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1.
Addict Biol ; 26(3): e12937, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-32638524

RESUMO

Inhalants containing the volatile solvent toluene are misused to induce euphoria or intoxication. Inhalant abuse is most common during adolescence and can result in cognitive impairments during an important maturational period. Despite evidence suggesting that epigenetic modifications may underpin the cognitive effects of inhalants, no studies to date have thoroughly investigated toluene-induced regulation of the transcriptome or discrete epigenetic modifications within the brain. To address this, we investigated effects of adolescent chronic intermittent toluene (CIT) inhalation on gene expression and DNA methylation profiles within the rat medial prefrontal cortex (mPFC), which undergoes maturation throughout adolescence and has been implicated in toluene-induced cognitive deficits. Employing both RNA-seq and genome-wide Methyl CpG Binding Domain (MBD) Ultra-seq analysis, we demonstrate that adolescent CIT inhalation (10 000 ppm for 1 h/day, 3 days/week for 4 weeks) induces both transient and persistent changes to the transcriptome and DNA methylome within the rat mPFC for at least 2 weeks following toluene exposure. We demonstrate for the first time that adolescent CIT exposure results in dynamic regulation of the mPFC transcriptome likely relating to acute inflammatory responses and persistent deficits in synaptic plasticity. These adaptations may contribute to the cognitive deficits associated with chronic toluene exposure and provide novel molecular targets for preventing long-term neurophysiological abnormalities following chronic toluene inhalation.


Assuntos
Metilação de DNA/efeitos dos fármacos , Proteínas de Ligação a DNA/genética , Córtex Pré-Frontal/efeitos dos fármacos , Tolueno/toxicidade , Transcriptoma/efeitos dos fármacos , Administração por Inalação , Animais , Expressão Gênica , Abuso de Inalantes , Masculino , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/fisiologia , Ratos , Ratos Wistar
2.
Neuropharmacology ; 143: 299-305, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30268522

RESUMO

Repeated cocaine administration induces many long-term structural and molecular changes in the dorsal medial prefrontal cortex (dmPFC) and are known to underlie aspects of cocaine-seeking behavior. DNA methylation is a key long-lasting epigenetic determinant of gene expression and is implicated in neuroplasticity, however, the extent to which this epigenetic modification is involved in the neuroplasticity associated with drug addiction has received limited attention. Here, we examine the relation between DNA methylation and gene expression within the dorsal medial prefrontal cortex (dmPFC) following limited cocaine self-administration (1 h/day), prolonged cocaine self-administration (6 h/day), and saline self-administration (1 h/day). Rats were fitted with intravenous catheters and allowed to lever press for saline or cocaine (0.25 mg/kg/0.1 mL infusion) in the different access conditions for 20 days. Prolonged-access rats exhibited escalation in cocaine intake over the course of training, while limited-access rats did not escalate cocaine intake. Additionally, limited-access and prolonged-access rats exhibited unique Homer2 epigenetic profiles and mRNA expression. In prolonged-access rats, Homer2 mRNA levels in the dmPFC were increased, which was accompanied by decreased DNA methylation and p300 binding within the Homer2 promoter. Limited-access animals exhibited decreased DNA methylation, decreased DNA hydroxymethylation, and increased p300 binding within the Homer2 promoter. These data indicate that distinct epigenetic profiles are induced by limited-versus prolonged-access self-administration conditions that contribute to transcriptional profiles and lend support to the notion that covalent modification of DNA is implicated in addiction-like changes in cocaine-seeking behavior.


Assuntos
Transtornos Relacionados ao Uso de Cocaína/metabolismo , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Proteínas de Arcabouço Homer/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Cocaína/administração & dosagem , Inibidores da Captação de Dopamina/administração & dosagem , Comportamento de Procura de Droga/fisiologia , Proteína p300 Associada a E1A/metabolismo , Proteínas de Arcabouço Homer/genética , Masculino , Córtex Pré-Frontal/metabolismo , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Autoadministração
3.
Learn Mem ; 24(1): 1-13, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27980071

RESUMO

Atypical PKM, a persistently active form of atypical PKC, is proposed to be a molecular memory trace, but there have been few examinations of the role of PKMs generated from other PKCs. We demonstrate that inhibitors used to inhibit PKMs generated from atypical PKCs are also effective inhibitors of other PKMs. In contrast, we demonstrate that dominant-negative PKMs show isoform-specificity. A dominant-negative PKM from the classical PKC Apl I blocks activity-dependent intermediate-term facilitation (a-ITF) when expressed in the sensory neuron, while a dominant-negative PKM from the atypical PKC Apl III does not. Consistent with a specific role for PKM Apl I in activity-dependent facilitation, live imaging FRET-based cleavage assays reveal that activity leads to cleavage of the classical PKC Apl I, but not the atypical PKC Apl III in the sensory neuron varicosities of Aplysia In contrast, massed intermediate facilitation (m-ITF) induced by 10 min of 5HT is sufficient for cleavage of the atypical PKC Apl III in the motor neuron. Interestingly, both cleavage of PKC Apl I in the sensory neuron during a-ITF and cleavage of PKC Apl III in the motor neuron during m-ITF are inhibited by a dominant-negative form of a penta-EF hand containing classical calpain cloned from Aplysia Consistent with a role for PKMs in plasticity, this dominant-negative calpain also blocks both a-ITF when expressed in the sensory neuron and m-ITF when expressed in the motor neuron. This study broadens the role of PKMs in synaptic plasticity in two significant ways: (i) PKMs generated from multiple isoforms of PKC, including classical isoforms, maintain memory traces; (ii) PKMs play roles in the presynaptic neuron.


Assuntos
Plasticidade Neuronal/fisiologia , Terminações Pré-Sinápticas/fisiologia , Proteína Quinase C/metabolismo , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/metabolismo , Animais , Aplysia , Benzofenantridinas/farmacologia , Calpaína/farmacologia , Células Cultivadas , Inibidores Enzimáticos/farmacologia , Transferência Ressonante de Energia de Fluorescência , Regulação da Expressão Gênica/efeitos dos fármacos , Potenciais da Membrana/fisiologia , Microinjeções , Neurônios Motores/efeitos dos fármacos , Neurônios Motores/fisiologia , Sistema Nervoso/citologia , Plasticidade Neuronal/efeitos dos fármacos , Cloreto de Potássio/farmacologia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteína Quinase C/química , Proteína Quinase C/efeitos dos fármacos , Proteína Quinase C/genética , Serotonina/farmacologia , Transdução Genética
4.
Neuroepigenetics ; 4: 1-11, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27213137

RESUMO

Continued vulnerability to relapse during abstinence is characteristic of cocaine addiction and suggests that drug-induced neuroadaptations persist during abstinence. However, the precise cellular and molecular attributes of these adaptations remain equivocal. One possibility is that cocaine self-administration leads to enduring changes in DNA methylation. To address this possibility, we isolated neurons from medial prefrontal cortex and performed high throughput DNA sequencing to examine changes in DNA methylation following cocaine self-administration. Twenty-nine genomic regions became persistently differentially methylated during cocaine self-administration, and an additional 28 regions became selectively differentially methylated during abstinence. Altered DNA methylation was associated with isoform-specific changes in the expression of co-localizing genes. These results provide the first neuron-specific, genome-wide profile of changes in DNA methylation induced by cocaine self-administration and protracted abstinence. Moreover, our findings suggest that altered DNA methylation facilitates long-term behavioral adaptation in a manner that extends beyond the perpetuation of altered transcriptional states.

5.
Proc Natl Acad Sci U S A ; 111(19): 7120-5, 2014 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-24757058

RESUMO

5-hydroxymethylcytosine (5-hmC) is a novel DNA modification that is highly enriched in the adult brain and dynamically regulated by neural activity. 5-hmC accumulates across the lifespan; however, the functional relevance of this change in 5-hmC and whether it is necessary for behavioral adaptation have not been fully elucidated. Moreover, although the ten-eleven translocation (Tet) family of enzymes is known to be essential for converting methylated DNA to 5-hmC, the role of individual Tet proteins in the adult cortex remains unclear. Using 5-hmC capture together with high-throughput DNA sequencing on individual mice, we show that fear extinction, an important form of reversal learning, leads to a dramatic genome-wide redistribution of 5-hmC within the infralimbic prefrontal cortex. Moreover, extinction learning-induced Tet3-mediated accumulation of 5-hmC is associated with the establishment of epigenetic states that promote gene expression and rapid behavioral adaptation.


Assuntos
Adaptação Fisiológica/fisiologia , Citosina/análogos & derivados , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Medo/fisiologia , Neocórtex/fisiologia , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , 5-Metilcitosina/análogos & derivados , Animais , Comportamento Animal/fisiologia , Condicionamento Psicológico/fisiologia , Citosina/metabolismo , Dioxigenases , Epigênese Genética/fisiologia , Extinção Psicológica/fisiologia , Estudo de Associação Genômica Ampla , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neocórtex/citologia , Neurônios/citologia , Neurônios/metabolismo
6.
Learn Mem ; 20(5): 237-40, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23589089

RESUMO

There are significant sex differences in vulnerability to develop fear-related anxiety disorders. Females exhibit twice the rate of post-traumatic stress disorder (PTSD) as males and sex differences have been observed in fear extinction learning in both humans and rodents, with a failure to inhibit fear emerging as a precipitating factor in the development of PTSD. Here we report that female mice are resistant to fear extinction, and exhibit increased DNA methylation of Bdnf exon IV and a concomitant decrease in mRNA expression within the medial prefrontal cortex. Activation of BDNF signaling by the trkB agonist 7,8-dihydroxyflavone blocks the return of fear in female mice after extinction training, and thus represents a novel approach to treating fear-related anxiety disorders that are characterized by a resistance to extinction and increased propensity for renewal.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Extinção Psicológica/fisiologia , Medo/fisiologia , Córtex Pré-Frontal/metabolismo , Transdução de Sinais/fisiologia , Animais , Transtornos de Ansiedade/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Metilação de DNA , Modelos Animais de Doenças , Éxons , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Feminino , Flavonas/farmacologia , Camundongos , Córtex Pré-Frontal/efeitos dos fármacos , RNA Mensageiro , Transdução de Sinais/efeitos dos fármacos
7.
Trends Neurosci ; 36(1): 3-13, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23041052

RESUMO

DNA methylation was once considered to be a static epigenetic modification whose primary function was restricted to directing the development of cellular phenotype. However, it is now evident that the methylome is dynamically regulated across the lifespan: during development as a putative mechanism by which early experience leaves a lasting signature on the genome and during adulthood as a function of behavioral adaptation. Here, we propose that experience-dependent variations in DNA methylation, particularly within the context of learning and memory, represent a form of genomic metaplasticity that serves to prime the transcriptional response to later learning-related stimuli and neuronal reactivation.


Assuntos
Adaptação Fisiológica/fisiologia , Encéfalo/fisiologia , Metilação de DNA/fisiologia , Aprendizagem/fisiologia , Memória/fisiologia , Animais , Genômica , Humanos
8.
Nat Neurosci ; 14(9): 1115-7, 2011 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-21841775

RESUMO

MicroRNAs are small non-coding RNAs that mediate post-transcriptional gene silencing. Fear-extinction learning in C57/Bl6J mice led to increased expression of the brain-specific microRNA miR-128b, which disrupted stability of several plasticity-related target genes and regulated formation of fear-extinction memory. Increased miR-128b activity may therefore facilitate the transition from retrieval of the original fear memory toward the formation of a new fear-extinction memory.


Assuntos
Encéfalo/metabolismo , Extinção Psicológica/fisiologia , Medo , Memória/fisiologia , MicroRNAs/metabolismo , Animais , Comportamento Animal , Moléculas de Adesão Celular Neuronais/metabolismo , Linhagem Celular Transformada , Condicionamento Clássico , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Proteínas do Tecido Nervoso/metabolismo , Cloreto de Potássio/farmacologia , Proteína Fosfatase 1/metabolismo , RNA Interferente Pequeno/metabolismo , Proteína Reelina , Serina Endopeptidases/metabolismo , Transativadores/metabolismo , Transdução Genética/métodos , Transfecção
9.
J Neurosci ; 31(20): 7486-91, 2011 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-21593332

RESUMO

It is well established that the coordinated regulation of activity-dependent gene expression by the histone acetyltransferase (HAT) family of transcriptional coactivators is crucial for the formation of contextual fear and spatial memory, and for hippocampal synaptic plasticity. However, no studies have examined the role of this epigenetic mechanism within the infralimbic prefrontal cortex (ILPFC), an area of the brain that is essential for the formation and consolidation of fear extinction memory. Here we report that a postextinction training infusion of a combined p300/CBP inhibitor (Lys-CoA-Tat), directly into the ILPFC, enhances fear extinction memory in mice. Our results also demonstrate that the HAT p300 is highly expressed within pyramidal neurons of the ILPFC and that the small-molecule p300-specific inhibitor (C646) infused into the ILPFC immediately after weak extinction training enhances the consolidation of fear extinction memory. C646 infused 6 h after extinction had no effect on fear extinction memory, nor did an immediate postextinction training infusion into the prelimbic prefrontal cortex. Consistent with the behavioral findings, inhibition of p300 activity within the ILPFC facilitated long-term potentiation (LTP) under stimulation conditions that do not evoke long-lasting LTP. These data suggest that one function of p300 activity within the ILPFC is to constrain synaptic plasticity, and that a reduction in the function of this HAT is required for the formation of fear extinction memory.


Assuntos
Extinção Psicológica/fisiologia , Medo/fisiologia , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Sinapses/enzimologia , Fatores de Transcrição de p300-CBP/antagonistas & inibidores , Animais , Extinção Psicológica/efeitos dos fármacos , Medo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Plasticidade Neuronal/efeitos dos fármacos , Sinapses/efeitos dos fármacos , Fatores de Transcrição de p300-CBP/metabolismo
10.
Neurobiol Learn Mem ; 96(1): 89-94, 2011 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-21524708

RESUMO

MicroRNAs (miRNAs) are a class of endogenous, small non-coding RNAs that mediate post-transcriptional gene silencing by complementary binding to the 3'untranslated region of target mRNAs. The transient and localized expression of these small RNAs in dendrites, their capacity to respond in an activity-dependent manner, and the observation that a single miRNA can simultaneously regulate many genes, make brain-specific miRNAs ideal candidates for the fine-tuning of gene expression associated with neural plasticity and memory formation. Here we provide an overview of the current literature, which supports the proposal that non-coding RNA-mediated regulation of gene function represents an important, yet underappreciated, layer of epigenetic control that contributes to learning and memory in the adult brain.


Assuntos
Encéfalo/metabolismo , Memória/fisiologia , MicroRNAs/genética , Plasticidade Neuronal/genética , Animais , Epigênese Genética , Regulação da Expressão Gênica , Humanos , MicroRNAs/metabolismo
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