RESUMEN
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.
Asunto(s)
Amígdala del Cerebelo/fisiología , Miedo/fisiología , Hipocampo/fisiología , Neurogénesis/fisiología , Neuronas/fisiología , Animales , Expresión Génica/genética , Masculino , Inhibición Neural/fisiología , Canales de Potasio/genética , Canales de Potasio/metabolismo , Ratas , Ratas Sprague-Dawley , Transgenes/genética , Transgenes/fisiología , Regulación hacia ArribaRESUMEN
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.
Asunto(s)
Arabidopsis/genética , Marcadores Genéticos/genética , Genoma de Planta , Ascomicetos/crecimiento & desarrollo , Mapeo Cromosómico , ADN de Plantas/genética , Genes de Plantas/genética , Predisposición Genética a la Enfermedad , Genotipo , Análisis de Secuencia por Matrices de Oligonucleótidos , Enfermedades de las Plantas/genética , Enfermedades de las Plantas/microbiología , Polimorfismo GenéticoRESUMEN
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.
Asunto(s)
Amígdala del Cerebelo/metabolismo , Ansiedad/patología , Ansiedad/terapia , Corticosterona/sangre , Dendritas/patología , Terapia Genética/métodos , Proteínas Serina-Treonina Quinasas/metabolismo , Amígdala del Cerebelo/patología , Análisis de Varianza , Animales , Ansiedad/etiología , Ansiedad/fisiopatología , Conducta Animal , Modelos Animales de Enfermedad , Vectores Genéticos/fisiología , Quinasas del Centro Germinal , Locomoción/genética , Masculino , Aprendizaje por Laberinto/fisiología , Neuronas/patología , Proteínas Serina-Treonina Quinasas/genética , Ratas , Ratas Wistar , Simplexvirus/genética , Simplexvirus/fisiología , Estrés PsicológicoRESUMEN
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.
Asunto(s)
Isquemia Encefálica/fisiopatología , Glucocorticoides/farmacología , Neuronas/efectos de los fármacos , Adrenalectomía , Animales , Encéfalo/citología , Encéfalo/efectos de los fármacos , Isquemia Encefálica/metabolismo , Corteza Cerebral/efectos de los fármacos , Trastornos Cerebrovasculares/fisiopatología , Cuerpo Estriado/efectos de los fármacos , Paro Cardíaco/fisiopatología , Hipocampo/efectos de los fármacos , Humanos , Masculino , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Hormona Liberadora de Corticotropina/metabolismo , Hipotálamo/metabolismo , Interleucina-1/fisiología , Corteza Suprarrenal/fisiología , Hormona Adrenocorticotrópica/metabolismo , Animales , Línea Celular , Corticosterona/metabolismo , Técnicas Inmunológicas , Masculino , Adenohipófisis/metabolismo , Neoplasias Hipofisarias/metabolismo , Ratas , Ratas EndogámicasRESUMEN
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.
Asunto(s)
Manejo Psicológico , Hipocampo/crecimiento & desarrollo , Envejecimiento , Animales , Animales Recién Nacidos , Dexametasona/metabolismo , Hipocampo/fisiología , Hipocampo/fisiopatología , Aprendizaje , Memoria , Ratas , Receptores de Glucocorticoides/metabolismoRESUMEN
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.
Asunto(s)
Mapeo Cromosómico/métodos , Desoxirribonucleótidos/genética , Técnicas Genéticas , Genoma Humano , Genotipo , Polimorfismo Genético , Algoritmos , Alelos , ADN Complementario , Bases de Datos Factuales , Fosfatos de Dinucleósidos , Expresión Génica , Marcadores Genéticos , Variación Genética , Heterocigoto , Homocigoto , Humanos , Datos de Secuencia Molecular , Hibridación de Ácido Nucleico , Reacción en Cadena de la Polimerasa , Reproducibilidad de los Resultados , Análisis de Secuencia de ADN , Lugares Marcados de SecuenciaRESUMEN
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)
Asunto(s)
Corteza Suprarrenal/fisiología , Hipocampo/fisiología , Hipotálamo/fisiología , Hipófisis/fisiología , Envejecimiento/fisiología , Animales , Retroalimentación , Humanos , Trastornos Mentales/fisiopatologíaRESUMEN
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.
Asunto(s)
Glucocorticoides/fisiología , Estrés Fisiológico/fisiopatología , Animales , Líquidos Corporales/metabolismo , Sistema Cardiovascular/fisiopatología , Endocrinología/tendencias , Humanos , Inflamación/fisiopatología , Sistema Nervioso/fisiopatología , Reproducción , Estrés Fisiológico/inmunología , Estrés Fisiológico/metabolismoRESUMEN
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.
Asunto(s)
Corteza Suprarrenal/metabolismo , Corticosterona/metabolismo , Hipocampo/fisiopatología , Sistema Hipotálamo-Hipofisario/fisiopatología , Trastornos de la Memoria/fisiopatología , Inhibición Neural/fisiología , Sistema Hipófiso-Suprarrenal/fisiopatología , Corteza Suprarrenal/efectos de los fármacos , Animales , Corticosterona/antagonistas & inhibidores , Hipocampo/lesiones , Hipocampo/cirugía , Ácido Kaínico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Memoria/fisiología , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/etiología , Degeneración Nerviosa/inducido químicamente , Degeneración Nerviosa/fisiopatología , Inhibición Neural/efectos de los fármacos , Vías Nerviosas/lesiones , Vías Nerviosas/fisiopatología , Vías Nerviosas/cirugía , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Tiempo de Reacción/fisiologíaRESUMEN
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.
Asunto(s)
Glucocorticoides/antagonistas & inhibidores , Neuronas/fisiología , Receptores de Glucocorticoides/metabolismo , Proteínas Recombinantes de Fusión/farmacología , Estrés Fisiológico/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/genética , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Animales , Western Blotting/métodos , Recuento de Células/métodos , Muerte Celular/efectos de los fármacos , Muerte Celular/genética , Técnicas de Cultivo , Receptor alfa de Estrógeno , Factores de Crecimiento de Fibroblastos/genética , Factores de Crecimiento de Fibroblastos/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Humanos , Proteínas Inmediatas-Precoces , Inmunohistoquímica/métodos , Indoles , Ácido Kaínico/toxicidad , Masculino , Proteínas Asociadas a Microtúbulos/metabolismo , Modelos Moleculares , Neuronas/efectos de los fármacos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Estructura Terciaria de Proteína/fisiología , ARN Mensajero/metabolismo , Ratas , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Glucocorticoides/genética , Receptores de N-Metil-D-Aspartato/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Estrés Fisiológico/genética , Transgenes , Translocación Genética/fisiologíaRESUMEN
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.
Asunto(s)
Adaptación Psicológica/fisiología , Conducta Animal/fisiología , Toxoplasmosis Animal/fisiopatología , Toxoplasmosis Animal/psicología , Análisis de Varianza , Animales , Reacción de Prevención/fisiología , Gatos , Condicionamiento Psicológico , Conducta Exploratoria/fisiología , Miedo , Heces , Masculino , Odorantes , Ratas , Ratas WistarRESUMEN
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.
Asunto(s)
Apoptosis/fisiología , Infarto de la Arteria Cerebral Media/fisiopatología , Simplexvirus/fisiología , Proteínas Virales/metabolismo , Análisis de Varianza , Animales , Apoptosis/genética , Factor Inductor de la Apoptosis/metabolismo , Bromodesoxiuridina/metabolismo , Recuento de Células/métodos , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Indoles , Masculino , Microscopía Confocal/métodos , Ratas , Ratas Sprague-Dawley , Daño por Reperfusión , Serpinas/genética , Serpinas/metabolismo , Proteínas Virales/genética , beta-GalactosidasaRESUMEN
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.
Asunto(s)
Cromosomas/metabolismo , Genes Fúngicos , Secuencias Reguladoras de Ácidos Nucleicos , Replicón , Saccharomyces cerevisiae/genética , Transcripción Genética , ADN de Hongos/genética , Galactosa/farmacología , Regulación de la Expresión Génica/efectos de los fármacos , Regiones Promotoras Genéticas/efectos de los fármacos , Estimulación QuímicaRESUMEN
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.
Asunto(s)
Apoptosis , Degeneración Nerviosa/patología , Neuronas/patología , Neurociencias/normas , Enfermedad Aguda , Animales , Necrosis , Neurociencias/tendenciasRESUMEN
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.
Asunto(s)
Terapia Genética/métodos , Enfermedades Neurodegenerativas/fisiopatología , Enfermedades Neurodegenerativas/terapia , Neuronas/fisiología , Animales , HumanosRESUMEN
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.
Asunto(s)
Cognición/fisiología , Estrés Psicológico/psicología , Animales , Catecolaminas/fisiología , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Glucocorticoides/fisiología , Humanos , Estrés Psicológico/fisiopatologíaRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/metabolismo , Ritmo Circadiano , Hidrocortisona/metabolismo , Saliva/metabolismo , Adulto , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/psicología , Neoplasias de la Mama/terapia , Femenino , Humanos , Radioisótopos de Yodo , Células Asesinas Naturales/metabolismo , Recuento de Linfocitos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Radioinmunoensayo , Apoyo Social , Análisis de SupervivenciaRESUMEN
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.
Asunto(s)
Hiperfunción de las Glándulas Suprarrenales/sangre , Sistema Nervioso Central/fisiología , Hidrocortisona/sangre , Papio/fisiología , Predominio Social , Hiperfunción de las Glándulas Suprarrenales/fisiopatología , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/fisiología , Animales , Conducta Animal/fisiología , Hormona Liberadora de Corticotropina/fisiología , Dexametasona/farmacología , MasculinoRESUMEN
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.