RESUMEN
New memories initially persist in a labile state and require protein synthesis-dependent processes of consolidation for long-term manifestation. Using differential conditioning to linearly frequency-modulated tones (FMs) we have recently shown that post-training injections of protein synthesis inhibitors into the auditory cortex of Mongolian gerbils interfere with long-term memory for a number of days. Here, we have used rapamycin as a pharmacological tool to elucidate signalling pathways that control the synthesis of proteins required for persistent memory storage. In mammalian cells, inhibition of target of rapamycin (TOR)-mediated pathways was shown to block the translation of distinct classes of mRNAs. Bilateral infusions of rapamycin into the gerbil auditory cortex shortly after FM discrimination training did not impair the maintenance of the newly acquired memory trace for 24 h, but caused profound retention deficits at 48 h after injection. Control experiments showed that the amnesic action is rapamycin-dependent, confined to the context of memory formation, and suppressed by the antagonist FK506. These data indicate that, in the mammalian brain, activation of rapamycin-sensitive signalling pathways contributes to long-term consolidation of a cerebral cortex-dependent form of memory. Moreover, the finding that rapamycin-induced amnesia parallels only late effects of conventional protein synthesis inhibitors on FM discrimination memory implies that at least two different protein synthesis-dependent processes control memory formation. Both are activated during or shortly after learning. Whereas one process is required for the initial maintenance of memory for about one day the second one is involved in the regulation of its long-lasting persistence in conditioning to FMs.
Asunto(s)
Corteza Auditiva/fisiología , Aprendizaje Discriminativo/fisiología , Memoria/fisiología , Inhibidores de la Síntesis de la Proteína/farmacología , Transducción de Señal/fisiología , Sirolimus/farmacología , Estimulación Acústica , Animales , Corteza Auditiva/efectos de los fármacos , Condicionamiento Clásico/efectos de los fármacos , Condicionamiento Clásico/fisiología , Aprendizaje Discriminativo/efectos de los fármacos , Gerbillinae , Inmunosupresores/farmacología , Inyecciones Intraventriculares , Masculino , Inhibidores de la Síntesis de la Proteína/administración & dosificación , ARN Mensajero/análisis , Transducción de Señal/efectos de los fármacos , Sirolimus/administración & dosificación , Tacrolimus/farmacología , Factores de Tiempo , Transcripción GenéticaRESUMEN
Differential conditioning of Mongolian gerbils to linearly frequency-modulated tones (FM) has recently received experimental attention. In the study of the role of cerebral protein synthesis for FM discrimination memory, gerbils received post-training bilateral injections of anisomycin into the auditory cortex under light halothane anesthesia. Compared with saline-treated controls, anisomycin-treated gerbils showed a discrimination decrement during the subsequent three days of training. They markedly improved their performance within training sessions, but started each session at low levels. When repeatedly trained gerbils received post-session injections of anisomycin, discrimination performance during subsequent sessions was similar to the pre-injection performance, indicating that retention, retrieval, reconsolidation, and expression of the established reaction were not affected. However, the improvement of a partially established discrimination reaction was impaired after this treatment. Intracortical injections of emetine confirmed this finding. Neither drug affected FM discrimination learning when given several days before the initial training. Our results suggest that protein-synthesis inhibitors applied to the auditory cortex of gerbils during the post-acquisition phase interfered with learning and memory-related aspects of FM processing. The resulting deficit was evident for a number of post-injection training days. This effect was probably due to impaired consolidation, i.e., processes required for long-term stabilization or retrieval of the memory trace while leaving short-term memory intact.