Here, we provide a direct link between retrieval-mediated encoding processes and flexible memory expression in the human brain. Using multivoxel pattern analysis, we demonstrate that prior experience is reactivated during encoding of related events, and that such online reactivation of memories is predictive of individuals’ ability to infer novel relationships between two discrete, overlapping episodes. We further show that reactivation within content-sensitive higher-order visual areas is related to anterior MTL cortex activation, suggesting that responses in this region may influence the extent and specificity of retrieved memories. Extensive controversy exists as to whether encoding activation relating to

subsequent inference reflects ZD6474 order memory integration during encoding or strengthening of individual learn more directly learned associations, leading to improved “on-the-fly” inference at retrieval (for a review, see Zeithamova et al., 2012). Here, decreasing hippocampal and increasing VMPFC engagement across repetitions of overlapping events were associated with superior inference even when controlling for memory of premise associations, providing a strong evidence for online integration of related memories as they are encoded. Furthermore, we observed increased connectivity between hippocampus and VMPFC across

interleaved presentations of overlapping events. These findings illustrate how a functionally coupled hippocampal-VMPFC circuit supports binding of reactivated memories with current experience, forming integrated memories that relate overlapping experiences. These relational memory networks enable the predictive application of memory by grouping related elements from multiple experiences in support of future inferential judgments. The present study organically builds upon and significantly extends prior studies examining the neural mechanisms supporting retrieval-mediated

learning. Prior rodent RANTES research has shown that the existence of a well-learned spatial schema speeds acquisition of new object-place associations (Tse et al., 2007 and Tse et al., 2011). Another recent report demonstrated that blocking hippocampal plasticity during contextual fear conditioning prevents the transfer of a newly acquired fear response to a previously experienced, overlapping spatial context (Iordanova et al., 2011). The presumption in each of these studies is that existing memories are reactivated during new learning and updated with new information, resulting in facilitated encoding and generalization. However, without an empirical measure of memory reactivation, such a presumption is only speculative. The methods employed in the current study enabled us to directly observe memory reactivation during encoding of related events, providing a key index of a process critical to retrieval-mediated learning. Furthermore, in contrast to prior studies, our findings emphasize the beneficial function of retrieval-mediated learning.