Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Eur Neuropsychopharmacol ; 36: 154-159, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32522387

RESUMO

A polymorphism in the gene encoding the serotonin (5-HT) transporter (5-HTT) has been shown to moderate the response to CO2 inhalation, an experimental model for panic attacks (PAs). Recurrent, unpredictable PAs represent, together with anticipatory anxiety of recurring attacks, the core feature of panic disorder (PD) and significantly interfere with patients' daily life. In addition to genetic components, accumulating evidence suggests that epigenetic mechanisms, which regulate gene expression by modifying chromatin structure, also play a fundamental role in the etiology of mental disorders. However, in PD, epigenetic mechanisms have barely been examined to date. In the present study, we investigated the relationship between methylation at the regulatory region of the gene encoding the 5-HTT and the reactivity to a 35% CO2 inhalation in PD patients. We focused on four specific CpG sites and found a significant association between the methylation level of one of these CpG sites and the fear response. This suggests that the emotional response to CO2 inhalation might be moderated by an epigenetic mechanism, and underlines the implication of the 5-HT system in PAs. Future studies are needed to further investigate epigenetic alterations in PD and their functional consequences. These insights can increase our understanding of the underlying pathophysiology and support the development of new treatment strategies.


Assuntos
Dióxido de Carbono/efeitos adversos , Metilação de DNA/fisiologia , Medo/fisiologia , Transtorno de Pânico/metabolismo , Sequências Reguladoras de Ácido Nucleico/fisiologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/metabolismo , Adulto , Sequência de Bases , Epigênese Genética/efeitos dos fármacos , Epigênese Genética/fisiologia , Medo/efeitos dos fármacos , Medo/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/genética , Transtorno de Pânico/psicologia , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética
2.
PLoS One ; 15(5): e0233387, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32437382

RESUMO

Real-time reverse transcription PCR (qPCR) normalized to an internal reference gene (RG), is a frequently used method for quantifying gene expression changes in neuroscience. Although RG expression is assumed to be constant independent of physiological or experimental conditions, several studies have shown that commonly used RGs are not expressed stably. The use of unstable RGs has a profound effect on the conclusions drawn from studies on gene expression, and almost universally results in spurious estimation of target gene expression. Approaches aimed at selecting and validating RGs often make use of different statistical methods, which may lead to conflicting results. Based on published RG validation studies involving hypoxia the present study evaluates the expression of 5 candidate RGs (Actb, Pgk1, Sdha, Gapdh, Rnu6b) as a function of hypoxia exposure and hypothermic treatment in the neonatal rat cerebral cortex-in order to identify RGs that are stably expressed under these experimental conditions-using several statistical approaches that have been proposed to validate RGs. In doing so, we first analyzed RG ranking stability proposed by several widely used statistical methods and related tools, i.e. the Coefficient of Variation (CV) analysis, GeNorm, NormFinder, BestKeeper, and the ΔCt method. Using the Geometric mean rank, Pgk1 was identified as the most stable gene. Subsequently, we compared RG expression patterns between the various experimental groups. We found that these statistical methods, next to producing different rankings per se, all ranked RGs displaying significant differences in expression levels between groups as the most stable RG. As a consequence, when assessing the impact of RG selection on target gene expression quantification, substantial differences in target gene expression profiles were observed. Altogether, by assessing mRNA expression profiles within the neonatal rat brain cortex in hypoxia and hypothermia as a showcase, this study underlines the importance of further validating RGs for each individual experimental paradigm, considering the limitations of the statistical methods used for this aim.


Assuntos
Encéfalo/metabolismo , Perfilação da Expressão Gênica/métodos , Genes Essenciais , Hipotermia/genética , Hipóxia Encefálica/genética , Animais , Animais Recém-Nascidos , Expressão Gênica , Hipotermia/metabolismo , Hipóxia Encefálica/metabolismo , Ratos , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reprodutibilidade dos Testes
3.
Prog Neurobiol ; 168: 42-68, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29653249

RESUMO

Human pluripotent stem cell (PSC) technology and direct somatic cell reprogramming have opened up a promising new avenue in the field of neuroscience. These recent advances allow researchers to obtain virtually any cell type found in the human brain, making it possible to produce and study functional neurons in laboratory conditions for both scientific and medical purposes. Although distinct approaches have shown to be successful in directing neuronal cell fate in vitro, their refinement and optimization, as well as the search for alternative approaches, remains necessary to help realize the full potential of the eventually derived neuronal populations. Furthermore, we are currently limited in the number of neuronal subtypes whose induction is fully established, and different cultivation protocols for each subtype exist, making it challenging to increase the reproducibility and decrease the variances that are observed between different protocols. In this review, we summarize the progress that has been made in generating various neuronal subtypes from PSCs and somatic cells, with special emphasis on chemically defined systems, transcription factor-mediated reprogramming and epigenetic-based approaches. We also discuss the efforts that are being made to increase the efficiency of current protocols and address the potential for the use of these cells in disease modelling, drug discovery and regenerative medicine.


Assuntos
Reprogramação Celular/fisiologia , Neurônios/fisiologia , Células-Tronco Pluripotentes/fisiologia , Células-Tronco Pluripotentes/transplante , Animais , Diferenciação Celular/efeitos dos fármacos , Epigenômica/métodos , Técnicas In Vitro , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo
4.
Behav Brain Res ; 353: 236-241, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-29481811

RESUMO

BACKGROUND: Behavioral testing provides an essential approach in further developing our understanding of brain structure and function. The aim of our study was to outline a more expanded approach to cognition- and anxiety-related behavior in the rabbit. METHODS: Twenty-one 70-day old rabbits (13 female, 8 male) were exposed to open field test, dark-light box test and object recognition testing with variations in inter-trial-interval, olfactory recognition and object location testing. Independent T-tests were used to compare data by individual baseline characteristics, i.e. birth weight, weight at testing, sex, litter #, litter size. RESULTS: In the open field test, median time spent in the center was 3.64 s (0.84-41.36) for the 9 rabbits who entered the center; median distance moved in the arena was 874.42 cm (54.20-3444.83). In the dark light box test, 12 rabbits entered the light compartment. In the object recognition task, rabbits spent significantly less time exploring the familiar object compared to the novel (0.40 s [0-2.8] vs. 3.17 s [1.30-32.69]; P = 0.003) when using a 30-min inter-trial interval, as well with a 90-min inter-trial interval: 0.87 s [0-7.8] vs. 7.65 s [0-37.6] (P = 0.008). However, recognition was lost when using a 24-h inter-trial interval (time spent exploring the familiar object: 3.33 [0-10.90]; novel object:3.87 [1.15-48.53]; n.s). In the object location task and in olfactory object recognition task, median discrimination indexes were 0.69 (-1 to 1) and 0.37 (-0.38 to 0.78) respectively, higher than level expected by chance (P < 0.001). Litter size >3 during the neonatal period was associated with increased explorative behavior in the dark light box test (P = 0.046) and in the visual object recognition task (P = 0.005), whereas body weight and sex were not. CONCLUSIONS: Settings and outcome measures for multiple behavioral tests, providing reference values and considerations for future developmental studies are reported. Discrimination and memory in the rabbit appear to relate to litter characteristics, although a larger sample size is needed to confirm our findings.


Assuntos
Comportamento Exploratório , Tamanho da Ninhada de Vivíparos , Reconhecimento Psicológico , Animais , Escala de Avaliação Comportamental , Discriminação Psicológica , Feminino , Masculino , Atividade Motora , Percepção Olfatória , Coelhos , Projetos de Pesquisa
5.
Neurosci Biobehav Rev ; 75: 166-182, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-28161509

RESUMO

Hypoxic-ischemic encephalopathy remains a common cause of brain damage in neonates. Preterm infants have additional complications, as prematurity by itself increases the risk of encephalopathy. Currently, therapy for this subset of asphyxiated infants is limited to supportive care. There is an urgent need for therapies in preterm infants - and for representative animal models for preclinical drug development. In 1991, a novel rodent model of global asphyxia in the preterm infant was developed in Sweden. This method was based on the induction of asphyxia during the birth processes itself by submerging pups, still in the uterine horns, in a water bath followed by C-section. This insult occurs at a time-point when the rodent brain maturity resembles the brain of a 22-32 week old human fetus. This model has developed over the past 25 years as an established model of perinatal global asphyxia in the early preterm brain. Here we summarize the knowledge gained on the short- and long-term neuropathological and behavioral effects of asphyxia on the immature central nervous system.


Assuntos
Asfixia , Encéfalo , Animais , Asfixia Neonatal , Feminino , Humanos , Hipóxia-Isquemia Encefálica , Recém-Nascido Prematuro , Gravidez , Ratos
6.
Cell Mol Life Sci ; 74(3): 509-523, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27628303

RESUMO

Even though the etiology of Alzheimer's disease (AD) remains unknown, it is suggested that an interplay among genetic, epigenetic and environmental factors is involved. An increasing body of evidence pinpoints that dysregulation in the epigenetic machinery plays a role in AD. Recent developments in genomic technologies have allowed for high throughput interrogation of the epigenome, and epigenome-wide association studies have already identified unique epigenetic signatures for AD in the cortex. Considerable evidence suggests that early dysregulation in the brainstem, more specifically in the raphe nuclei and the locus coeruleus, accounts for the most incipient, non-cognitive symptomatology, indicating a potential causal relationship with the pathogenesis of AD. Here we review the advancements in epigenomic technologies and their application to the AD research field, particularly with relevance to the brainstem. In this respect, we propose the assessment of epigenetic signatures in the brainstem as the cornerstone of interrogating causality in AD. Understanding how epigenetic dysregulation in the brainstem contributes to AD susceptibility could be of pivotal importance for understanding the etiology of the disease and for the development of novel diagnostic and therapeutic strategies.


Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Tronco Encefálico/patologia , Metilação de DNA , Epigênese Genética , Animais , Tronco Encefálico/metabolismo , Núcleo Dorsal da Rafe/metabolismo , Núcleo Dorsal da Rafe/patologia , Humanos
7.
Transl Psychiatry ; 6(9): e885, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27598969

RESUMO

The current diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders are being challenged by the heterogeneity and the symptom overlap of psychiatric disorders. Therefore, a framework toward a more etiology-based classification has been initiated by the US National Institute of Mental Health, the research domain criteria project. The basic neurobiology of human psychiatric disorders is often studied in rodent models. However, the differences in outcome measurements hamper the translation of knowledge. Here, we aimed to present a translational panic model by using the same stimulus and by quantitatively comparing the same outcome measurements in rodents, healthy human subjects and panic disorder patients within one large project. We measured the behavioral-emotional and bodily response to CO2 exposure in all three samples, allowing for a reliable cross-species comparison. We show that CO2 exposure causes a robust fear response in terms of behavior in mice and panic symptom ratings in healthy volunteers and panic disorder patients. To improve comparability, we next assessed the respiratory and cardiovascular response to CO2, demonstrating corresponding respiratory and cardiovascular effects across both species. This project bridges the gap between basic and human research to improve the translation of knowledge between these disciplines. This will allow significant progress in unraveling the etiological basis of panic disorder and will be highly beneficial for refining the diagnostic categories as well as treatment strategies.


Assuntos
Comportamento Animal/efeitos dos fármacos , Dióxido de Carbono/farmacologia , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Camundongos , Transtorno de Pânico/psicologia , Pânico/efeitos dos fármacos , Adolescente , Adulto , Animais , Pressão Sanguínea/efeitos dos fármacos , Capnografia , Dióxido de Carbono/efeitos adversos , Feminino , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Transtorno de Pânico/fisiopatologia , Adulto Jovem
9.
Eur Neuropsychopharmacol ; 26(1): 65-77, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26653128

RESUMO

Growing evidence indicates that impairment of the stress response, in particular the negative feedback regulation mechanism exerted by the hypothalamo-pituitary-adrenal (HPA) axis, might be responsible for the hippocampal atrophy observed in depressed patients. Antidepressants, possibly through the activation of BDNF signaling, may enhance neuroplasticity and restore normal hippocampal functions. In this context, glucocorticoid receptor-impaired (GR-i) mice-a transgenic mouse model of reduced GR-induced negative feedback regulation of the HPA axis-were used to investigate the role of BDNF/TrkB signaling in the behavioral and neurochemical effects of the new generation antidepressant drug, agomelatine. GR-i mice exhibited marked alterations in depressive-like and anxiety-like behaviors, together with a decreased cell proliferation and altered levels of neuroplastic and epigenetic markers in the hippocampus. GR-i mice and their wild-type littermates were treated for 21 days with vehicle, agomelatine (50mg/kg/day; i.p) or the TrkB inhibitor Ana-12 (0.5mg/kg/day, i.p) alone, or in combination with agomelatine. Chronic treatment with agomelatine resulted in antidepressant-like effects in GR-i mice and reversed the deficit in hippocampal cell proliferation and some of the alterations of mRNA plasticity markers in GR-i mice. Ana-12 blocked the effect of agomelatine on motor activity as well as its ability to restore a normal hippocampal cell proliferation and expression of neurotrophic factors. Altogether, our findings indicate that agomelatine requires TrkB signaling to reverse some of the molecular and behavioral alterations caused by HPA axis impairment.


Assuntos
Acetamidas/farmacologia , Antidepressivos/farmacologia , Transtorno Depressivo/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Receptor trkB/metabolismo , Receptores de Glucocorticoides/metabolismo , Animais , Azepinas/farmacologia , Benzamidas/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proliferação de Células/efeitos dos fármacos , Transtorno Depressivo/metabolismo , Transtorno Depressivo/patologia , Modelos Animais de Doenças , Medo/efeitos dos fármacos , Medo/fisiologia , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Receptor trkB/antagonistas & inibidores , Receptores de Glucocorticoides/genética , Método Simples-Cego , Comportamento Social
10.
Transl Psychiatry ; 5: e642, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26393488

RESUMO

The selective serotonin reuptake inhibitor (SSRI) fluoxetine is widely prescribed for the treatment of symptoms related to a variety of psychiatric disorders. After chronic SSRI treatment, some symptoms remediate on the long term, but the underlying mechanisms are not yet well understood. Here we studied the long-term consequences (40 days after treatment) of chronic fluoxetine exposure on genome-wide gene expression. During the treatment period, we measured body weight; and 1 week after treatment, cessation behavior in an SSRI-sensitive anxiety test was assessed. Gene expression was assessed in hippocampal tissue of adult rats using transcriptome analysis and several differentially expressed genes were validated in independent samples. Gene ontology analysis showed that upregulated genes induced by chronic fluoxetine exposure were significantly enriched for genes involved in myelination. We also investigated the expression of myelination-related genes in adult rats exposed to fluoxetine at early life and found two myelination-related genes (Transferrin (Tf) and Ciliary neurotrophic factor (Cntf)) that were downregulated by chronic fluoxetine exposure. Cntf, a neurotrophic factor involved in myelination, showed regulation in opposite direction in the adult versus neonatally fluoxetine-exposed groups. Expression of myelination-related genes correlated negatively with anxiety-like behavior in both adult and neonatally fluoxetine-exposed rats. In conclusion, our data reveal that chronic fluoxetine exposure causes on the long-term changes in expression of genes involved in myelination, a process that shapes brain connectivity and contributes to symptoms of psychiatric disorders.


Assuntos
Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Ciliar/genética , Fluoxetina/farmacologia , Hipocampo , Efeitos Adversos de Longa Duração , Transferrina/genética , Regulação para Cima/efeitos dos fármacos , Animais , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hipocampo/metabolismo , Hipocampo/patologia , Efeitos Adversos de Longa Duração/diagnóstico , Efeitos Adversos de Longa Duração/etiologia , Efeitos Adversos de Longa Duração/metabolismo , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/genética , Farmacogenética , Ratos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
11.
Prog Neurobiol ; 129: 58-78, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25930682

RESUMO

Panic attacks (PAs), the core feature of panic disorder, represent a common phenomenon in the general adult population and are associated with a considerable decrease in quality of life and high health care costs. To date, the underlying pathophysiology of PAs is not well understood. A unique feature of PAs is that they represent a rare example of a psychopathological phenomenon that can be reliably modeled in the laboratory in panic disorder patients and healthy volunteers. The most effective techniques to experimentally trigger PAs are those that acutely disturb the acid-base homeostasis in the brain: inhalation of carbon dioxide (CO2), hyperventilation, and lactate infusion. This review particularly focuses on the use of CO2 inhalation in humans and rodents as an experimental model of panic. Besides highlighting the different methodological approaches, the cardio-respiratory and the endocrine responses to CO2 inhalation are summarized. In addition, the relationships between CO2 level, changes in brain pH, the serotonergic system, and adaptive physiological and behavioral responses to CO2 exposure are presented. We aim to present an integrated psychological and neurobiological perspective. Remaining gaps in the literature and future perspectives are discussed.


Assuntos
Encéfalo/fisiopatologia , Dióxido de Carbono/metabolismo , Homeostase/fisiologia , Transtorno de Pânico/fisiopatologia , Serotonina/metabolismo , Animais , Humanos , Concentração de Íons de Hidrogênio
12.
Transl Psychiatry ; 4: e473, 2014 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-25335169

RESUMO

The serotonin transporter gene (5-HTT/SLC6A4)-linked polymorphic region has been suggested to have a modulatory role in mediating effects of early-life stress exposure on psychopathology rendering carriers of the low-expression short (s)-variant more vulnerable to environmental adversity in later life. The underlying molecular mechanisms of this gene-by-environment interaction are not well understood, but epigenetic regulation including differential DNA methylation has been postulated to have a critical role. Recently, we used a maternal restraint stress paradigm of prenatal stress (PS) in 5-HTT-deficient mice and showed that the effects on behavior and gene expression were particularly marked in the hippocampus of female 5-Htt+/- offspring. Here, we examined to which extent these effects are mediated by differential methylation of DNA. For this purpose, we performed a genome-wide hippocampal DNA methylation screening using methylated-DNA immunoprecipitation (MeDIP) on Affymetrix GeneChip Mouse Promoter 1.0 R arrays. Using hippocampal DNA from the same mice as assessed before enabled us to correlate gene-specific DNA methylation, mRNA expression and behavior. We found that 5-Htt genotype, PS and their interaction differentially affected the DNA methylation signature of numerous genes, a subset of which showed overlap with the expression profiles of the corresponding transcripts. For example, a differentially methylated region in the gene encoding myelin basic protein (Mbp) was associated with its expression in a 5-Htt-, PS- and 5-Htt × PS-dependent manner. Subsequent fine-mapping of this Mbp locus linked the methylation status of two specific CpG sites to Mbp expression and anxiety-related behavior. In conclusion, hippocampal DNA methylation patterns and expression profiles of female prenatally stressed 5-Htt+/- mice suggest that distinct molecular mechanisms, some of which are promoter methylation-dependent, contribute to the behavioral effects of the 5-Htt genotype, PS exposure and their interaction.


Assuntos
Metilação de DNA/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Efeitos Tardios da Exposição Pré-Natal/genética , Proteínas da Membrana Plasmática de Transporte de Serotonina/genética , Estresse Fisiológico/genética , Estresse Psicológico/genética , Animais , Comportamento Animal , Feminino , Expressão Gênica/genética , Hipocampo , Camundongos , Camundongos Endogâmicos C57BL , Gravidez
13.
Neuropharmacology ; 77: 120-30, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24067928

RESUMO

Phosphodiesterase type 4 inhibitors (PDE4-Is) have received increasing attention as cognition-enhancers and putative treatment strategies for Alzheimer's disease (AD). By preventing cAMP breakdown, PDE4-Is can enhance intracellular signal transduction and increase the phosphorylation of cAMP response element-binding protein (CREB) and transcription of proteins related to synaptic plasticity and associated memory formation. Unfortunately, clinical development of PDE4-Is has been seriously hampered by emetic side effects. The new isoform-specific PDE4D-I, GEBR-7b, has shown to have beneficial effects on memory at non-emetic doses. The aim of the current study was to investigate chronic cognition-enhancing effects of GEBR-7b in a mouse model of AD. To this extent, 5-month-old (5M) APPswe/PS1dE9 mice received daily subcutaneous injections with GEBR-7b (0.001 mg/kg) or vehicle for a period of 3 weeks, and were tested on affective and cognitive behavior at 7M. We demonstrated a cognition-enhancing potential in APPswe/PS1dE9 mice as their spatial memory function at 7M in the object location test was improved by prior GEBR-7b treatment. APPswe/PS1dE9 mice displayed lower levels of CREB phosphorylation, which remained unaltered after chronic GEBR-7b treatment, and higher levels of tau in the hippocampus. Hippocampal brain-derived neurotrophic factor levels and synaptic densities were not different between experimental groups and no effects were observed on hippocampal GSK3ß and tau phosphorylation or Aß levels. In conclusion, GEBR-7b can enhance spatial memory function in the APPswe/PS1dE9 mouse model of AD. Although the underlying mechanisms of its cognition-enhancing potential remain to be elucidated, PDE4D inhibition appears an interesting novel therapeutic option for cognitive deficits in AD.


Assuntos
Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Hipocampo/efeitos dos fármacos , Iminas/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Morfolinas/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Modelos Animais de Doenças , Proteína 4 Homóloga a Disks-Large , Guanilato Quinases/metabolismo , Hipocampo/metabolismo , Iminas/uso terapêutico , Proteínas de Membrana/metabolismo , Camundongos , Morfolinas/uso terapêutico , Inibidores da Fosfodiesterase 4/uso terapêutico , Fosforilação/efeitos dos fármacos
14.
Eur Neuropsychopharmacol ; 24(4): 595-607, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24139910

RESUMO

Exposure to prenatal stress (PS) can predispose individuals to the development of psychopathology later in life. We examined the effects of unpredictable chronic mild stress (CMS) exposure during adolescence on a background of PS in male and female Sprague-Dawley rats. PS induced more anxiety-like behavior in the elevated zero maze in both sexes, an effect that was normalized by subsequent exposure to CMS. Moreover, PS was associated with increased depression-like behavior in the forced swim test in males only. Conversely, sucrose intake was increased in PS males, whilst being decreased in females when consecutively exposed to PS and CMS. Hypothalamo-pituitary-adrenal (HPA) axis reactivity was affected in males only, with higher stress-induced plasma corticosterone levels after PS. Markedly, CMS normalized the effects of PS on elevated zero maze behavior as well as basal and stress-induced plasma corticosterone secretion. At the neurochemical level, both PS and CMS induced various sex-specific alterations in serotonin (5-HT) and tryptophan hydroxylase 2 (TPH2) immunoreactivity in the dorsal raphe nucleus, hippocampus and prefrontal cortex with, in line with the behavioral observations, more profound effects in male offspring. In conclusion, these findings show that prenatal maternal stress in Sprague-Dawley rats induces various anxiety- and depression-related behavioral and neuroendocrine changes, as well as alterations in central 5-HT and TPH2 function, predominantly in male offspring. Moreover, CMS exposure partially normalized the effects of previous PS experience, suggesting that the outcome of developmental stress exposure largely depends on the environmental conditions later in life and vice versa.


Assuntos
Alostase , Ansiedade/etiologia , Depressão/etiologia , Modelos Animais de Doenças , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Neurônios Serotoninérgicos/metabolismo , Estresse Fisiológico , Animais , Ansiedade/sangue , Ansiedade/prevenção & controle , Comportamento Animal , Depressão/sangue , Depressão/prevenção & controle , Feminino , Hipocampo/enzimologia , Hipocampo/metabolismo , Hipocampo/patologia , Sistema Hipotálamo-Hipofisário/metabolismo , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Proteínas do Tecido Nervoso/metabolismo , Sistema Hipófise-Suprarrenal/metabolismo , Sistema Hipófise-Suprarrenal/fisiopatologia , Córtex Pré-Frontal/enzimologia , Córtex Pré-Frontal/metabolismo , Córtex Pré-Frontal/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/psicologia , Núcleos da Rafe/enzimologia , Núcleos da Rafe/metabolismo , Núcleos da Rafe/patologia , Ratos , Ratos Sprague-Dawley , Neurônios Serotoninérgicos/enzimologia , Neurônios Serotoninérgicos/patologia , Caracteres Sexuais , Triptofano Hidroxilase/metabolismo
15.
J Chem Neuroanat ; 48-49: 23-8, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23333161

RESUMO

Plastic changes in the adult mammal hippocampus can be altered by many factors and perhaps the most well-documented is stress. Stress and elevated corticosterone levels have been shown to decrease hippocampal neurogenesis and decrease the complexity of CA3 pyramidal neurons. However, the extent of these changes in relation to low and moderately elevated levels of corticosterone has yet to be fully investigated. Therefore, the aim of the present study was to determine how low to moderately elevated circulating corticosterone levels affect dendritic morphology of CA3 pyramidal cells and hippocampal neurogenesis in adult male rats. To do this, three groups of adult male Wistar rats were used: (1) Sham-operated, (2) Adrenalectomized (ADX), and (3) ADX+corticosterone replacement. Primary results show that adrenalectomy, but not moderately elevated levels of corticosterone replacement, resulted in significant atrophy of CA3 pyramidal neurons. Interestingly, moderate corticosterone replacement resulted in significantly more surviving new cells in the dentate gyrus when compared to sham controls. This work shows that circulating levels of corticosterone differentially affect plasticity in the CA3 region and the dentate gyrus.


Assuntos
Adrenalectomia , Região CA3 Hipocampal/citologia , Corticosterona/farmacologia , Dendritos/efeitos dos fármacos , Terapia de Reposição Hormonal , Animais , Antimetabólitos , Bromodesoxiuridina , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/ultraestrutura , Sobrevivência Celular/efeitos dos fármacos , Dendritos/ultraestrutura , Giro Denteado/citologia , Giro Denteado/efeitos dos fármacos , Implantes de Medicamento , Hipocampo/citologia , Imuno-Histoquímica , Masculino , Células Piramidais/efeitos dos fármacos , Ratos , Ratos Wistar
16.
Eur Neuropsychopharmacol ; 23(10): 1226-46, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23199416

RESUMO

Adverse life events during pregnancy may impact upon the developing fetus, predisposing prenatally stressed offspring to the development of psychopathology. In the present study, we examined the effects of prenatal restraint stress (PS) on anxiety- and depression-related behavior in both male and female adult Sprague-Dawley rats. In addition, gene expression profiles within the hippocampus and frontal cortex (FC) were examined in order to gain more insight into the molecular mechanisms that mediate the behavioral effects of PS exposure. PS significantly increased anxiety-related behavior in male, but not female offspring. Likewise, depression-related behavior was increased in male PS rats only. Further, male PS offspring showed increased basal plasma corticosterone levels in adulthood, whereas both PS males and females had lower stress-induced corticosterone levels when compared to controls. Microarray-based profiling of the hippocampus and FC showed distinct sex-dependent changes in gene expression after PS. Biological processes and/or signal transduction cascades affected by PS included glutamatergic and GABAergic neurotransmission, mitogen-activated protein kinase (MAPK) signaling, neurotrophic factor signaling, phosphodiesterase (PDE)/ cyclic nucleotide signaling, glycogen synthase kinase 3 (GSK3) signaling, and insulin signaling. Further, the data indicated that epigenetic regulation is affected differentially in male and female PS offspring. These sex-specific alterations may, at least in part, explain the behavioral differences observed between both sexes, i.e. relative vulnerability versus resilience to PS in male versus female rats, respectively. These data reveal novel potential targets for antidepressant and mood stabilizing drug treatments including PDE inhibitors and histone deacetylase (HDAC) inhibitors.


Assuntos
Lobo Frontal/metabolismo , Hipocampo/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Complicações na Gravidez/fisiopatologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Estresse Fisiológico , Estresse Psicológico/fisiopatologia , Animais , Ansiedade/sangue , Ansiedade/etiologia , Ansiedade/metabolismo , Comportamento Animal , Corticosterona/sangue , Depressão/sangue , Depressão/etiologia , Depressão/metabolismo , Suscetibilidade a Doenças , Epigênese Genética , Feminino , Lobo Frontal/enzimologia , Regulação da Expressão Gênica , Hipocampo/enzimologia , Masculino , Proteínas do Tecido Nervoso/biossíntese , Proteínas do Tecido Nervoso/genética , Neurônios/enzimologia , Neurônios/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/sangue , Efeitos Tardios da Exposição Pré-Natal/etiologia , Ratos , Ratos Sprague-Dawley , Restrição Física , Caracteres Sexuais , Transdução de Sinais
17.
Horm Behav ; 62(1): 10-7, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22584108

RESUMO

Brain-derived neurotrophic factor (BDNF) signaling has been implicated in the onset of depression and in antidepressant efficacy, although the exact role of this neurotrophin in the pathophysiology of depression remains to be elucidated. Also, the interaction between chronic stress, which may precede depression, corticosteroids and BDNF is not fully understood. The present study aimed at investigating whether long-lasting, recurrent tethering of sows during a period of 1.5 or 4.5 years leads to enduring effects on measures that may be indicative of chronic stress, compared with animals kept in a group housing system ('loose' sows). Immediately after slaughter, the frontal cortex, dorsal and ventral hippocampus were dissected and protein levels of BDNF and its receptors were analyzed and compared with plasma cortisol levels and adrenal weights. Results indicate that tethering stress reduced BDNF protein levels in the dorsal hippocampus and the frontal cortex, but not in the ventral hippocampus. In addition, levels of TrkB, the high affinity receptor for BDNF, were increased in the dorsal hippocampus. Plasma cortisol levels and adrenal weight were increased after tethering. These stress effects on BDNF levels were more pronounced after 4.5 years of recurrent tethering and negatively correlated in particular in the frontal cortex with cortisol levels and adrenal weight. This suggests that the stress effect of tethered housing on neurotrophin levels may be mediated via cortisol. Taken together, these data indicate that recurrent tethering stress in sows over 4.5 years results in a loss of neurotrophic support by BDNF, mediated by an overactive neuroendocrine system.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Estresse Psicológico/metabolismo , Glândulas Suprarrenais/anatomia & histologia , Animais , Depressão/metabolismo , Depressão/psicologia , Modelos Animais de Doenças , Feminino , Hidrocortisona/sangue , Receptor trkB/análise , Suínos/metabolismo , Suínos/psicologia
18.
Mol Psychiatry ; 17(6): 584-96, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21894152

RESUMO

Abnormal brain-derived neurotrophic factor (BDNF) signaling seems to have a central role in the course and development of various neurological and psychiatric disorders. In addition, positive effects of psychotropic drugs are known to activate BDNF-mediated signaling. Although the BDNF gene has been associated with several diseases, molecular mechanisms other than functional genetic variations can impact on the regulation of BDNF gene expression and lead to disturbed BDNF signaling and associated pathology. Thus, epigenetic modifications, representing key mechanisms by which environmental factors induce enduring changes in gene expression, are suspected to participate in the onset of various psychiatric disorders. More specifically, various environmental factors, particularly when occurring during development, have been claimed to produce long-lasting epigenetic changes at the BDNF gene, thereby affecting availability and function of the BDNF protein. Such stabile imprints on the BDNF gene might explain, at least in part, the delayed efficacy of treatments as well as the high degree of relapses observed in psychiatric disorders. Moreover, BDNF gene has a complex structure displaying differential exon regulation and usage, suggesting a subcellular- and brain region-specific distribution. As such, developing drugs that modify epigenetic regulation at specific BDNF exons represents a promising strategy for the treatment of psychiatric disorders. Here, we present an overview of the current literature on epigenetic modifications at the BDNF locus in psychiatric disorders and related animal models.


Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Epigênese Genética/fisiologia , Interação Gene-Ambiente , Transtornos Mentais/genética , Transtornos Mentais/metabolismo , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Fator Neurotrófico Derivado do Encéfalo/genética , Sistemas de Liberação de Medicamentos/métodos , Sistemas de Liberação de Medicamentos/psicologia , Humanos , Modelos Genéticos
20.
Brain Behav Immun ; 25(4): 616-23, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21172419

RESUMO

Recent studies have suggested that DNA methylation is implicated in age-related changes in gene expression as well as in cognition. DNA methyltransferase 3a (Dnmt3a), which catalyzes DNA methylation, is essential for memory formation and underlying changes in neuronal and synaptic plasticity. Because caloric restriction (CR) and upregulation of antioxidants have been suggested as strategies to attenuate age-related alterations in the brain, we hypothesized that both a diet restricted in calories and transgenic overexpression of normal human Cu/Zn superoxide dismutase 1 (SOD) attenuate age-related changes in Dnmt3a in the aging mouse hippocampus. For this purpose, we performed qualitative and quantitative analyses of Dnmt3a-immunoreactivity (IR) for the hippocampal dentate gyrus (DG), CA3 and CA1-2 regions in 12- and 24-month-old mice from 4 groups, i.e. (1) wild-type (WT) mice on a control diet (WT-CD), (2) SOD-CD mice, (3) WT mice on CR (WT-CR), and (4) SOD-CR. Qualitative analyses revealed two types of Dnmt3a immunoreactive cells: type I cells--present throughout all hippocampal cell layers showing moderate levels of nuclear Dnmt3a-IR, and type II cells--a subpopulation of hippocampal cells showing very intense nuclear Dnmt3a-IR, and colocalization with Bromodeoxyuridine. Quantitative analyses indicated that the age-related increase in Dnmt3a-IR within the CA3 and CA1-2 in type I cells was attenuated by CR, but not by SOD overexpression. In contrast, the density of type II Dnmt3a immunoreactive cells showed an age-related reduction, without significant effects of both CR and SOD. These changes in Dnmt3a levels in the mouse hippocampus may have a significant impact on gene expression and associated cognitive functioning.


Assuntos
Envelhecimento/fisiologia , Restrição Calórica , DNA (Citosina-5-)-Metiltransferases/metabolismo , Hipocampo/enzimologia , Superóxido Dismutase/metabolismo , Animais , DNA Metiltransferase 3A , Metabolismo Energético/fisiologia , Feminino , Regulação da Expressão Gênica/fisiologia , Hipocampo/citologia , Humanos , Imuno-Histoquímica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Regulação para Cima
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...