The Long and the Short of It
Authors: Wendy A Suzuki
Journal: Neuron (1999)

The ability to form and retain new long-term declarative memories for facts and events requires the integrity of medial temporal lobe structures including the hippocampus and surrounding entorhinal, perirhinal and parahippocampal cortices (Figure 1; 17Squire L.R Zola S.M Proc. Natl. Acad. Sci. USA. 1996; 93: 13515-13522Crossref PubMed Scopus (844) Google Scholar). A fundamental goal of memory research is to define the neural signals underlying memory function in these areas. This minireview focuses on the patterns of mnemonic activity that have been described throughout the monkey medial temporal lobe. Most such studies have examined patterns of neural activity as animals performed various short-term memory tasks (i.e., tasks requiring memory for seconds to minutes). These studies show that neurons in the perirhinal and entorhinal cortices convey robust short-term memory signals. The evidence for short-term memory signals in the hippocampus has been mixed with some studies reporting memory-related signals and some not. Little is known about mnemonic signals in the parahippocampal cortex. A fundamental function of the medial temporal lobe is the formation and maintenance of long-term memory (i.e., memory lasting from minutes to hours or more). Thus, an important question is: how do the short-term memory signals described in medial temporal lobe neurons relate to the long-term memory functions of these areas? This minireview addresses two points relevant to this question. First, the available data show that in some cases, the neural signals underlying both short-term and long-term memory are variations on a single theme. That is, the same pattern of neural activity signaling memory that lasts for seconds or minutes (short-term memory) is also used to signal memory lasting for hours or more (long-term memory). In other cases, tasks requiring long-term memory have revealed novel patterns of mnemonic activity. The second point concerns the role of the hippocampus in memory. While findings from physiological studies in monkeys have been mixed, a convergence of findings in humans—including findings from neuropsychological studies, functional imaging studies, as well as a recent neurophysiological study—have started to identify some of the specific memory demands required to activate the hippocampal region. Insight from these findings in humans could help resolve the current debate in the literature concerning the contribution of the monkey hippocampus to memory. Here, I provide a brief review of both the short- and the long-term memory signals that have been described in the monkey medial temporal lobe. The majority of memory studies in the monkey medial temporal lobe have examined neural activity as animals perform a variant of the delayed match-to-sample (DMS) task with short retention intervals of only a few seconds. In a typical version of the DMS task (referred to as the standard version), a sample stimulus is followed by the presentation of a variable number of nonmatching test stimuli. Trials always end with the repetition of the sample stimulus, also called the match (6Li L Miller E.K Desimone R J. Neurophysiol. 1993; 69: 1918-1929PubMed Google Scholar, 9Miller E.K Li L Desimone R J. Neurosci. 1993; 13: 1460-1478PubMed Google Scholar, 19Suzuki W.A Miller E.K Desimone R J. Neurophysiol. 1997; 78: 1062-1081PubMed Google Scholar). If A, B, and C represent different visual stimuli, a typical trial might consist of the sequence A…B…C…A. Animals are rewarded for responding to the second presentation of A (i.e., the match). To perform this task, animals must (1) discriminate between the visual stimuli and (2) determine if the current stimulus matches the sample stimulus held in memory. Cells in the perirhinal and entorhinal cortex participate in both of these task requirements. Consistent with the first requirement, cells in these areas respond selectively to some visual stimuli and not to others (i.e., stimulus-selective responses; 12Riches I.P Wilson F.A Brown M.W J. Neurosci. 1991; 11: 1763-1779PubMed Google Scholar, 9Miller E.K Li L Desimone R J. Neurosci. 1993; 13: 1460-1478PubMed Google Scholar, 19Suzuki W.A Miller E.K Desimone R J. Neurophysiol. 1997; 78: 1062-1081PubMed Google Scholar). Consistent with the memory demand of the task, about half of the visually selective cells in these areas signal a matching stimulus with a decreased firing rate (12Riches I.P Wilson F.A Brown M.W J. Neurosci. 1991; 11: 1763-1779PubMed Google Scholar, 2Fahy F.L Riches I.P Brown M.W Exp. Brain Res. 1993; 96: 457-472Crossref PubMed Scopus (266) Google Scholar, 9Miller E.K Li L Desimone R J. Neurosci. 1993; 13: 1460-1478PubMed Google Scholar, 19Suzuki W.A Miller E.K Desimone R J. Neurophysiol. 1997; 78: 1062-1081PubMed Google Scholar). This decreased response is specific for the neuron's preferred stimulus and is termed match suppression (9Miller E.K Li L Desimone R J. Neurosci. 1993; 13: 1460-1478PubMed Google Scholar). Many fewer neurons signal the occurrence of a matching stimulus with an enhanced response. Importantly, match suppression is not simply a form of sensory habituation or fatigue because the suppression disappears if the same stimulus is shown as the sample on the next trial (9Miller E.K Li L Desimone R J. Neurosci. 1993; 13: 1460-1478PubMed Google Scholar). Thus, the match suppression signal appears to actively reset between trials of the DMS task. In contrast to the robust short-term memory signals observed in the perirhinal and entorhinal cortices, reports of mnemonic signals in the hippocampus have been inconsistent. Some studies report no clear evidence for recognition memory signals (12Riches I.P Wilson F.A Brown M.W J. Neurosci. 1991; 11: 1763-1779PubMed Google Scholar, 1Colombo M Gross C.G Behav. Neurosci. 1994; 108: 443-455Crossref PubMed Scopus (95) Google Scholar). Other studies report a small number of hippocampal cells (2% of recorded cells) that signal recognition memory with an enhanced response (14Rolls E.T Cahusac P.M Feigenbaum J.D Miyashita Y Exp. Brain Res. 1993; 93: 299-306Crossref PubMed Scopus (95) Google Scholar) or that signal a combination of spatial information along with information about the previous occurrence of a stimulus (2% of recorded cells; 13Rolls E.T Miyashita Y Cahusac P.M Kesner R.P Niki H Feigenbaum J.D Bach L J. Neurosci. 1989; 9: 1835-1845PubMed Google Scholar). Taken together, these findings suggest that the perirhinal and entorhinal cortices play a more important role in short-term recognition memory than the hippocampus. A different pattern of activity was observed in the entorhinal and perirhinal cortices when animals performed a variant of the standard version of the DMS task termed the "ABBA" version of the task (8Miller E.K Desimone R Science. 1994; 263: 520-522Crossref PubMed Scopus (454) Google Scholar, 19Suzuki W.A Miller E.K Desimone R J. Neurophysiol. 1997; 78: 1062-1081PubMed Google Scholar). In this task, animals were required to differentiate the repetition of the sample stimulus from the repetition of a nonmatching test item. Thus, a stimulus sequence might be A…B…B…A. The animal learned to respond only to the second presentation of A and not to the second presentation of B. This relatively subtle change in the task produced a striking shift in the pattern of mnemonic activity observed. Specifically, a larger proportion of perirhinal neurons (in one case, 35% compared to 9% in the standard version of the DMS) now signaled a matching stimulus with an enhanced rather than a suppressed response. Notably, this enhanced response was specific for the to-be-remembered sample stimulus (the second A in the sequence above) and did not signal the repetition of the nonmatching test item (the second B). In contrast, neurons that responded to the matching stimulus with a suppressed response were equally suppressed for the repeated nonmatch and for the repetition of the sample. Thus, the match enhancement signal appears to represent an active mnemonic signal specific for the behaviorally relevant matching stimulus (8Miller E.K Desimone R Science. 1994; 263: 520-522Crossref PubMed Scopus (454) Google Scholar). Although the cells that exhibit match suppression also have an active component in that they reset between trials, match suppression appears to be a more general mnemonic signal identifying any repeated stimulus within a trial. While these studies have provided important insight into the patterns of activity underlying memory function in the medial temporal lobe, additional studies will be needed to further characterize the specific memory demands required to engage either suppressed or enhanced responses in the perirhinal and entorhinal cortices. Hippocampal neurons have not been examined during the performance of either version of the DMS task. Another well-described short-term memory signal first observed in the prefrontal cortex is reflected by sustained, stimulus-selective activity during the delay interval of various memory-demanding tasks (4Fuster J.M The Prefrontal Cortex. Raven Press, New York1989Google Scholar). Findings from a recent physiology study suggest that this kind of maintained delay activity in the prefrontal cortex also contributes to the performance of the ABBA version of the DMS task (10Miller E.K Erickson C.A Desimone R J. Neurosci. 1996; 16: 5154-5167PubMed Google Scholar). Specifically, a substantial portion of prefrontal neurons signal selective information about the to-be-remembered sample stimulus during the delay intervals of this task, and this selective signal is maintained despite the presentation of multiple intervening test items (10Miller E.K Erickson C.A Desimone R J. Neurosci. 1996; 16: 5154-5167PubMed Google Scholar). While selective activity is observed in the perirhinal cortex during the delay interval immediately following the sample stimulus, this selective activity is abolished by the presentation of even one intervening test item. Surprisingly, a small number of neurons in the entorhinal cortex (6% of the total number of isolated cells) exhibit selective delay activity that is maintained following the presentation of multiple intervening test stimuli (19Suzuki W.A Miller E.K Desimone R J. Neurophysiol. 1997; 78: 1062-1081PubMed Google Scholar). These findings suggest that the robust maintained delay activity in the prefrontal cortex as well as in the entorhinal cortex (but not in the perirhinal cortex) signals information about the to-be-remembered sample stimulus throughout the trial. While the findings described above suggest that stimulus-selective response enhancement or suppression is a common short-term memory signal in the medial temporal lobe, an important question concerns whether the same signals are also used in tasks of long-term memory when the delay intervals are minutes or hours instead of seconds. While neural responses during the performance of a DMS task with long delay intervals have not been examined, another long-lasting mnemonic signal related to stimulus familiarity has been described. Numerous studies showed that neurons in the monkey entorhinal and perirhinal cortices respond with their highest firing rate for certain novel visual stimuli, and that these selective responses decline systematically with repeated presentations as the novel stimuli gradually become familiar (referred to as the familiarity effect). While early studies identified this familiarity effect in passive viewing situations (2Fahy F.L Riches I.P Brown M.W Exp. Brain Res. 1993; 96: 457-472Crossref PubMed Scopus (266) Google Scholar, 6Li L Miller E.K Desimone R J. Neurophysiol. 1993; 69: 1918-1929PubMed Google Scholar), a recent study showed that similar long-lasting familiarity signals are also observed when monkeys are performing a serial recognition task. In this task, monkeys view individual visual stimuli and are required to make a right panel touch if the stimulus is familiar and a left panel touch if the stimulus is novel (20Xiang J.Z Brown M.W Neuropharmacology. 1998; 37: 657-676Crossref PubMed Scopus (297) Google Scholar). Neurons in the perirhinal and entorhinal cortex signaled a familiar stimulus with a response suppression even when the stimulus had not been seen for 24 hr (20Xiang J.Z Brown M.W Neuropharmacology. 1998; 37: 657-676Crossref PubMed Scopus (297) Google Scholar). In the same study, no such familiarity signals were observed in hippocampal neurons. In contrast, another study reported familiarity effects lasting up to about 2 min in a similar running recognition task in the monkey hippocampus (14Rolls E.T Cahusac P.M Feigenbaum J.D Miyashita Y Exp. Brain Res. 1993; 93: 299-306Crossref PubMed Scopus (95) Google Scholar). Taken together, these studies support the idea that neurons in the perirhinal and entorhinal cortices signal both short- and long-term memory with a response suppression. The physiological evidence for the role of the monkey hippocampus in recognition memory, however, remains mixed. Additional insight into the neural correlates of long-term recognition memory in the hippocampus has come from a single-unit physiology study in neurological patients with intracranial electrodes implanted to identify seizure focus (3Fried I MacDonald K.A Wilson C.L Neuron. 1997; 18: 753-765Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar). Individual neurons in the hippocampus, amygdala, and entorhinal cortex were recorded during either an encoding phase in which faces and objects were presented for study or a yes/no recognition phase between 1 and 10 hr later. The vast majority of neurons were recorded in the hemisphere contralateral to the presumed seizure focus. Despite the caveats associated with interpreting neurophysiological data from epileptic patients, the overall pattern of findings was strikingly similar to the findings just described in the monkey perirhinal and entorhinal cortices. That is, neurons in the human hippocampus and entorhinal cortex responded selectively during the encoding phase of the task. Moreover, neural responses during the recognition phase were modulated not only by the stimulus identity but also by whether the stimulus had been seen before. The responses of 35% of cells recorded in the hippocampus and 40% of cells recorded in the entorhinal cortex were influenced by whether a stimulus was new or old. The majority of these cells exhibited enhanced activity in response to previously seen stimuli. These findings support the idea that neurons in the human hippocampus and entorhinal cortex signal long-term recognition memory for objects or faces. These findings are also consistent with findings from human neuropsychological studies showing that subjects with discrete lesions presumably limited to the hippocampus exhibit significant recognition memory impairments on a wide variety of tasks (11Reed J.M Squire L.R Behav. Neurosci. 1997; 111: 667-675Crossref PubMed Scopus (232) Google Scholar). Similarly, a growing number of recent functional imaging studies report significant activations of the hippocampal region during a variety of declarative memory tasks, including recognition tasks (16Schacter D.L Alpert N.M Savage C.R Rauch S.L Albert M.S Proc. Natl. Acad. Sci. USA. 1996; 93: 321-325Crossref PubMed Scopus (516) Google Scholar) and associative memory tasks (5Henke K Buck A Weber B Wieser H.G Hippocampus. 1997; 7: 249-256Crossref PubMed Scopus (285) Google Scholar), as well as responses to novelty (as reviewed by 7Martin A Hippocampus. 1999; 9: 62-70Crossref PubMed Scopus (139) Google Scholar). Thus, findings in humans support the idea that the hippocampus contributes importantly to declarative memory. Given these robust findings in humans, a key question becomes: what factors may underlie the variable results from the monkey neurophysiological literature? One possibility is that the mixed findings in monkeys are due to the relatively small number and limited variety of memory tasks that have been used to address this issue in monkeys. For example, because many of these studies used highly overtrained tasks (12Riches I.P Wilson F.A Brown M.W J. Neurosci. 1991; 11: 1763-1779PubMed Google Scholar, 1Colombo M Gross C.G Behav. Neurosci. 1994; 108: 443-455Crossref PubMed Scopus (95) Google Scholar), it is possible that some of the animals may have been using a nonhippocampal, habit-like strategy to perform the tasks. This suggests that a more extensive evaluation of task parameters may be needed in order to identify the specific memory demands required to engage hippocampal neurons in monkeys. A similar phenomenon was observed in the early days of the human functional imaging literature when little or no evidence of medial temporal lobe/hippocampal activation was seen during the performance of memory-demanding tasks. As a wider variety of tasks were examined, and baseline conditions were refined, increasingly more groups found robust hippocampal activations (reviewed by 7Martin A Hippocampus. 1999; 9: 62-70Crossref PubMed Scopus (139) Google Scholar). Indeed, the range of declarative memory tasks shown to activate the hippocampal region in humans may serve to guide the development of new tasks that can be used in monkeys. For example, some of the factors that differ between the tasks typically used in human studies and those typically used in monkey studies include the use of longer delay intervals (16Schacter D.L Alpert N.M Savage C.R Rauch S.L Albert M.S Proc. Natl. Acad. Sci. USA. 1996; 93: 321-325Crossref PubMed Scopus (516) Google Scholar, 3Fried I MacDonald K.A Wilson C.L Neuron. 1997; 18: 753-765Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar), more interference (16Schacter D.L Alpert N.M Savage C.R Rauch S.L Albert M.S Proc. Natl. Acad. Sci. USA. 1996; 93: 321-325Crossref PubMed Scopus (516) Google Scholar, 3Fried I MacDonald K.A Wilson C.L Neuron. 1997; 18: 753-765Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar), and a much wider range of tasks including associative memory tasks (see below; 5Henke K Buck A Weber B Wieser H.G Hippocampus. 1997; 7: 249-256Crossref PubMed Scopus (285) Google Scholar). Neural activity has also been studied using a different kind of long-term memory task requiring the formation and maintenance of long-term associative memories (15Sakai K Miyashita Y Nature. 1991; 354: 152-155Crossref PubMed Scopus (503) Google Scholar). In this task, monkeys learned a series of arbitrary associations between pairs of complex visual stimuli. This group found that some neurons in and around the perirhinal cortex responded selectively to both visual stimuli of a pair that had been associated in memory (termed pair-coding neurons). Activity in other medial temporal lobe areas has not been examined during the performance of this task. While this report remains one of the clearest demonstrations of long-term memory signals in the medial temporal lobe, many questions remain to be addressed. For example, one question concerns the time course of development of these pair-coding responses in relation to behavioral learning. Because these recordings have been made only in animals performing well-learned associations, this relationship has not been established. Neurophysiological studies of memory in monkeys have made substantial progress in identifying the patterns of neural activity underlying various forms of short-term memory as well as some forms of long-term memory. An important idea to emerge from these studies is that the patterns of neural activity used to signal memory for seconds to minutes (short-term memory) can also be used to signal memory for hours or more (long-term memory). For example, both match suppression and match enhancement signal recognition memory for short delay intervals of several seconds (9Miller E.K Li L Desimone R J. Neurosci. 1993; 13: 1460-1478PubMed Google Scholar, 19Suzuki W.A Miller E.K Desimone R J. Neurophysiol. 1997; 78: 1062-1081PubMed Google Scholar) as well as long delay intervals of hours or more (3Fried I MacDonald K.A Wilson C.L Neuron. 1997; 18: 753-765Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar, 20Xiang J.Z Brown M.W Neuropharmacology. 1998; 37: 657-676Crossref PubMed Scopus (297) Google Scholar). These findings suggest that short-term memory signals can provide useful predictions for the patterns of neural activity that may be observed in long-term memory tasks. However, while the many studies of short-term recognition memory have provided substantial information about the kinds of memory signals conveyed by the perirhinal and entorhinal cortex, much less is known about the neural correlates of memory in the monkey hippocampus. Thus, a clear direction for future research involves the development of more and varied memory tasks designed to identify the precise mnemonic parameters required to engage the monkey hippocampus. The use a of a wider variety of memory tasks, including tasks of associative long-term memory, will also help expand our understanding of the contributions of the perirhinal and entorhinal cortices beyond recognition memory and toward the realm of declarative memory.