Parsing storage from retrieval in experimentally induced amnesia.

By 1970, a new framework had begun to emerge with which to understand both memory storage and memory loss. During this period, a number of independent laboratories had demonstrated that both experimentally induced and naturally occurring instances of ‘‘memory failure’’ could be reversed by exposing amnestic subjects to isolated aspects of the training conditions upon which the forgotten memory had been based (Campbell and Jaynes 1966; Lewis et al. 1968; Miller and Springer 1972). While these data suggested a nominally novel interpretation of memory ‘‘loss’’ (better described as a ‘‘lapse’’ in these cases), they were, in some respect, a reassertion of what had long been known: Seemingly forgotten memories are often recovered. Colloquially, what is forgotten is not necessarily gone. To experience this effect outside of the laboratory, one need only look up a long ‘‘forgotten’’ phone number. The phone number will be instantly recognizable and easily relearned, indicative of the intact storage of a memory that seems, superficially, to have been ‘‘lost. ’’ Empirical observations from the 1960s led many to conclude that experimentally induced amnesia, as well as naturally occurring memory loss, might reflect instances of retrieval rather than storage failure (Lewis 1969; Spear 1978). Despite the compelling nature of the experimental results and the fundamental significance of the theory that they encouraged, available data have left unresolved this long-standing controversy, and this conundrum may have limited the acceptance of ‘‘retrieval theory’’ by the larger field of memory researchers. In their recent paper, Hardt et al. (2009) correctly identify this enduring stalemate, arguing that prevailing methodologies have left unanswered the most basic of questions, i.e., does experimental amnesia reflect a memory loss or a retrieval failure? As Hardt et al. note, if an instance of memory failure seems immune to recovery, it cannot be said with certainty whether the memory is actually absent or simply that the retrieval blockade is too strong to be overcome with the applied technique (e.g., a specific ‘‘retrieval cue’’). On the other hand, the recovery of a seemingly lost memory could simply reflect an intact, but subthreshold (or degraded), memory being nudged across some previously unreached threshold for activation. Hardt et al. argue that a true test of the opposing views would require a test in which retrieval and storage interpretations of memory failure make opposite predictions regarding a tangible result (i.e., a result that is not dependent on the observation of a null effect). It is that approach that Hardt et al. (2009) take in their recent paper in Learning & Memory. Hart et al.’s approach to this problem is a welcome point of departure from prior efforts, and brings forth a strategy and techniques that were not available when this vein of research was originally struck. It has been previously observed that contextual fear conditioning (in which a context, or place, comes to evoke fear owing to its association with foot shock) is dependent on plasticity within the dorsal hippocampus, and that this plasticity requires the participation of N-methyl-D-aspartate (NMDA) receptors. However, it has also been established that this requirement for NMDA receptors subsides after the first training trial, such that NMDA receptor antagonists (such as 2-amino-5phosphonopentanoic acid; AP5) block learning on the first conditioning event, but not on subsequent exposures to the context paired with shock (Sanders and Fanselow 2003). Hardt et al. exploit this observation for the present purpose. They argue that if inducing experimental amnesia (through the post-training administration of the protein synthesis inhibitor anisomycin; ANI) impairs memory storage after the first training event, then no residual memory will persist into the second training event, and consequently an NMDA receptor antagonist (e.g., AP5) should effectively block learning on the second event, as though prior learning had never occurred. In contrast, if ANI disrupts retrieval of the memory effectively stored after the first training event, then the memory of that event will remain intact into the second training event, and therefore AP5 should be ineffective in blocking learning during the second event; that is, learning in the presence of AP5 during the second training would suggest that a memory of the first training event had survived the amnesic effects of ANI. When these predictions were tested, Hardt et al. find that AP5 impairs learning of the second training event despite ANI having been infused into the dorsal hippocampus after the first training event. This led them to conclude that ANI-induced experimental amnesia impairs memory via its impact on the storage, not retrieval, of the previously coded memory. Despite the virtues of their approach, the results of Hardt et al. are not immune from alternative interpretations, and in fact, introduce a new set of complications akin to those that have plagued prior efforts to parse storage failures from retrieval failures in experimental amnesia. First is the issue raised by the assumption that contextual fear memories reside exclusively in the dorsal hippocampus (dHPC). While it is clear that the dHPC plays a critical role in the mediation of contextually mediated learning, available data suggest that the HPC is not the sole storage site of nominally context-based memories (Good and Honey 1991; Good et al. 2007). Of course it is also possible that learned fear responses may depend intimately on the integrity of the HPC, while actual storage (or some component of the stored memory) may reside in other brain structures (Berger et al. 1976, 1980; Talk et al. 2002). It is indisputable that exactly these types of considerations have complicated any definitive statement regarding the function of the HPC in memory storage. If one accepts even the remote possibility that contextual fear memories reside (even to a functionally trivial degree) in some brain areas in addition to the dHPC, then the dHPC-limited ANI injections administered by Hardt et al. will have left those residual memory traces intact. Were such the case, then those residual memories would have been available to the animal on Hardt et al.’s second training event, and Corresponding author. E-mail matzel@rci.rutgers. edu; fax (732) 445-2263. Article is online at http://www.learnmem. org/cgi/doi/10.1101/lm.1478709.