Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 229
Filtrar
Mais filtros

Base de dados
País/Região como assunto
Tipo de documento
Intervalo de ano de publicação
1.
Mol Psychiatry ; 17(5): 527-36, 2012 May.
Artigo em Inglês | MEDLINE | ID: mdl-21670733

RESUMO

Impaired regulation of emotional memory is a feature of several affective disorders, including depression, anxiety and post-traumatic stress disorder. Such regulation occurs, in part, by interactions between the hippocampus and the basolateral amygdala (BLA). Recent studies have indicated that within the adult hippocampus, newborn neurons may contribute to support emotional memory, and that regulation of hippocampal neurogenesis is implicated in depressive disorders. How emotional information affects newborn neurons in adults is not clear. Given the role of the BLA in hippocampus-dependent emotional memory, we investigated whether hippocampal neurogenesis was sensitive to emotional stimuli from the BLA. We show that BLA lesions suppress adult neurogenesis, while lesions of the central nucleus of the amygdala do not. Similarly, we show that reducing BLA activity through viral vector-mediated overexpression of an outwardly rectifying potassium channel suppresses neurogenesis. We also show that BLA lesions prevent selective activation of immature newborn neurons in response to a fear-conditioning task. These results demonstrate that BLA activity regulates adult hippocampal neurogenesis and the fear context-specific activation of newborn neurons. Together, these findings denote functional implications for proliferation and recruitment of new neurons into emotional memory circuits.


Assuntos
Tonsila do Cerebelo/fisiologia , Medo/fisiologia , Hipocampo/fisiologia , Neurogênese/fisiologia , Neurônios/fisiologia , Animais , Expressão Gênica/genética , Masculino , Inibição Neural/fisiologia , Canais de Potássio/genética , Canais de Potássio/metabolismo , Ratos , Ratos Sprague-Dawley , Transgenes/genética , Transgenes/fisiologia , Regulação para Cima
2.
Nat Genet ; 23(2): 203-7, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10508518

RESUMO

Single-nucleotide polymorphisms, as well as small insertions and deletions (here referred to collectively as simple nucleotide polymorphisms, or SNPs), comprise the largest set of sequence variants in most organisms. Positional cloning based on SNPs may accelerate the identification of human disease traits and a range of biologically informative mutations. The recent application of high-density oligonucleotide arrays to allele identification has made it feasible to genotype thousands of biallelic SNPs in a single experiment. It has yet to be established, however, whether SNP detection using oligonucleotide arrays can be used to accelerate the mapping of traits in diploid genomes. The cruciferous weed Arabidopsis thaliana is an attractive model system for the construction and use of biallelic SNP maps. Although important biological processes ranging from fertilization and cell fate determination to disease resistance have been modelled in A. thaliana, identifying mutations in this organism has been impeded by the lack of a high-density genetic map consisting of easily genotyped DNA markers. We report here the construction of a biallelic genetic map in A. thaliana with a resolution of 3.5 cM and its use in mapping Eds16, a gene involved in the defence response to the fungal pathogen Erysiphe orontii. Mapping of this trait involved the high-throughput generation of meiotic maps of F2 individuals using high-density oligonucleotide probe array-based genotyping. We developed a software package called InterMap and used it to automatically delimit Eds16 to a 7-cM interval on chromosome 1. These results are the first demonstration of biallelic mapping in diploid genomes and establish means for generalizing SNP-based maps to virtually any genetic organism.


Assuntos
Arabidopsis/genética , Marcadores Genéticos/genética , Genoma de Planta , Ascomicetos/crescimento & desenvolvimento , Mapeamento Cromossômico , DNA de Plantas/genética , Genes de Plantas/genética , Predisposição Genética para Doença , Genótipo , Análise de Sequência com Séries de Oligonucleotídeos , Doenças das Plantas/genética , Doenças das Plantas/microbiologia , Polimorfismo Genético
3.
Mol Psychiatry ; 14(9): 847-55, 827, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19204724

RESUMO

The basolateral amygdala is critical for generation of anxiety. In addition, exposure to both stress and glucocorticoids induces anxiety. Demonstrated ability of the amygdala to change in response to stress and glucocorticoids could thus be important therapeutic target for anxiety management. Several studies have reported a relationship between anxiety and dendritic arborization of the amygdaloid neurons. In this study we employed a gene therapeutic approach to reduce anxiety and dendritic arborization of the amygdala neurons. Specifically, we overexpressed SK2 potassium channel in the basolateral amygdala using a herpes simplex viral system. Our choice of therapeutic cargo was guided by the indications that activation of the amygdala might underlie anxiety and that SK2 could reduce neuronal activation by exerting inhibitory influence on action potentials. We report that SK2 overexpression reduced anxiety and stress-induced corticosterone secretion at a systemic level. SK2 overexpression also reduced dendritic arborization of the amygdala neurons. Hence, SK2 is a potential gene therapy candidate molecule that can be used against stress-related neuropsychiatric disorders such as anxiety.


Assuntos
Tonsila do Cerebelo/metabolismo , Ansiedade/patologia , Ansiedade/terapia , Corticosterona/sangue , Dendritos/patologia , Terapia Genética/métodos , Proteínas Serina-Treonina Quinases/metabolismo , Tonsila do Cerebelo/patologia , Análise de Variância , Animais , Ansiedade/etiologia , Ansiedade/fisiopatologia , Comportamento Animal , Modelos Animais de Doenças , Vetores Genéticos/fisiologia , Quinases do Centro Germinativo , Locomoção/genética , Masculino , Aprendizagem em Labirinto/fisiologia , Neurônios/patologia , Proteínas Serina-Treonina Quinases/genética , Ratos , Ratos Wistar , Simplexvirus/genética , Simplexvirus/fisiologia , Estresse Psicológico
4.
Science ; 229(4720): 1397-400, 1985 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-4035356

RESUMO

Sustained exposure to glucocorticoids, the adrenocortical stress hormones, is toxic to neurons, and such toxicity appears to play a role in neuron loss during aging. Previous work has shown that glucocorticoids compromise the capacity of neurons to survive a variety of metabolic insults. This report extends those observations by showing that ischemic injury to neurons in rat brain is also potentiated by exposure to high physiological titers of glucocorticoids and is attenuated by adrenalectomy. The synergy between ischemic and glucocorticoid brain injury was seen even when glucocorticoid levels were manipulated after the ischemic insult. Pharmacological interventions that diminish the adrenocortical stress response may improve neurological outcome from stroke or cardiac arrest.


Assuntos
Isquemia Encefálica/fisiopatologia , Glucocorticoides/farmacologia , Neurônios/efeitos dos fármacos , Adrenalectomia , Animais , Encéfalo/citologia , Encéfalo/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Córtex Cerebral/efeitos dos fármacos , Transtornos Cerebrovasculares/fisiopatologia , Corpo Estriado/efeitos dos fármacos , Parada Cardíaca/fisiopatologia , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Ratos , Ratos Endogâmicos
5.
Science ; 238(4826): 522-4, 1987 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-2821621

RESUMO

There is now evidence that the immune system, during times of infectious challenge, can stimulate the secretion of glucocorticoids, the adrenal steroids that mediate important aspects of the response to stress. Specifically, secretion of interleukin-1 (IL-1), a monocyte lymphokine secreted after infection, appears at least in part responsible for this effect. Glucocorticoids are secreted in response to a neuroendocrine cascade involving, first, the brain, then the pituitary, and finally the adrenal gland. In this report, human IL-1 is shown to activate the adrenocortical axis at the level of the brain, stimulating the release of the controlling hormone corticotropin-releasing factor (CRF) from the hypothalamus. Infusion of IL-1 induced a significant secretion of CRF into the circulation exiting the hypothalamus, whereas immunoneutralization of CRF blocked the stimulatory effect of IL-1 on glucocorticoid secretion. IL-1 appeared to have no acute direct stimulatory effects on the pituitary or adrenal components of this system. Furthermore, IL-1 did not cause a nonspecific release of other hypothalamic hormones. Thus, the lymphokine acts in a specific manner to activate the adrenocortical axis at the level of the brain; this effect appears to be unrelated to the known pyrogenic effects of IL-1 within the hypothalamus.


Assuntos
Hormônio Liberador da Corticotropina/metabolismo , Hipotálamo/metabolismo , Interleucina-1/fisiologia , Córtex Suprarrenal/fisiologia , Hormônio Adrenocorticotrópico/metabolismo , Animais , Linhagem Celular , Corticosterona/metabolismo , Técnicas Imunológicas , Masculino , Adeno-Hipófise/metabolismo , Neoplasias Hipofisárias/metabolismo , Ratos , Ratos Endogâmicos
6.
Science ; 239(4841 Pt 1): 766-8, 1988 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-3340858

RESUMO

In rats, an environmental manipulation occurring early in life resulted in changes in the adrenocortical axis that persisted throughout the entire life of the animals and attenuated certain deficits associated with aging. Rats handled during infancy had a permanent increase in concentrations of receptors for glucocorticoids in the hippocampus, a critical region in the negative-feedback inhibition of adrenocortical activity. Increased receptor concentrations led to greater hippocampal sensitivity to glucocorticoids and enhanced negative-feedback efficacy in the handled rats. Thus, at all ages tested, rats that were not handled secreted more glucocorticoids in response to stress than did handled rats. At later ages, nonhandled rats also showed elevated basal glucocorticoid levels, with the result that there was a greater cumulative exposure to glucocorticoids in nonhandled rats. Increased exposure to adrenal glucocorticoids can accelerate hippocampal neuron loss and cognitive impairments in aging. Hippocampal cell loss and pronounced spatial memory deficits emerged with age in the nonhandled rats, but were almost absent in the handled rats. Previous work showed that glucocorticoid hypersecretion, hippocampal neuron death, and cognitive impairments form a complex degenerative cascade of aging in the rat. The present study shows that a subtle manipulation early in life can retard the emergence of this cascade.


Assuntos
Manobra Psicológica , Hipocampo/crescimento & desenvolvimento , Envelhecimento , Animais , Animais Recém-Nascidos , Dexametasona/metabolismo , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Aprendizagem , Memória , Ratos , Receptores de Glucocorticoides/metabolismo
7.
Science ; 280(5366): 1077-82, 1998 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-9582121

RESUMO

Single-nucleotide polymorphisms (SNPs) are the most frequent type of variation in the human genome, and they provide powerful tools for a variety of medical genetic studies. In a large-scale survey for SNPs, 2.3 megabases of human genomic DNA was examined by a combination of gel-based sequencing and high-density variation-detection DNA chips. A total of 3241 candidate SNPs were identified. A genetic map was constructed showing the location of 2227 of these SNPs. Prototype genotyping chips were developed that allow simultaneous genotyping of 500 SNPs. The results provide a characterization of human diversity at the nucleotide level and demonstrate the feasibility of large-scale identification of human SNPs.


Assuntos
Mapeamento Cromossômico/métodos , Desoxirribonucleotídeos/genética , Técnicas Genéticas , Genoma Humano , Genótipo , Polimorfismo Genético , Algoritmos , Alelos , DNA Complementar , Bases de Dados Factuais , Fosfatos de Dinucleosídeos , Expressão Gênica , Marcadores Genéticos , Variação Genética , Heterozigoto , Homozigoto , Humanos , Dados de Sequência Molecular , Hibridização de Ácido Nucleico , Reação em Cadeia da Polimerase , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Sitios de Sequências Rotuladas
8.
Endocr Rev ; 12(2): 118-34, 1991 May.
Artigo em Inglês | MEDLINE | ID: mdl-2070776

RESUMO

There is considerable, although not entirely consistent, evidence that the hippocampus inhibits most aspects of HPA activity, including basal (circadian nadir) and circadian peak secretion as well as the onset and termination of responses to stress. Although much of the evidence for these effects rests only on the measurement of corticosteroids, recent lesion and implant studies indicate that the hippocampus regulates adrenocortical activity at the hypothalamic level, via the expression and secretion of ACTH secretagogues. Such inhibition results largely from the mediation of corticosteroid feedback, although more work is required to determine whether the hippocampus supplies a tonic inhibitory input in the absence of corticosteroids. It must be noted that the hippocampus is not the only feedback site in the adrenocortical system, since removal of its input only reduces, but does not abolish, the efficacy of corticosteroid inhibition, and since other elements of the axis appear eventually to compensate for deficits in feedback regulation. The importance of other feedback sites is further suggested not only by the presence of corticosteroid receptors in other parts of the brain and pituitary, but also by the improved prediction of CRF levels by combined hypothalamic and hippocampal receptor occupancy. The likelihood of feedback mediated by nonhippocampal sites underscores the need for future work to characterize hippocampal influence on HPA activity in the absence of changes in corticosteroid secretion. However, despite the fact that the hippocampus is not the only feedback site, it is distinguished from most potential feedback sites, including the hypothalamus and pituitary, by its high content of both type I and II corticosteroid receptors. The hippocampus is therefore capable of mediating inhibition over a wide range of steroid levels. The low end of this range is represented by corticosteroid inhibition of basal (circadian nadir) HPA activity. The apparent type I receptor specificity of this inhibition and the elevation of trough corticosteroid levels after hippocampal damage support a role for hippocampal type I receptors in regulating basal HPA activity. It is possible that basal activity is controlled in part through hippocampal inhibition of vasopressin, since the inhibition of portal blood vasopressin correlates with lower levels of hippocampal receptor occupancy, and the expression of vasopressin by some CRF neurons is sensitive to very low corticosteroid levels. At the high end of the physiological range, stress-induced or circadian peak corticosteroid secretion correlates strongly with occupancy of the lower affinity hippocampal type II receptors.(ABSTRACT TRUNCATED AT 400 WORDS)


Assuntos
Córtex Suprarrenal/fisiologia , Hipocampo/fisiologia , Hipotálamo/fisiologia , Hipófise/fisiologia , Envelhecimento/fisiologia , Animais , Retroalimentação , Humanos , Transtornos Mentais/fisiopatologia
9.
Endocr Rev ; 21(1): 55-89, 2000 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-10696570

RESUMO

The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stress-response or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole.


Assuntos
Glucocorticoides/fisiologia , Estresse Fisiológico/fisiopatologia , Animais , Líquidos Corporais/metabolismo , Sistema Cardiovascular/fisiopatologia , Endocrinologia/tendências , Humanos , Inflamação/fisiopatologia , Sistema Nervoso/fisiopatologia , Reprodução , Estresse Fisiológico/imunologia , Estresse Fisiológico/metabolismo
10.
Nat Neurosci ; 4(12): 1169-71, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11713467

RESUMO

There is evidence that in rats, partial hippocampal lesions or selective ablation of the CA3 subfield can disrupt retrieval of spatial memory and that hippocampal damage disinhibits hypothalamic-pituitary-adrenocortical (HPA)-axis activity, thereby elevating plasma levels of adrenocorticotropin and corticosterone. Here we report evidence that attenuation of CA3 lesion-induced increases in circulating corticosterone levels with the synthesis inhibitor metyrapone, administered shortly before water-maze retention testing, blocks the impairing effects of the lesion on memory retrieval. These findings suggest that elevated adrenocortical activity is critical in mediating memory retrieval deficits induced by hippocampal damage.


Assuntos
Córtex Suprarrenal/metabolismo , Corticosterona/metabolismo , Hipocampo/fisiopatologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Transtornos da Memória/fisiopatologia , Inibição Neural/fisiologia , Sistema Hipófise-Suprarrenal/fisiopatologia , Córtex Suprarrenal/efeitos dos fármacos , Animais , Corticosterona/antagonistas & inibidores , Hipocampo/lesões , Hipocampo/cirurgia , Ácido Caínico , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Degeneração Neural/induzido quimicamente , Degeneração Neural/fisiopatologia , Inibição Neural/efeitos dos fármacos , Vias Neurais/lesões , Vias Neurais/fisiopatologia , Vias Neurais/cirurgia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Piridinas/farmacologia , Ratos , Ratos Sprague-Dawley , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia
11.
Nat Neurosci ; 7(9): 947-53, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15300253

RESUMO

Glucocorticoids, the adrenal steroids released during stress, compromise the ability of neurons to survive neurological injury. In contrast, estrogen protects neurons against such injuries. We designed three genetic interventions to manipulate the actions of glucocorticoids, which reduced their deleterious effects in both in vitro and in vivo rat models. The most effective of these interventions created a chimeric receptor combining the ligand-binding domain of the glucocorticoid receptor and the DNA-binding domain of the estrogen receptor. Expression of this chimeric receptor reduced hippocampal lesion size after neurological damage by 63% and reversed the outcome of the stress response by rendering glucocorticoids protective rather than destructive. Our findings elucidate three principal steps in the neuronal stress-response pathway, all of which are amenable to therapeutic intervention.


Assuntos
Glucocorticoides/antagonistas & inibidores , Neurônios/fisiologia , Receptores de Glucocorticoides/metabolismo , Proteínas Recombinantes de Fusão/farmacologia , Estresse Fisiológico/metabolismo , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/genética , 11-beta-Hidroxiesteroide Desidrogenase Tipo 2/metabolismo , Animais , Western Blotting/métodos , Contagem de Células/métodos , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Técnicas de Cultura , Receptor alfa de Estrogênio , Fatores de Crescimento de Fibroblastos/genética , Fatores de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Proteínas Imediatamente Precoces , Imuno-Histoquímica/métodos , Indóis , Ácido Caínico/toxicidade , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Modelos Moleculares , Neurônios/efeitos dos fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Estrutura Terciária de Proteína/fisiologia , RNA Mensageiro/metabolismo , Ratos , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptores de Glucocorticoides/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Estresse Fisiológico/genética , Transgenes , Translocação Genética/fisiologia
12.
Neuroscience ; 148(2): 342-8, 2007 Aug 24.
Artigo em Inglês | MEDLINE | ID: mdl-17683872

RESUMO

Parasite Toxoplasma gondii blocks the innate aversion of rats for cat urine, putatively increasing the likelihood of a cat predating a rat. This is thought to reflect an adaptive behavioral manipulation, because toxoplasma can reproduce only in cat intestines. While it will be adaptive for the parasite to cause an absolute behavioral change, fitness costs associated with the manipulation itself suggest that the change is optimized and not maximized. We investigate these conflicting suggestions in the present report. Furthermore, exposure to cat odor causes long-lasting acquisition of learnt fear in the rodents. If toxoplasma manipulates emotional valence of cat odor rather than just sensory response, infection should affect learning driven by the aversive properties of the odor. As a second aim of the present study, we investigate this assertion. We demonstrate that behavioral changes in rodents induced by toxoplasma infection do not represent absolute all-or-none effects. Rather, these effects follow a non-monotonous function dependent on strength of stimulus, roughly resembling an inverted-U curve. Furthermore, infection affects conditioning to cat odor in a manner dependent upon strength of unconditioned stimulus employed. Non-monotonous relationship between behavioral manipulation and strength of cat odor agrees with the suggestion that a dynamic balance exists between benefit obtained and costs incurred by the parasite during the manipulation. This report also demonstrates that toxoplasma affects emotional valence of the cat odor as indicated by altered learned fear induced by cat odor.


Assuntos
Adaptação Psicológica/fisiologia , Comportamento Animal/fisiologia , Toxoplasmose Animal/fisiopatologia , Toxoplasmose Animal/psicologia , Análise de Variância , Animais , Aprendizagem da Esquiva/fisiologia , Gatos , Condicionamento Psicológico , Comportamento Exploratório/fisiologia , Medo , Fezes , Masculino , Odorantes , Ratos , Ratos Wistar
13.
Neuroscience ; 149(4): 804-12, 2007 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-17945431

RESUMO

Apoptosis, a predominant cause of neuronal death after stroke, can be executed in a caspase-dependent or apoptosis inducing factor (AIF)-dependent manner. Herpes simplex virus (HSV) vectors expressing caspase inhibitors p35 and crmA have been shown to be neuroprotective against various excitotoxic insults. Here we further evaluated the possible neuroprotective role of p35 and crmA in a rat stroke model. Overexpression of p35, but not crmA, significantly increased neuronal survival. Results of double immunofluorescence staining indicate that compared with neurons infected with crmA or control vectors, p35-infected neurons had less active caspase-3 expression, cytosolic cytochrome c and nuclear AIF translocation.


Assuntos
Apoptose/fisiologia , Infarto da Artéria Cerebral Média/fisiopatologia , Simplexvirus/fisiologia , Proteínas Virais/metabolismo , Análise de Variância , Animais , Apoptose/genética , Fator de Indução de Apoptose/metabolismo , Bromodesoxiuridina/metabolismo , Contagem de Células/métodos , Citocromos c/metabolismo , Modelos Animais de Doenças , Indóis , Masculino , Microscopia Confocal/métodos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão , Serpinas/genética , Serpinas/metabolismo , Proteínas Virais/genética , beta-Galactosidase
14.
Mol Cell Biol ; 8(5): 2184-94, 1988 May.
Artigo em Inglês | MEDLINE | ID: mdl-3290652

RESUMO

Transcription directed into a Saccharomyces cerevisiae autonomously replicating sequence (ARS) causes high-frequency loss of minichromosomes. Conditionally stable artificial yeast chromosomes were constructed that contain an inducible GAL promoter upstream of ARS1. Under growth conditions in which the promoter was inactive, these chromosomes were mitotically stable; however, when the GAL promoter was induced, the chromosomes became extremely unstable as a result of transcriptional impairment of ARS function. This interference by the GAL promoter occurred only in cis but can occur from either side of ARS1. Transcriptional interference of ARS function can be monitored readily by using a visual colony-color assay (P. Hieter, C. Mann, M. Snyder, and R.W. Davis, Cell 40:381-392, 1985), which was further developed as a sensitive in vivo assay for sequences which rescue ARS from transcription. DNA fragments from the 3' ends of genes, inserted downstream of the GAL promoter, protected ARS function from transcriptional interference. This assay is expected to be independent of both RNA transcript stability and processing. Philippsen et al. have shown that transcription into a yeast centromere inhibits CEN function in vivo (L. Panzeri, I. Groth-Clausen, J. Shepard, A. Stotz, and P. Philippsen, Chromosomes Today 8:46-58, 1984). We identified two 200- to 300-base-pair DNA fragments flanking CEN4 that rescued ARS1 from transcription. Both of these fragments protected ARS from transcription when inserted in either orientation. The 3' ends of stable transcripts are encoded by fragments that protected the ARS from transcription, suggesting that the protection was achieved by transcription termination. It is suggested that protection of elements important for the replication and segregation of eucaryotic chromosomes from transcription is necessary for their proper function in vivo.


Assuntos
Cromossomos/metabolismo , Genes Fúngicos , Sequências Reguladoras de Ácido Nucleico , Replicon , Saccharomyces cerevisiae/genética , Transcrição Gênica , DNA Fúngico/genética , Galactose/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Regiões Promotoras Genéticas/efeitos dos fármacos , Estimulação Química
15.
Trends Neurosci ; 22(10): 419-22, 1999 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-10481182

RESUMO

It is now recognized that necrotic neurological insults often trigger apoptosis in a subset of neurons. It is also now apparent that such apoptosis rarely matches the 'classical' apoptosis seen during development or the physiological turnover of cells outside the nervous system. As a result, the view has emerged that the 'apoptosis-like' changes that follow necrotic insults represent a different phenomenon, which is on a vague continuum with the necrotic features of cell death. We suggest that apoptosis following neurological insults is, in actuality, mechanistically identical to classical apoptosis. However, the atypical apoptotic endpoints that are observed are inevitable, given the way in which insult-triggered apoptosis is likely to have evolved.


Assuntos
Apoptose , Degeneração Neural/patologia , Neurônios/patologia , Neurociências/normas , Doença Aguda , Animais , Necrose , Neurociências/tendências
16.
Trends Neurosci ; 24(12): 695-700, 2001 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-11718873

RESUMO

Increasing knowledge of neuron death mediators has led to gene therapy techniques for neuroprotection. Overexpression of numerous genes enhances survival after necrotic or neurodegenerative damage. Nonetheless, although encouraging, little is accomplished if a neuron is spared from death, but not from dysfunction. This article reviews neuroprotection experiments that include some measure of function, and synthesizes basic principles relating to its maintenance. Variations in gene delivery systems, including virus-type and latency between damage onset and vector delivery, probably impact the therapeutic outcome. Additionally, functional sparing might depend on factors related to insult severity, neuron type involved or the step in the death cascade that is targeted.


Assuntos
Terapia Genética/métodos , Doenças Neurodegenerativas/fisiopatologia , Doenças Neurodegenerativas/terapia , Neurônios/fisiologia , Animais , Humanos
17.
Curr Opin Neurobiol ; 5(2): 205-16, 1995 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-7620309

RESUMO

Stress affects cognition in a number of ways, acting rapidly via catecholamines and more slowly via glucocorticoids. Catecholamine actions involve beta adrenergic receptors and also availability of glucose, whereas glucocorticoids biphasically modulate synaptic plasticity over hours and also produce longer-term changes in dendritic structure that last for weeks. Prolonged exposure to stress leads to loss of neurons, particularly in the hippocampus. Recent evidence suggests that the glucocorticoid- and stress-related cognitive impairments involving declarative memory are probably related to the changes they effect in the hippocampus, whereas the stress-induced catecholamine effects on emotionally laden memories are postulated to involve structures such as the amgydala.


Assuntos
Cognição/fisiologia , Estresse Psicológico/psicologia , Animais , Catecolaminas/fisiologia , Transtornos Cognitivos/fisiopatologia , Transtornos Cognitivos/psicologia , Glucocorticoides/fisiologia , Humanos , Estresse Psicológico/fisiopatologia
18.
J Natl Cancer Inst ; 92(12): 994-1000, 2000 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-10861311

RESUMO

BACKGROUND: : Abnormal circadian rhythms have been observed in patients with cancer, but the prognostic value of such alterations has not been confirmed. We examined the association between diurnal variation of salivary cortisol in patients with metastatic breast cancer and subsequent survival. We explored relationships between cortisol rhythms, circulating natural killer (NK) cell counts and activity, prognostic indicators, medical treatment, and psychosocial variables. METHODS: Salivary cortisol levels of 104 patients with metastatic breast cancer were assessed at study entry at 0800, 1200, 1700, and 2100 hours on each of 3 consecutive days, and the slope of diurnal cortisol variation was calculated using a regression of log-transformed cortisol concentrations on sample collection time. NK cell numbers were measured by flow cytometry, and NK cell activity was measured by the chromium release assay. The survival analysis was conducted by the Cox proportional hazards regression model with two-sided statistical testing. RESULTS: Cortisol slope predicted subsequent survival up to 7 years later. Earlier mortality occurred among patients with relatively "flat" rhythms, indicating a lack of normal diurnal variation (Cox proportional hazards, P =. 0036). Patients with chest metastases, as opposed to those with visceral or bone metastases, had more rhythmic cortisol profiles. Flattened profiles were linked with low counts and suppressed activity of NK cells. After adjustment for each of these and other factors, the cortisol slope remained a statistically significant, independent predictor of survival time. NK cell count emerged as a secondary predictor of survival. CONCLUSIONS: Patients with metastatic breast cancer whose diurnal cortisol rhythms were flattened or abnormal had earlier mortality. Suppression of NK cell count and NK function may be a mediator or a marker of more rapid disease progression.


Assuntos
Neoplasias da Mama/metabolismo , Ritmo Circadiano , Hidrocortisona/metabolismo , Saliva/metabolismo , Adulto , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/psicologia , Neoplasias da Mama/terapia , Feminino , Humanos , Radioisótopos do Iodo , Células Matadoras Naturais/metabolismo , Contagem de Linfócitos , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Radioimunoensaio , Apoio Social , Análise de Sobrevida
19.
Arch Gen Psychiatry ; 46(11): 1047-51, 1989 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-2554841

RESUMO

Recent studies suggest that the hypercortisolism and dexamathasone resistance of depression arise, at least in part, at the level of the brain, ie, cortisol-releasing factor (CRF) and/or other corticotropin-secretagogues are hypersecreted. This article suggests a similar cause of the hypercortisolism of social subordinance. Two troops of wild olive baboons, living freely in the Serengeti Ecosystem of East Africa, have been under long-term study. Consistently, in stable dominance hierachies, subordinate males are hypercortisolemic relative to dominant animals. Furthermore, hypercortisolemic males are dexamethasone resistant. There are no rank-related difference in cortisol clearance or adrenal sensitivity to corticotropin, suggesting a pituitary and/or neural locus of the hypercortisolism. Subordinate males were shown to secrete less corticotropin in response to a CRF-challenge than did dominant males. Following the logic used in similar studies with depressives, if subordinate males were hypercortisolemic despite decreased pituitary sensitivity to CRF, then this implies that the hyperactivity of the adrenocortical axis is driven at the level of the brain. Furthermore, subordinate males were hyporesponsive to CRF after administration of metyrapone, which blocks cortisol secretion and disinhibits the pituitary from feedback inhibition. Thus, the pituitary appears to have lost sensitivity to CRF itself in these low-ranking males. These observations are interpreted in light of behavioral data suggesting that these subordinate males are under sustained social stress.


Assuntos
Hiperfunção Adrenocortical/sangue , Sistema Nervoso Central/fisiologia , Hidrocortisona/sangue , Papio/fisiologia , Predomínio Social , Hiperfunção Adrenocortical/fisiopatologia , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/fisiologia , Animais , Comportamento Animal/fisiologia , Hormônio Liberador da Corticotropina/fisiologia , Dexametasona/farmacologia , Masculino
20.
Arch Gen Psychiatry ; 57(10): 925-35, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11015810

RESUMO

An extensive literature stretching back decades has shown that prolonged stress or prolonged exposure to glucocorticoids-the adrenal steroids secreted during stress-can have adverse effects on the rodent hippocampus. More recent findings suggest a similar phenomenon in the human hippocampus associated with many neuropsychiatric disorders. This review examines the evidence for hippocampal atrophy in (1) Cushing syndrome, which is characterized by a pathologic oversecretion of glucocorticoids; (2) episodes of repeated and severe major depression, which is often associated with hypersecretion of glucocorticoids; and (3) posttraumatic stress disorder. Key questions that will be examined include whether the hippocampal atrophy arises from the neuropsychiatric disorder, or precedes and predisposes toward it; whether glucocorticoids really are plausible candidates for contributing to the atrophy; and what cellular mechanisms underlie the overall decreases in hippocampal volume. Explicit memory deficits have been demonstrated in Cushing syndrome, depression, and posttraumatic stress disorder; an extensive literature suggests that hippocampal atrophy of the magnitude found in these disorders can give rise to such cognitive deficits.


Assuntos
Síndrome de Cushing/diagnóstico , Transtorno Depressivo/diagnóstico , Glucocorticoides/fisiologia , Hipocampo/anatomia & histologia , Transtornos de Estresse Pós-Traumáticos/diagnóstico , Transtornos de Estresse Pós-Traumáticos/fisiopatologia , Adulto , Animais , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/fisiopatologia , Síndrome de Cushing/fisiopatologia , Dendritos/fisiologia , Transtorno Depressivo/fisiopatologia , Feminino , Hipocampo/fisiologia , Hipocampo/fisiopatologia , Humanos , Imageamento por Ressonância Magnética/estatística & dados numéricos , Masculino , Transtornos da Memória/diagnóstico , Transtornos da Memória/etiologia , Transtornos da Memória/fisiopatologia , Neurônios/fisiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA