To Cortex: Thanks for the Memories
Authors: Howard Eichenbaum
Journal: Neuron (1997)

Where and how memories are stored in the cerebral cortex are central questions about cognition that have daunted neuroscientists for over four decades (see17Squire L.R Memory and Brain. Oxford University Press, New York1987Google Scholar). Considerations of the “where” question have predominated, and can be traced back at least as far as Gall's phrenology, where memory was viewed as part of the contents of various faculties localized in cortical areas. Pavlov's reflexology replaced this view with the radically different notion that memories are mediated by stimulus-response circuits. However, this idea too was discarded after Karl Lashley failed in his exhaustive attempts to disconnect cortical circuits and E. Roy John found memory “readout” in evoked potentials that were distributed throughout the cortex. Since that time, more sophisticated neuropsychological approaches have identified selective roles in memory for all cortical areas beyond the early stages of sensory and motor representation (6Fuster J.M Memory in the Cerebral Cortex. MIT Press, Cambridge, MA1995Google Scholar, 7Goldman-Rakic P Proc. Nat. Acad. Sci. USA. 1996; 93: 13473-13480Crossref PubMed Scopus (648) Google Scholar). However, these successes notwithstanding, the experimental ablation approach has two inherent limitations. First, for sensory association areas, distinguishing impairment in perceiving stimuli from that in remembering them has proved futile, leading to the view that the same areas that perform high level sensory processing are also the storage sites of sensory memories. Ablations limited to some prefrontal or medial temporal lobe areas do result in selective memory deficits, but even in these areas a second limitation is that the ablation approach offers only indirect and general insights into the nature of information stored. To fully understand how cortical areas contribute to memory we need to identify the memory code, that is, the neural firing patterns that capture and read out memories. The mechanism of the encoding of memory within neural circuits has not received as much experimental attention, although this cannot be attributed to absence of guiding theory. For example8Hebb D.O The Organization of Behavior. Wiley, New York1949Google Scholar proposed the cortex might sustain sensory or motor representations at least briefly in “reverberating circuits,” and mediate learned associations by “phase sequences” linking these representations. However evidence concerning this and other hypotheses about memory coding has been slow to come. Recent physiological studies have revealed a plethora of “memory correlates” in various cortical areas, but not an overall theoretical account to explain how they mediate the experience of memory. These data come mainly from studies on long term associative learning or working memory; I will review some of the findings of each. Associative learning tasks are commonly defined by a consistent predictive relationship between an arbitrary stimulus and a subsequent stimulus, reward, or response. A good example is provided in this issue of Neuron (11Quirk G.J Armony J.L LeDoux J.E Neuron. 1997; 19 (this issue)Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar). In this experiment cells in the auditory cortex were recorded as rats were presented with pairings of a pure tone followed by a brief foot shock, the magnitude of tone-evoked responses in many of the cells was increased by conditioning. The responses were longer in latency and slower to appear during training than in the part of the amygdala necessary for expression of fear conditioning, indicating that simple tone conditioning is likely mediated by an alternative, direct thalamo-amygdala route (see9LeDoux J.E Ann. Rev. Psychol. 1995; 46: 209-235Crossref PubMed Scopus (1289) Google Scholar). However, unlike amygdala cells, incremental responses in cortical cells did not disappear when the tone was presented repeatedly without foot shocks and some cells showed their peak response at about the time of the foot shock delivery, suggesting a role for the cortex in the expectancy of foot shock. That study is but one good example of the memory correlates that can be observed in cortical cells. Our own recent research has focused on cells in the orbital prefrontal and piriform cortex recorded in rats performing an olfactory discrimination task (16Schoenbaum G Eichenbaum H J. Neurophysiol. 1995; 74: 733-750PubMed Google Scholar). The stimuli consisted of eight odors, half associated with reward and half with nonreward. Many of the cells had selective odor responses that were strongly modulated by the assigned reward contingency (Figure 1). About half of these odor responses were greater in magnitude for rewarded than nonrewarded odors, and the other half involved the opposite pattern, indicating that learning can “bias” sensory responses both incrementally and decrementally. In other studies learning resulted in a “retuning” of sensory responses. For example18Weinberger, N.M. (1995) In The Cognitive Neurosciences, M. Gazzaniga, ed. (Cambridge, MA: MIT Press).Google Scholar initially characterized the tuning curves of guinea pig auditory cortical cells, then paired a non-optimal tone with foot shocks, and finally re-assessed the sensory evoked responses of the same cells. He and his colleagues found suppressed responses to the initially optimal stimulus and enhanced responses to the conditioning stimulus, constituting a shift in the tuning curve towards the newly important stimulus frequency. Similar findings have been made in studies on tactile discrimination training in monkeys, showing an enlargement of the relevant area in the somatosensory cortex and decreased response latencies (10Merznich M.M Recanzone G.H Jenkins W.M Grajski K.A Cold Spring Harbor Symp.Quant. Biol. 1990; 55: 873-883Crossref PubMed Scopus (107) Google Scholar). Also, the size of individual receptive fields was decreased, corresponding to a combination of enhanced and suppressed responses to adjacent points on the skin surface. A similar reorganization of tonotopic cortex occurs subsequent to auditory discrimination training in monkeys (see references in 14Sakai K Naya Y Miyashita Y Learn. Mem. 1994; 1: 83-105PubMed Google Scholar, 6Fuster J.M Memory in the Cerebral Cortex. MIT Press, Cambridge, MA1995Google Scholar). Other studies have focused on the learning of associations between pairs of sensory stimuli. In one study monkeys were trained to recognize contingencies between pairs of visual cues (13Sakai K Miyashita Y Nature. 1991; 354: 152-155Crossref PubMed Scopus (505) Google Scholar). Subsequently some cells in the temporal cortex could be activated by either of the stimuli within a pair. Other cells that were activated by one of the stimuli also fired in anticipation of presentation of its associate. Similarly, cells in somatosensory or visual cortex learned to respond to presentation of an auditory cue that signaled an impending tactile or visual stimulus, respectively (see6Fuster J.M Memory in the Cerebral Cortex. MIT Press, Cambridge, MA1995Google Scholar). In rats, cells in the orbital prefrontal cortex demonstrated a similar capacity for associating odor stimuli. Following training on a task where presentation of an odor stimulus that predicted the succeeding presentation of another, some neurons that were directly activated by the second cue also began to fire just as the animal initiated the trial in which the expected odor would be presented (16Schoenbaum G Eichenbaum H J. Neurophysiol. 1995; 74: 733-750PubMed Google Scholar). In working memory tasks the animal is briefly presented with a sample cue that must be retained across a delay and then recognized among one or more cues in a subsequent choice test. Analyses of neural activity have focused on the distinct trial periods associated with sample presentation, the memory delay, and recognition responses to matching and nonmatching choice stimuli. Fuster's pioneering studies identified cells in the monkey dorsolateral prefrontal cortex that began to fire when a spatial cue was presented and continued to be active throughout the memory delay; some of these cells reflected the memory for the cue location whereas others reflected the location of an intended behavioral response (6Fuster J.M Memory in the Cerebral Cortex. MIT Press, Cambridge, MA1995Google Scholar). In the inferior convexity of prefrontal cortex, cells show similar sustained activity to specific visual patterns, suggesting that the prefrontal cortex contains segregated regions processing working memories for different types of material (7Goldman-Rakic P Proc. Nat. Acad. Sci. USA. 1996; 93: 13473-13480Crossref PubMed Scopus (648) Google Scholar). In another recent study where monkeys were required to remember pattern and spatial cues, prefrontal activity reflected the convergence of these stimulus qualities (Miller, 1997). Sustained stimulus-specific firing is not limited to prefrontal areas, but rather has also been identified in widespread areas of the parietal and temporal cortex of monkeys (6Fuster J.M Memory in the Cerebral Cortex. MIT Press, Cambridge, MA1995Google Scholar, 1Brown M.W Sem. Neurosci. 1996; 8: 23-32Crossref Scopus (46) Google Scholar). Also, stimulus- specific delay activity has been observed in rats in the perirhinal and entorhinal cortex (20Young B.J Otto T Fox G.D Eichenbaum H J. Neurosci. 1997; 17: 5183-5195PubMed Google Scholar; Figure 2A) and in auditory cortex (15Sakurai Y Behav. Neurosci. 1990; 104: 856-868Crossref PubMed Scopus (34) Google Scholar). In addition, anticipatory stimulus selective neural activity associated with working memory has now also been observed in the perirhinal and entorhinal cortex (20Young B.J Otto T Fox G.D Eichenbaum H J. Neurosci. 1997; 17: 5183-5195PubMed Google Scholar). In rats performing an odor-guided working memory task some cells that were activated by a particular sample odor ceased firing during most of the delay, then re-activated their stimulus-selective firing pattern as the animal initiated the test trial, that is, just before presentation of the comparison cue (Figure 2B). Finally, during the test phase of working memory tasks, repetition of the sample stimulus sometimes results in incremental or decremental biasing of the cortical sensory response. Cells in the perirhinal cortex of monkeys showed enhanced evoked responses selectively during repetition of the optimal visual stimulus when it had to be remembered across a delay filled with intervening stimuli (3Desimone R Science. 1992; 258: 245-246Crossref PubMed Scopus (61) Google Scholar). Other cells showed suppressed evoked responses selectively to the optimal visual stimulus whenever it was repeated, regardless of whether it was the cue that had to be remembered, and a few cells showed enhanced responses to repeated stimuli. Similarly, in rats performing an odor-guided working memory task, different cells in the perirhinal and entorhinal cortex showed enhanced or suppressed evoked responses selectively during repetition of the optimal odor stimulus (Figure 3). The list of cellular memory correlates seems almost as large as the number of studies that report them. However, these diverse findings can be consolidated by thinking about memory as encoded in two general ways. First, memory is reflected in the capacity of cortical cells to bias or modulate their stimulus-evoked responses. These codings occur as incremental (enhanced) and decremental (suppressed) responsiveness. Furthermore the combination of these can shift a tuning curve, and many coordinated tuning curve shifts could account for the expansion or shrinkage of parts of the overall sensory representation within a cortical area. These response biases can be held briefly, as observed in the working memory tasks, or permanently, as observed in the increased resolution in the cortical maps for relevant stimuli. In working memory tasks enhanced responses could selectively pass an attentional “filter” (3Desimone R Science. 1992; 258: 245-246Crossref PubMed Scopus (61) Google Scholar). Suppressed responses could reflect subthreshold sustained activation, that is, “primed” neural activity that subsequently requires less processing to identify the familiar stimulus. Second, memory is reflected in the capacity of cortical cells to sustain or reactivate responses in the absence of the stimulus ordinarily required to evoke the representation. This type of coding can be observed in firing patterns maintained during the delay in working memory tasks, providing a confirmation of Hebb's “reverberating circuit” notion. In addition, the capacity of cortical cells to regenerate item-specific firing patterns when cued by an associated event seems to confirm Hebb's model of complex memories as “phase sequences” involving replays of linked stimulus representations. The hippocampus is the ultimate site of convergence in the temporal lobe, receiving a cascade of inputs from all of the cortical association areas via the surrounding parahippocampal region. Furthermore, the hippocampus is critical to memory for spatial and other relational information in animals, and is essential in humans for memory that can be expressed by explicit recollection (5Eichenbaum H Ann. Rev. Psychol. 1997; 48: 547-572Crossref PubMed Scopus (248) Google Scholar). Based on this evidence one should expect to find striking memory-related neural activity in the hippocampus. Hippocampal neurons are difficult to drive by single sensory stimuli, but after learning and during exploration of the environment they can demonstrate striking activity patterns associated with stimulus configurations, or relations among cues, as well as between cues and associated behavioral responses. Perhaps the best known of these is the so-called “place cell” phenomenon by which many hippocampal principal neurons fire when the animal is in a particular location in the environment defined by spatial relations among distinctive cues (4Eichenbaum H Curr. Opin. Neurobiol. 1996; 6: 187-195Crossref PubMed Scopus (134) Google Scholar). Hippocampal place cells are capable of sustaining or re-generating spatially specific firing patterns during exploration when most of the salient cues are removed, and during the memory delay in a working memory task (2Deadwyler S.A Bunn T Hampson E J. Neurosci. 1995; 16: 354-372Google Scholar). Traces of coordinated hippocampal activity associated with exploration have been observed to persist or re-occur during subsequent sleep (19Wilson M.A McNaughton B.L Science. 1994; 265: 676-679Crossref PubMed Scopus (1885) Google Scholar). So, perhaps even more readily than cells in cortex, hippocampal cells rapidly acquire responses evoked by learned cue configurations and can sustain or regenerate those firing patterns based on partial cues or recent experience with the same stimuli. However, some contrasts between firing patterns in the hippocampus and other regions of cortex are also quite striking. For example, in monkeys and rats performing the working memory tasks described above, hippocampal neurons do not show stimulus-selective activity for cues, sustained delay activity, or enhancement/suppression to specific repeated cues (Brown, 1995; 4Eichenbaum H Curr. Opin. Neurobiol. 1996; 6: 187-195Crossref PubMed Scopus (134) Google Scholar). Instead hippocampal neural activity during stimulus sampling reflects the match or nonmatch correspondence between any choice comparison and its preceding sample cue, i.e., an abstraction of the relevant relationships between the stimuli. Another unique property of hippocampal cells is their propensity for rapidly and unpredictably changing their firing patterns when some of the cues or contingencies are altered. These observations suggest that the hippocampal code differs substantially from that of the cerebral cortex, and emphasizes the coding of relations among cues and differentiation between new and old information. These observations should re-focus how we think about memory coding in the cortex. Since the discrediting of phrenology and reflexology, ideas about memory storage have too often been guided by an implicit view that memories are entities that can be distinguished from perceptions, actions, and thoughts. This common perspective is reflected even in the way we ask the basic questions, “Where are memories stored?” and “How are memories encoded?” The conception of memories as distinct items that are created and stored, and by some views transferred in succeeding stages from one chemical state or brain locus to another, may be misleading. The present considerations, consistent with 8Hebb D.O The Organization of Behavior. Wiley, New York1949Google Scholar model, suggest that memory should be conceived as intimately intertwined with information processing in the cortex, indeed so much so that the “memory” and “nonmemory” are inherently indistinguishable. By one construal of this view, memory is nothing more nor less than the plastic properties of specific cortical information processings. By another equally valid construal, all cortical information processing inherently involves adaptations to stimulus regularities and contingencies. By either view, in the cerebral cortex information processing and memory combine to constitute the structure of our knowledge about the world. The memory code is thus both constrained by and revealed in acquired biases in evoked activity patterns and in the ability to recreate those knowledge representations. In addition, the secret to understanding hippocampal involvement in memory coding may lie in its anatomical and functional associations with the cortex. The main outputs of the hippocampus are directly back to the widespread areas of cortex that are the origin of its inputs. Thus the role of hippocampal processing should be constrained within the framework of the two types of cortical memory coding outlined above. One possibility, consistent with a large body of data on the characteristics of hippocampal-dependent memory, is that hippocampal relational codings may mediate the property of cortical coding by which related cues can activate the representations of their associates according to the organized knowledge structure. The other property of cortical coding, by which evoked representations are biased through repetition, attention, and reinforcement, may underlie the forms of learning that can occur without hippocampal mediation, consistent with a large body of data on the characteristics of hippocampal-independent memory (5Eichenbaum H Ann. Rev. Psychol. 1997; 48: 547-572Crossref PubMed Scopus (248) Google Scholar).