Recent accumulating evidence in animals and humans has shown that memory strengthening occurs, at least partially, during sleep and relies on the covert reactivation of individual memory episodes. However, it remains to be determined whether the hippocampus critically promotes memory consolidation via the reactivation of individual memories during sleep. To investigate the hippocampal-dependent nature of this phenomenon in humans, we selected two groups of chronic temporal lobe epileptic (TLE) patients with selective unilateral (TLE+UHS) or bilateral (TLE+BHS) hippocampal sclerosis and a group of matched healthy controls, and we requested them to learn the association of sounds cueing the appearance of words. On the basis of other similar behavioral paradigms in healthy populations, sounds that cued only half of the learned memories were presented again during the slow-wave sleep stage (SWS) at night, thus promoting memory reactivation of a select set of encoded episodes. A memory test administered on the subsequent day showed that the strengthening of reactivated memories was observed only in the control subjects and TLE+UHS patients. Importantly, the amount of memory strengthening was predicted by the volume of spared hippocampus. Thus, the greater the structural integrity of the hippocampus, the higher the degree of memory benefit driven by memory reactivation. Finally, sleep-specific neurophysiological responses, such as spindles and slow waves, differed between the sample groups, and the spindle density during SWS predicted the degree of memory benefit observed on day 2. Taken together, these findings demonstrate that the hippocampus plays a crucial role in the consolidation of memories via covert reactivation during sleep.

Research in reversal learning has mainly focused on the functional role of dopamine and striatal structures in driving behavior on the basis of classic reinforcement learning mechanisms. However, recent evidence indicates that, beyond classic reinforcement learning adaptations, individuals may also learn the inherent task structure and anticipate the occurrence of reversals. A candidate structure to support such task representation is the hippocampus, which might create a flexible representation of the environment that can be adaptively applied to goaldirected behavior. To investigate the functional role of the hippocampus in the implementation of anticipatory strategies in reversal learning, we first studied, in 20 healthy individuals (11 women), whether the gray matter anatomy and volume of the hippocampus were related to anticipatory strategies in a reversal learning task. Second, we tested 20 refractory temporal lobe epileptic patients (11 women) with unilateral hippocampal sclerosis, who served as a hippocampal lesion model. Our results indicate that healthy participants were able to learn the task structure and useittoguidetheirbehaviorandoptimizetheirperformance.Participants'abilitytoadoptanticipatorystrategiescorrelatedwiththegraymatter volume of the hippocampus. In contrast, hippocampal patients were unable to grasp the higher-order structure of the task with the same success than controls. Present results indicate that the hippocampus is necessary to respond in an appropriately flexible manner to high-order environments, and disruptions in this structure can render behavior habitual and inflexible.

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