RESUMEN
OBJECTIVE: The goal of this study was to validate the French version of the Quality of Life in Bipolar Disorder (QoL.BD) scale, a condition-specific measure for bipolar disorder (BD). METHOD: The QoL.BD scale was translated into French in accordance with the recommendations for transcultural adaptation. It was administered to 125 participants with BD living in Quebec, Canada. Construct validity was evaluated through correlations with other measures of self-reported quality of life (QoL), functioning, and symptoms. Factorial structure was examined through an exploratory factor analysis. RESULTS: Internal reliability and test-retest reliability standards were met. Correlations in expected directions with other QoL, functioning, and depressive symptom scales supported convergent validity. The item loadings structure of the French QoL.BD largely replicated the original English version, with some modifications. CONCLUSION: The French version of the QoL.BD (full and brief) is comparable in its psychometric properties to the English version. It is a valid and sound measure for the evaluation of the QoL of French-speaking patients with BD.
Asunto(s)
Trastorno Bipolar , Calidad de Vida , Comparación Transcultural , Humanos , Psicometría , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , TraduccionesRESUMEN
Polymorphisms in circadian genes such as CLOCK convey risk for bipolar disorder. While studies have begun to elucidate the molecular mechanism whereby disruption of Clock alters cellular function within mesolimbic brain regions, little remains known about how these changes alter gross neural circuit function and generate mania-like behaviors in Clock-Δ19 mice. Here we show that the phasic entrainment of nucleus accumbens (NAC) low-gamma (30-55 Hz) oscillations to delta (1-4 Hz) oscillations is negatively correlated with the extent to which wild-type (WT) mice explore a novel environment. Clock-Δ19 mice, which display hyperactivity in the novel environment, exhibit profound deficits in low-gamma and NAC single-neuron phase coupling. We also demonstrate that NAC neurons in Clock-Δ19 mice display complex changes in dendritic morphology and reduced GluR1 expression compared to those observed in WT littermates. Chronic lithium treatment ameliorated several of these neurophysiological deficits and suppressed exploratory drive in the mutants. These results demonstrate that disruptions of Clock gene function are sufficient to promote alterations in NAC microcircuits, and raise the hypothesis that dysfunctional NAC phase signaling may contribute to the mania-like behavioral manifestations that result from diminished circadian gene function.
Asunto(s)
Trastorno Bipolar/genética , Proteínas CLOCK/genética , Ritmo Circadiano/fisiología , Modelos Animales de Enfermedad , Litio/uso terapéutico , Núcleo Accumbens/fisiopatología , Animales , Relojes Biológicos/efectos de los fármacos , Relojes Biológicos/fisiología , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/fisiopatología , Ritmo Circadiano/efectos de los fármacos , Litio/farmacología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Red Nerviosa/efectos de los fármacos , Red Nerviosa/fisiología , Núcleo Accumbens/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
In Medicago truncatula nodules, the soil bacterium Sinorhizobium meliloti reduces atmospheric dinitrogen into nitrogenous compounds that the legume uses for its own growth. In nitrogen-fixing nodules, each infected cell contains symbiosomes, which include the rhizobial cell, the symbiosome membrane surrounding it, and the matrix between the bacterium and the symbiosome membrane, termed the symbiosome space. Here, we describe the localization of ENOD8, a nodule-specific esterase. The onset of ENOD8 expression occurs at 4 to 5 days postinoculation, before the genes that support the nitrogen fixation capabilities of the nodule. Expression of an ENOD8 promoter-gusA fusion in nodulated hairy roots of composite transformed M. truncatula plants indicated that ENOD8 is expressed from the proximal end of interzone II to III to the proximal end of the nodules. Confocal immunomicroscopy using an ENOD8-specific antibody showed that the ENOD8 protein was detected in the same zones. ENOD8 protein was localized in the symbiosome membrane or symbiosome space around the bacteroids in the infected nodule cells. Immunoblot analysis of fractionated symbiosomes strongly suggested that ENOD8 protein was found in the symbiosome membrane and symbiosome space, but not in the bacteroid. Determining the localization of ENOD8 protein in the symbiosome is a first step in understanding its role in symbiosome membrane and space during nodule formation and function.
Asunto(s)
Medicago truncatula/genética , Proteínas de Plantas/genética , Nódulos de las Raíces de las Plantas/genética , Transcripción Genética , Regulación de la Expresión Génica de las Plantas , Immunoblotting , Medicago truncatula/metabolismo , Medicago truncatula/microbiología , Fijación del Nitrógeno/genética , Proteínas de Plantas/metabolismo , Raíces de Plantas/genética , Raíces de Plantas/metabolismo , Raíces de Plantas/microbiología , Nódulos de las Raíces de las Plantas/metabolismo , Nódulos de las Raíces de las Plantas/microbiología , Sinorhizobium meliloti/crecimiento & desarrollo , Simbiosis/genéticaRESUMEN
Lithium has been used extensively for mood stabilization, and it is particularly efficacious in the treatment of bipolar mania. Like other drugs used in the treatment of psychiatric diseases, it has little effect on the mood of healthy individuals. Our previous studies found that mice with a mutation in the Clock gene (ClockΔ19) have a complete behavioral profile that is very similar to human mania, which can be reversed with chronic lithium treatment. However, the cellular and physiological effects that underlie its targeted therapeutic efficacy remain unknown. Here we find that ClockΔ19 mice have an increase in dopaminergic activity in the ventral tegmental area (VTA), and that lithium treatment selectively reduces the firing rate in the mutant mice with no effect on activity in wild-type mice. Furthermore, lithium treatment reduces nucleus accumbens (NAc) dopamine levels selectively in the mutant mice. The increased dopaminergic activity in the Clock mutants is associated with cell volume changes in dopamine neurons, which are also rescued by lithium treatment. To determine the role of dopaminergic activity and morphological changes in dopamine neurons in manic-like behavior, we manipulated the excitability of these neurons by overexpressing an inwardly rectifying potassium channel subunit (Kir2.1) selectively in the VTA of ClockΔ19 mice and wild-type mice using viral-mediated gene transfer. Introduction of this channel mimics the effects of lithium treatment on the firing rate of dopamine neurons in ClockΔ19 mice and leads to a similar change in dopamine cell volume. Furthermore, reduction of dopaminergic firing rates in ClockΔ19 animals results in a normalization of locomotor- and anxiety-related behavior that is very similar to lithium treatment; however, it is not sufficient to reverse depression-related behavior. These results suggest that abnormalities in dopamine cell firing and associated morphology underlie alterations in anxiety-related behavior in bipolar mania, and that the therapeutic effects of lithium come from a reversal of these abnormal phenotypes.
Asunto(s)
Potenciales de Acción/genética , Trastorno Bipolar/genética , Trastorno Bipolar/patología , Proteínas CLOCK/genética , Dopamina/metabolismo , Mutación/genética , Neuronas/fisiología , Área Tegmental Ventral/patología , Potenciales de Acción/efectos de los fármacos , Análisis de Varianza , Animales , Ansiedad/genética , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/fisiopatología , Recuento de Células , Cromatografía Líquida de Alta Presión , Adaptación a la Oscuridad/efectos de los fármacos , Adaptación a la Oscuridad/genética , Depresión/genética , Modelos Animales de Enfermedad , Proteínas Fluorescentes Verdes/genética , Desamparo Adquirido , Histonas/metabolismo , Técnicas In Vitro , Cloruro de Litio/uso terapéutico , Locomoción/efectos de los fármacos , Locomoción/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Ratones Noqueados , Neuronas/efectos de los fármacos , Técnicas de Placa-Clamp , Natación/psicología , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
BACKGROUND: Circadian rhythm abnormalities are strongly associated with bipolar disorder; however the role of circadian genes in mood regulation is unclear. Previously, we reported that mice with a mutation in the Clock gene (ClockDelta19) display a behavioral profile that is strikingly similar to bipolar patients in the manic state. METHODS: Here, we used RNA interference and viral-mediated gene transfer to knock down Clock expression specifically in the ventral tegmental area (VTA) of mice. We then performed a variety of behavioral, molecular, and physiological measures. RESULTS: We found that knockdown of Clock, specifically in the VTA, results in hyperactivity and a reduction in anxiety-related behavior, which is similar to the phenotype of the ClockDelta19 mice. However, VTA-specific knockdown also results in a substantial increase in depression-like behavior, creating an overall mixed manic state. Surprisingly, VTA knockdown of Clock also altered circadian period and amplitude, suggesting a role for Clock in the VTA in the regulation of circadian rhythms. Furthermore, VTA dopaminergic neurons expressing the Clock short hairpin RNA have increased activity compared with control neurons, and this knockdown alters the expression of multiple ion channels and dopamine-related genes in the VTA that could be responsible for the physiological and behavioral changes in these mice. CONCLUSIONS: Taken together, these results suggest an important role for Clock in the VTA in the regulation of dopaminergic activity, manic and depressive-like behavior, and circadian rhythms.