Long-term expression of human contextual fear and extinction memories involves amygdala, hippocampus and ventromedial prefrontal cortex: a reinstatement study in two independent samples Short title: fear/extinction recall & reinstatement

Human context conditioning studies have focused on acquisition and extinction. Subsequent long-term changes in fear behaviors not only depend on associative learning processes during those phases but also on memory consolidation processes and the later ability to retrieve and express fear and extinction memories. Clinical theories explain relapse after successful exposure-based treatment with return of fear memories and remission with stable extinction memory expression. We probed contextual fear and extinction memories one week (day8) after conditioning (day1) and subsequent extinction (day2) by presenting conditioned contexts before (Test1) and after (Test2) a reinstatement manipulation. We find consistent activation patterns in two independent samples: activation of a subgenual part of the ventromedial prefrontal cortex (vmPFC) before reinstatement (Test1) and (albeit with different temporal profiles between samples) of the amygdala after reinstatement (Test2) as well as up-regulation of anterior hippocampus activity after reinstatement (Test2>Test1). These areas have earlier been implicated in the expression of cued extinction and fear memories. The present results suggest a general role for these structures in defining the balance between fear and extinction memories, independent of the conditioning-mode. The results are discussed in the light of hypotheses implicating the anterior hippocampus in the processing of situational ambiguity.