It has been proposed that a core network of brain regions, including the hippocampus, supports both past remembering and future imagining. We investigated the importance of the hippocampus for these functions. Five patients with bilateral hippocampal damage and one patient with large medial temporal lobe lesions were tested for their ability to recount autobiographical episodes from the remote past, the recent past, and to imagine plausible episodes in the near future. The patients with hippocampal damage had intact remote autobiographical memory, modestly impaired recent memory, and an intact ability to imagine the future. The patient with large medial temporal lobe lesions had intact remote memory, markedly impaired recent memory, and also had an intact ability to imagine the future. The findings suggest that the capacity for imagining the future, like the capacity for remembering the remote past, is independent of the hippocampus.episodic memory | semantic memory | medial temporal lobe | remote memory | amnesia B ilateral damage to medial temporal lobe structures impairs the formation of new memories and also impairs recall of facts, events, and autobiographical experiences that were acquired during the years before the damage occurred (1, 2). This finding suggests that common mechanisms may underlie the ability to form new memories and the ability to recollect recent memories. There has also been interest in the possible link between remembering past experiences and imagining plausible episodes in the future (3). It was noted, for example, that the memory-impaired patient KC was impaired at generating autobiographical details about his past and also could not imagine future autobiographical episodes (4, 5). A link between past remembering and future imagining has received additional support from other patient studies. Thus, the densely amnesic patient DB had difficulty imagining future episodes (6). Similarly, four of five memory-impaired patients with lesions involving the hippocampus were reported to have difficulty constructing future autobiographical scenarios (7). Moreover, elderly individuals who provided fewer specific details about the recent past also provided fewer specific details about the future (8). Last, patients with mild Alzheimer's disease were impaired at providing autobiographical details about both past and future events (9).Consistent with these observations, neuroimaging studies have described substantial overlap between the brain regions activated when volunteers retrieve past memories and when they imagine future experiences (e.g., refs. 10-14). Schacter et al. (14) suggested that a core network of brain regions supports past remembering and future imagining. The key components of this network are proposed to be the medial prefrontal cortex, posterior regions in medial and lateral parietal cortex, lateral temporal cortex, and the medial temporal lobe including hippocampus (14,15).Within this network, the importance of the hippocampus and related medial temporal lobe structures for f...

Working memory has traditionally been viewed as independent of the hippocampus and related medial temporal lobe structures. Yet memory-impaired patients with medial temporal lobe damage are sometimes impaired at remembering relational information (e.g., an object and its location) across delays as short as a few seconds. This observation has raised the possibility that medial temporal lobe structures are sometimes critical for maintaining relational information, regardless of whether the task depends on working or long-term memory. An alternativepossibilityisthatthesestructuresarecriticalformaintainingrelationalinformationonlywhenthetaskexceedsworkingmemorycapacity anddependsinsteadonlong-termmemory.Totesttheseideas,wedrewonamethodusedpreviouslyinaclassicstudyofdigitspaninpatientHM that distinguished immediate memory from long-term memory. In two experiments, we assessed the ability of four patients with medial temporal lobe lesions to maintain varying numbers of object-location associations across a 1 s retention interval. In both experiments, the patients exhibited a similar pattern of performance. They performed similarly to controls when only a small number of object-location associations needed to be maintained, and they exhibited an abrupt discontinuity in performance with larger set sizes. This pattern of results supports the idea that maintenance of relational information in working memory is intact after damage to the hippocampus and related medial temporal lobe structures and that damage to these structures impairs performance only when the task depends on long-term memory.

Patients with hippocampal damage are sometimes impaired at remembering information across delays as short as a few seconds. How are these impairments to be understood? One possibility is that retention of some kinds of information is critically dependent on the hippocampus, regardless of the retention interval and regardless of whether the task depends on working memory or long-term memory. Alternatively, retention may be dependent on the hippocampus only when the task involves a memory load large enough to exceed working memory capacity. To explore these possibilities, we assessed the performance of patients with hippocampal lesions on two tasks requiring retention of the same objectin-scene information across a brief delay. The tasks placed different demands on memory. In one task, which used a continuous recognition format, participants needed to try to hold up to nine scenes in mind, even when no scene intervened between the study scene and the corresponding test scene. Patients were impaired in this condition. In a second task, using a conventional study-test format, participants needed to hold in mind only one scene at a time for either 3 or 14 sec. With this procedure, patients performed as well as controls after a 3-sec delay but were impaired after a 14-sec delay. We suggest that retention of object-in-scene information is dependent on the hippocampus only when working memory is insufficient to support performance (because memory load is high or the retention interval is long). In these circumstances performance depends, at least in part, on long-term memory.[Supplemental material is available for this article.]Working memory refers to the ability to hold a limited amount of information actively in mind, usually across a brief time interval (Baddeley 2003). Early studies of memory-impaired patients with medial temporal lobe (MTL) damage, including the noted patient H.M., found this ability to be spared despite their severe impairment in long-term memory (Drachmann and Arbit 1966;Baddeley and Warrington 1970;Milner 1972;Cave and Squire 1992;Squire 2009). The principle that emerged from these investigations was that working memory (sometimes termed shortterm memory) is independent of the hippocampus and adjacent MTL structures. It is therefore notable that a number of recent studies have reported that patients with MTL damage can be impaired at remembering information across quite brief time intervals (Hannula et al. 2006;Nichols et al. 2006; Olson et al. 2006a,b;Hartley et al. 2007;Kan et al. 2007;Piekema et al. 2007;Bird and Burgess 2008;Ezzyat and Olson 2008;Finke et al. 2008). In addition, functional magnetic resonance imaging (fMRI) studies have reported MTL activation during short-delay recognition memory tasks (Ranganath and D'Esposito 2001;Schon et al. 2004;Nichols et al. 2006;Piekema et al. 2006Piekema et al. , 2010Axmacher et al. 2007;Hannula and Ranganath 2008;Toepper et al. 2010). These observations have raised the possibility that working memory may sometimes depend on the MTL.While the emer...

Age-related learning deficits are often attributed to deterioration of hippocampal function. Conversely, a well studied index of hippocampal activity, the rhythm, is known to enhance hippocampal plasticity and accelerate learning rate in young subjects, suggesting that manipulations of activity might be used as a means to counteract impairments related to the aging process. Here, young and older rabbits were given eyeblink conditioning trials either when exhibiting hippocampal (؉) or regardless of hippocampal activity (yoked control). Although, as expected, older-yoked control animals showed a learning deficit, the older ؉ group learned as fast as young controls, demonstrating that aging deficits, at least in eyeblink classical conditioning, can be overcome by giving trials during episodes of hippocampal activity. The use of several learning criteria showed that the benefits of hippocampal occur in multiple phases of learning that may depend on different cognitive or motor processes. Whereas there was a benefit of -triggered training in both age groups during the early phase of acquisition, the enhancement persisted in older animals, peaking during later performance. These findings have implications for theories of age-related memory deficits and may contribute to the development of beneficial treatments.aging ͉ eyeblink conditioning ͉ memory ͉ Alzheimer's disease C linical applications derived from basic neuroscience are a crucial source of ideas and methods to address disorders of learning and memory, including amelioration of the growing economic and personal impact of age-related learning deficits. One promising line of inquiry includes recent observations of oscillatory neurobiological potentials that have earned them increased study as correlates, perhaps mechanisms, of cognitive processes including perception and learning (1-6). Much current work is devoted to theoretical and empirical studies of these phenomena, especially neocortical ␥ (40 Hz; ref. 6) and . Behavioral studies of Pavlovian or classical eyeblink (EB) conditioning have yielded a productive convergence of empirical observations and theoretical interpretations between human and animal studies, especially in the involvement of essential cerebellar and modulatory hippocampal systems (see refs. 10 and 11 for review). This growing neurobiological foundation derives, in part, from precise manipulation and͞or localized recording of electrophysiological events in awake, undrugged animals during the acquisition and performance of widely used and well-defined cognitive tasks. In brief, EB conditioning in the trace paradigm starts with onset of a conditioned stimulus (CS, e.g., tone), and CS offset occurs before the unconditioned stimulus (US, e.g., airpuff) onset, creating a period when there is no stimulus present between the CS and US (trace period). Conditioned responses (CRs) occur to the CS and are adaptively timed to precede and overlap the US. Especially important for this study, the trace paradigm has been shown to depend on the integrity of ...

Rabbits were given concurrent training in eyeblink (EB) and jaw movement (JM) conditioning in which one tone predicted an airpuff and another tone predicted water. After 10 days of discrimination training, the animals were given 10 days of reversal training. In the discrimination phase, acquisition of the two conditioned responses was not significantly different; however JM discrimination errors were much more frequent than EB errors. In the reversal phase, correct performance on EB trials increased gradually, as expected, whereas there was immediate behavioral reversal on JM trials. Differences in size and topography of dorsal CA1 multiple unit responses reflected the ability of the hippocampus to discriminate between stimuli in trained animals, corresponding to the performance of the behavioral discrimination. During jaw movement trials, the rhythmicity of the neural response was further modulated by the type of the prior trial, suggesting the coding of sequential events by the hippocampus. Thus, hippocampal conditioned activity can rapidly change its magnitude and pattern depending on the specific trial type during a concurrent EB/JM discrimination task and its reversal.