RESUMEN
Changes in transcription levels of brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate (cAMP) response element binding (CREB), Synapsin I, Ca(2+)/calmodulin-dependent protein kinase II (CamKII), activity-regulated cytoskeleton-associated protein (Arc), c-jun and c-fos have been associated to several learning paradigms in different brain areas. In this study, we measured mRNA expression in the hippocampus by real time (RT)-PCR mRNA levels of BDNF, CREB, Synapsin I, CamKII, Arc, c-jun and c-fos, during learning and operant conditioning task. Experimental groups were as follows: control (C, the animals never left the bioterium), when the animals reached 50-65% of the expected response (Incompletely Trained, IT), when animals reached 100% of the expected response with a latency time lower than 5 s (Trained, Tr), Box Control of Incompletely Trained (BCIT), animals spent the same time as the IT in the operant conditioning box and Box Control of Trained (BCTr) animals spent the same time as the Tr in the operant conditioning box. All rats were killed at the same time by cervical dislocation 15 min after training and hippocampi were removed and processed. We found increments of mRNA levels of most genes (BDNF, CREB, Synapsin I, Arc, c-jun and c-fos) in IT and Tr groups compared to their box controls, but increments in Tr were smaller compared with IT. These results describe a differential gene expression in the rat hippocampus when the animals are learning and when animals have already learned. Taking together the results presented herein with the known functions of these genes, we propose a link between changes in gene expression in the hippocampus and different degrees of cellular activation and plasticity during learning of an operant conditioning task.
Asunto(s)
Condicionamiento Operante/fisiología , Hipocampo/fisiología , Aprendizaje/fisiología , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/genética , Proteína Quinasa Tipo 2 Dependiente de Calcio Calmodulina/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/genética , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismo , Expresión Génica , Masculino , Proteínas del Tejido Nervioso/genética , Proteínas del Tejido Nervioso/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-jun/genética , Proteínas Proto-Oncogénicas c-jun/metabolismo , ARN Mensajero/metabolismo , Ratas , Ratas Long-Evans , Sinapsinas/genética , Sinapsinas/metabolismo , Factores de TiempoRESUMEN
Long-term exposure to stressful situations can affect the immune system. The T-cell response is an important component of anti-tumoral immunity. Hence, impairment of the immune function induced by a chronic stressor has been postulated to alter the immunosurveillance of tumors, thus leading to a worse neoplastic prognosis. Here, we show that chronic restraint stress affects T-cell mediated immunity in mice. This was evidenced by a decrease of mitogen-induced T-cell proliferation, a reduction in CD4(+)T lymphocyte number and a decrease of tumor necrosis factor-alpha (TNF-alpha) and Interferon-gamma (IFN-gamma) production in stressed mice. Additionally, mice subjected to chronic restraint stress displayed an enhancement of tumor growth in a syngeneic lymphoma model, i.e. an increase of tumor proliferation and a reduction of animal survival. Finally, stressed mice had a reduced specific cytotoxic response against these tumor cells. These results suggest that chronic exposure to stress promotes cancer establishment and subsequent progression, probably by depressing T-cell mediated immunity. The T-cell immunity impairment as well as the tumor progression enhancement emphasize the importance of the therapeutic management of stress to improve the prognosis of cancer patients.