Abstract:

Human and animal studies have shown that damage to the hippocampus results in disruption of the ability to form new memories while older memories remain intact. Systems consolidation theory suggests this is due to the time-limited role the hippocampus plays in long term memory storage and retrieval. After a period of time in which the memory relies upon the hippocampus it is then "transferred" to the cerebral cortex for long term storage. It is unknown whether the molecular mechanisms underlying initial encoding and retrieval differ between newly formed and older memories. To address this question we used western blot analysis to measure indicators of memory formation (phosphorylated P70s6K and Zif268) as well as the phosphatases PP1?1 and calcineurin after contextual fear conditioning. These proteins were measured after retrieval 1, 10 or 36 days after training in either the training (Context A) or novel context (Context B). As time between training and testing increased animals ability to discriminate between the contexts degraded. Protein expression was measured in brain structures proposed to be important for fear memory retrieval at recent (hippocampus) and remote (anterior cingulate) time points. Consistent with system consolidation theory phosphorylated P70s6K was increased in the hippocampus following retrieval of recent, not remote, memory. In contrast, phosphorylated P70s6K was increased in the anterior cingulate after remote retrieval regardless of the context to which they were exposed. Phosphatase expression was generally increased across conditions over time. Exposure to the training context prior to training facilitated remote memory for context A. Pre exposure to Context A increased expression of phosphorylated P70s6K in the hippocampus and decreased it in the anterior cingulate cortex. Phosphatase expression was decreased across brain structures in pre exposed rats. Infusion of the calcineurin inhibitor FK506 enhanced memory for remote context discrimination. These data show that under normal conditions the mTOR pathway is activated in a way predicted by systems consolidation theory. However, facilitation of a memory with pre-exposure or blockade of calcineurin affects the pattern of protein expression and facilitates memory at remote time points.