with more severe recent stressful life events and increased mortality. Thus, Klf9 functions as a stress-responsive transcription factor that mediates circuit and behavioral resilience in a sex-specific manner.


Assuntos
Espinhas Dendríticas/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Neurônios/metabolismo , Estresse Psicológico , Animais , Corticosterona/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/patologia , Giro Denteado/metabolismo , Feminino , Inativação Gênica , Hipocampo/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/patologia , Fatores Sexuais
10.
Neuroscience ; 353: 1-6, 2017 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-28412501

RESUMO

Chromatin regulation, in particular ATP-dependent chromatin remodelers, have previously been shown to be important in the regulation of reward-related behaviors in animal models of mental illnesses. Here we demonstrate that BAZ1A, an accessory subunit of the ISWI family of chromatin remodeling complexes, is downregulated in the nucleus accumbens (NAc) of mice exposed repeatedly to cocaine and of cocaine-addicted humans. Viral-mediated overexpression of BAZ1A in mouse NAc reduces cocaine reward as assessed by conditioned place preference (CPP), but increases cocaine-induced locomotor activation. Furthermore, we investigate nucleosome repositioning genome-wide by conducting chromatin immunoprecipitation (ChIP)-sequencing for total H3 in NAc of control mice and after repeated cocaine administration, and find extensive nucleosome occupancy and shift changes across the genome in response to cocaine exposure. These findings implicate BAZ1A in molecular and behavioral plasticity to cocaine and offer new insight into the pathophysiology of cocaine addiction.


Assuntos
Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Proteínas Cromossômicas não Histona/genética , Cocaína/administração & dosagem , Núcleo Accumbens/metabolismo , Fatores de Transcrição/genética , Animais , Transtornos Relacionados ao Uso de Cocaína/genética , Condicionamento Clássico/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Atividade Motora/efeitos dos fármacos , Nucleossomos/efeitos dos fármacos , Nucleossomos/metabolismo , RNA Mensageiro/metabolismo
11.
Neuron ; 91(6): 1356-1373, 2016 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-27593178

RESUMO

The neural circuit mechanisms underlying the integration and functions of adult-born dentate granule cell (DGCs) are poorly understood. Adult-born DGCs are thought to compete with mature DGCs for inputs to integrate. Transient genetic overexpression of a negative regulator of dendritic spines, Kruppel-like factor 9 (Klf9), in mature DGCs enhanced integration of adult-born DGCs and increased NSC activation. Reversal of Klf9 overexpression in mature DGCs restored spines and activity and reset neuronal competition dynamics and NSC activation, leaving the DG modified by a functionally integrated, expanded cohort of age-matched adult-born DGCs. Spine elimination by inducible deletion of Rac1 in mature DGCs increased survival of adult-born DGCs without affecting proliferation or DGC activity. Enhanced integration of adult-born DGCs transiently reorganized adult-born DGC local afferent connectivity and promoted global remapping in the DG. Rejuvenation of the DG by enhancing integration of adult-born DGCs in adulthood, middle age, and aging enhanced memory precision.


Assuntos
Envelhecimento/fisiologia , Giro Denteado/fisiologia , Memória/fisiologia , Células-Tronco Adultas/citologia , Animais , Proliferação de Células/genética , Sobrevivência Celular/genética , Espinhas Dendríticas/fisiologia , Giro Denteado/metabolismo , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Fatores de Transcrição Kruppel-Like/fisiologia , Camundongos , Mutação , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Neuropeptídeos/genética , Regulação para Cima , Proteínas rac1 de Ligação ao GTP/genética
12.
Neuron ; 90(5): 969-83, 2016 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-27181059

RESUMO

Depression is a complex, heterogeneous disorder and a leading contributor to the global burden of disease. Most previous research has focused on individual brain regions and genes contributing to depression. However, emerging evidence in humans and animal models suggests that dysregulated circuit function and gene expression across multiple brain regions drive depressive phenotypes. Here, we performed RNA sequencing on four brain regions from control animals and those susceptible or resilient to chronic social defeat stress at multiple time points. We employed an integrative network biology approach to identify transcriptional networks and key driver genes that regulate susceptibility to depressive-like symptoms. Further, we validated in vivo several key drivers and their associated transcriptional networks that regulate depression susceptibility and confirmed their functional significance at the levels of gene transcription, synaptic regulation, and behavior. Our study reveals novel transcriptional networks that control stress susceptibility and offers fundamentally new leads for antidepressant drug discovery.


Assuntos
Encéfalo/metabolismo , Depressão/genética , Redes Reguladoras de Genes , Predisposição Genética para Doença/genética , Vias Neurais/metabolismo , Transcriptoma , Animais , Depressão/metabolismo , Potenciais Pós-Sinápticos Excitadores/fisiologia , Hipocampo/fisiologia , Camundongos , Comportamento Social
13.
CNS Neurol Disord Drug Targets ; 14(6): 727-30, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26022260

RESUMO

As of 2008, according to the National Survey on Drug Use and Health, nearly 1.4 million Americans met the Diagnostic and Statistical Manual of Mental Disorders criteria for dependence or abuse of cocaine (in any form) in the past 12 months. However, there are no treatments for cocaine use disorders approved by the Federal Drug Administration (FDA). Alterations in gene regulation contribute significantly to the changes that occur in the brain, both structurally and functionally, and the resultant addictive phenotype that occurs with chronic exposure to drugs of abuse. The Emerging Targets of Cocaine Use Disorders meeting sought to explore novel targets for the treatment of stimulant use disorder. The evidence for a role of one novel target, Poly(ADP)-ribose polymerase-1 (PARP-1), was presented at the meeting and will be summarized in this review.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Poli(ADP-Ribose) Polimerases/metabolismo , Animais , Transtornos Relacionados ao Uso de Cocaína/enzimologia , Epigenômica , Humanos
14.
Nat Med ; 21(10): 1146-53, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26390241

RESUMO

Improved treatment for major depressive disorder (MDD) remains elusive because of the limited understanding of its underlying biological mechanisms. It is likely that stress-induced maladaptive transcriptional regulation in limbic neural circuits contributes to the development of MDD, possibly through epigenetic factors that regulate chromatin structure. We establish that persistent upregulation of the ACF (ATP-utilizing chromatin assembly and remodeling factor) ATP-dependent chromatin-remodeling complex, occurring in the nucleus accumbens of stress-susceptible mice and depressed humans, is necessary for stress-induced depressive-like behaviors. We found that altered ACF binding after chronic stress was correlated with altered nucleosome positioning, particularly around the transcription start sites of affected genes. These alterations in ACF binding and nucleosome positioning were associated with repressed expression of genes implicated in susceptibility to stress. Together, our findings identify the ACF chromatin-remodeling complex as a critical component in the development of susceptibility to depression and in regulating stress-related behaviors.


Assuntos
Montagem e Desmontagem da Cromatina , Depressão/metabolismo , Estresse Psicológico , Animais , Proteínas Cromossômicas não Histona , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fatores de Transcrição/genética , Fatores de Transcrição/fisiologia
15.
Nat Neurosci ; 18(3): 415-22, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25643298

RESUMO

Brain-derived neurotrophic factor (BDNF) has a crucial role in modulating neural and behavioral plasticity to drugs of abuse. We found a persistent downregulation of exon-specific Bdnf expression in the ventral tegmental area (VTA) in response to chronic opiate exposure, which was mediated by specific epigenetic modifications at the corresponding Bdnf gene promoters. Exposure to chronic morphine increased stalling of RNA polymerase II at these Bdnf promoters in VTA and altered permissive and repressive histone modifications and occupancy of their regulatory proteins at the specific promoters. Furthermore, we found that morphine suppressed binding of phospho-CREB (cAMP response element binding protein) to Bdnf promoters in VTA, which resulted from enrichment of trimethylated H3K27 at the promoters, and that decreased NURR1 (nuclear receptor related-1) expression also contributed to Bdnf repression and associated behavioral plasticity to morphine. Our findings suggest previously unknown epigenetic mechanisms of morphine-induced molecular and behavioral neuroadaptations.


Assuntos
Analgésicos Opioides/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epigênese Genética/fisiologia , Área Tegmentar Ventral/metabolismo , Analgésicos Opioides/farmacologia , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Cocaína/farmacologia , Condicionamento Operante/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Proteína Potenciadora do Homólogo 2 de Zeste , Epigênese Genética/efeitos dos fármacos , Dependência de Heroína/patologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/genética , Complexo Repressor Polycomb 2/genética , Complexo Repressor Polycomb 2/metabolismo , Mudanças Depois da Morte , RNA Polimerase II/genética , RNA Polimerase II/metabolismo , Ratos , Ratos Sprague-Dawley , Área Tegmentar Ventral/efeitos dos fármacos
16.
Science ; 338(6103): 124-8, 2012 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-23042896

RESUMO

Brain-derived neurotrophic factor (BDNF) is a key positive regulator of neural plasticity, promoting, for example, the actions of stimulant drugs of abuse such as cocaine. We discovered a surprising opposite role for BDNF in countering responses to chronic morphine exposure. The suppression of BDNF in the ventral tegmental area (VTA) enhanced the ability of morphine to increase dopamine (DA) neuron excitability and promote reward. In contrast, optical stimulation of VTA DA terminals in nucleus accumbens (NAc) completely reversed the suppressive effect of BDNF on morphine reward. Furthermore, we identified numerous genes in the NAc, a major target region of VTA DA neurons, whose regulation by BDNF in the context of chronic morphine exposure mediated this counteractive function. These findings provide insight into the molecular basis of morphine-induced neuroadaptations in the brain's reward circuitry.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/fisiologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Dependência de Morfina/fisiopatologia , Morfina/farmacologia , Área Tegmentar Ventral/efeitos dos fármacos , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Dopamina/metabolismo , Neurônios Dopaminérgicos/fisiologia , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Técnicas de Inativação de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dependência de Morfina/genética , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/fisiopatologia , Estimulação Luminosa , Receptor trkB/genética , Receptor trkB/fisiologia , Área Tegmentar Ventral/fisiologia
17.
Nat Neurosci ; 15(6): 891-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22522400

RESUMO

Repeated cocaine administration increases the dendritic arborization of nucleus accumbens neurons, but the underlying signaling events remain unknown. Here we show that repeated exposure to cocaine negatively regulates the active form of Rac1, a small GTPase that controls actin remodeling in other systems. Further, we show, using viral-mediated gene transfer, that overexpression of a dominant negative mutant of Rac1 or local knockout of Rac1 is sufficient to increase the density of immature dendritic spines on nucleus accumbens neurons, whereas overexpression of a constitutively active Rac1 or light activation of a photoactivatable form of Rac1 blocks the ability of repeated cocaine exposure to produce this effect. Downregulation of Rac1 activity likewise promotes behavioral responses to cocaine exposure, with activation of Rac1 producing the opposite effect. These findings establish that Rac1 signaling mediates structural and behavioral plasticity in response to cocaine exposure.


Assuntos
Cocaína/farmacologia , Espinhas Dendríticas/efeitos dos fármacos , Inibidores da Captação de Dopamina/farmacologia , Plasticidade Neuronal/efeitos dos fármacos , Neuropeptídeos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteínas rac de Ligação ao GTP/metabolismo , Animais , Western Blotting , Transtornos Relacionados ao Uso de Cocaína , Espinhas Dendríticas/metabolismo , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/genética , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/fisiologia , Proteínas rac de Ligação ao GTP/genética , Proteínas rac1 de Ligação ao GTP
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