RESUMO
Circadian rhythms and the genes that make up the molecular clock have long been implicated in bipolar disorder. Genetic evidence in bipolar patients suggests that the central transcriptional activator of molecular rhythms, CLOCK, may be particularly important. However, the exact role of this gene in the development of this disorder remains unclear. Here we show that mice carrying a mutation in the Clock gene display an overall behavioral profile that is strikingly similar to human mania, including hyperactivity, decreased sleep, lowered depression-like behavior, lower anxiety, and an increase in the reward value for cocaine, sucrose, and medial forebrain bundle stimulation. Chronic administration of the mood stabilizer lithium returns many of these behavioral responses to wild-type levels. In addition, the Clock mutant mice have an increase in dopaminergic activity in the ventral tegmental area, and their behavioral abnormalities are rescued by expressing a functional CLOCK protein via viral-mediated gene transfer specifically in the ventral tegmental area. These findings establish the Clock mutant mice as a previously unrecognized model of human mania and reveal an important role for CLOCK in the dopaminergic system in regulating behavior and mood.
Assuntos
Transtorno Bipolar/genética , Ritmo Circadiano/genética , Transativadores/genética , Análise de Variância , Animais , Sintomas Comportamentais/genética , Transtorno Bipolar/tratamento farmacológico , Transtorno Bipolar/patologia , Transtorno Bipolar/terapia , Proteínas CLOCK , Estimulação Elétrica , Regulação da Expressão Gênica/genética , Técnicas de Transferência de Genes , Terapia Genética/métodos , Quinase 3 da Glicogênio Sintase/genética , Glicogênio Sintase Quinase 3 beta , Imuno-Histoquímica , Lítio/farmacologia , Lítio/uso terapêutico , Compostos de Lítio/farmacologia , Compostos de Lítio/uso terapêutico , Locomoção/efeitos dos fármacos , Camundongos , Mutagênese , Mutação/genética , Transativadores/uso terapêutico , Área Tegmentar Ventral/efeitos dos fármacosRESUMO
BACKGROUND: Indirect evidence suggests that loss of brain-derived neurotrophic factor (BDNF) from forebrain regions contributes to an individual's vulnerability for depression, whereas upregulation of BDNF in these regions is suggested to mediate the therapeutic effect of antidepressants. METHODS: We have tested this hypothesis by generating two independent lines of conditional BDNF knockout mice in which the BDNF gene is deleted selectively in forebrain. RESULTS: We show that male conditional knockouts exhibit hyperactivity but normal depression-related behaviors. In contrast, female conditional knockouts display normal locomotor activity but a striking increase in depression-like behavior. We also demonstrate that loss of BDNF in both male and female mice attenuates the actions of the antidepressant desipramine in the forced swim test. CONCLUSIONS: These gender differences in depression-related behaviors in BDNF conditional knockout mice provide direct evidence for a role of BDNF in depression. The results also support the view that forebrain BDNF may be essential in mediating antidepressant efficacy.
