Activation of c-Fos Expression in the Retrosplenial Cortex but Not the Hippocampus Accompanies Formation of an Association between the Context and the Unconditioned Stimulus and Its Subsequent Retrieval in Mice

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Identification of the neural mechanisms of associative memory is one of the fundamental tasks in neuroscience. We report here use of a model of associative learning in mice in which formation of a memory of a neutral context and subsequent association of transient presentation of this context with an unconditioned electrocutaneous stimulus (footshock) were separated in time. This provided for studies of relationship between different stages in the formation of this memory and protein synthesis and allowed us to study genomic activation of various brain structures during association and the memory of the context of the footshock. These studies showed that blockade of protein synthesis both during exploration of the novel context and during application of immediate footshock in an already familiar context impaired conditioned reflex freezing to this context. The association of the memory trace of the context of the footshock retrieved in response to a reminder was accompanied by activation of the expression of transcription factor c-Fos in the retrosplenial cortex. The retrosplenial cortex was also specifically activated by subsequent retrieval of the associative memory of the context. This activation was not seen in mice with impaired memory. No such differences were seen in the hippocampus, where activation of c-Fos expression occurred in relation to exploration of the novel context and not its association with the footshock. These results provide evidence that the retrosplenial cortex may be part of the neocortex supporting formation of associations between context and aversive unconditioned stimuli.