Spatial firing properties of hippocampal CA1 populations in an environment containing two visually identical regions.

Populations of 10-39 CA1 pyramidal cells were recorded from four rats foraging for food reward in an environment consisting of two nearly identical boxes connected by a corridor. For each rat, a higher-than-chance fraction of cells had similarly shaped spatial firing fields in both boxes, but other cells had completely different fields in the two boxes. The level of correlation of fields in the two boxes differed greatly across rats and, for three of the four rats, across recording sessions. Thus, the factors controlling the level of correlation are likely to be subtle. Two control manipulations were performed. First, the two boxes were physically interchanged. In no case did firing fields move along with the boxes. Second, on the final session of recording, the rat was started in the south box, after having been started in the north box for every previous session. For at least two of the four rats, the north fields from the previous session were instantiated in the south during the first visit of the second session, but thereafter reverted. Thus neither differences between the physical boxes nor sensory input from outside the apparatus could account for the differences in firing fields: most likely they were caused by a combination of learned expectations and a neural mechanism for remembering movements. These findings could be explained either by hypothesizing a more sophisticated attractor-map architecture than has been proposed previously, or by hypothesizing that the hippocampus conjunctively encodes both map information and some other type of information.

Memory reprocessing in corticocortical and hippocampocortical neuronal ensembles.

Hippocampal cells that fire together during behaviour exhibit enhanced activity correlations during subsequent sleep, with some preservation of temporal order information. Thus, information reflecting experiences during behaviour is re-expressed in hippocampal circuits during subsequent 'offline' periods, as postulated by some theories of memory consolidation. If the hippocampus orchestrates the reinstatement of experience-specific activity patterns in the neocortex, as also postulated by such theories, then correlation patterns both within the neocortex and between hippocampus and neocortex should also re-emerge during sleep. Ensemble recordings were made in the posterior parietal neocortex, in CA1, and simultaneously in both areas, in seven rats. Each session involved an initial sleep episode (S1), behaviour on a simple maze (M), and subsequent sleep (S2). The ensemble activity-correlation structure within and between areas during S2 resembled that of M more closely than did the correlation pattern of S1. Temporal order (i.e. the asymmetry of the cross-correlogram) was also preserved within, but not between, structures. Thus, traces of recent experience are re-expressed in both hippocampal and neocortical circuits during sleep, and the representations in the two areas tend to correspond to the same experience. The poorer preservation of temporal firing biases between neurons in the different regions may reflect the less direct synaptic coupling between regions than within them. Alternatively, it could result from a shift, between behavioural states, in the relative dominance relations in the corticohippocampal dialogue. Between-structure order will be disrupted, for example, if, during behaviour, neocortical patterns tend to drive corresponding hippocampal patterns, whereas during sleep the reverse occurs. This possibility remains to be investigated.

The effect of aging on experience-dependent plasticity of hippocampal place cells.

The firing characteristics of 1437 CA1 pyramidal neurons were studied in relation to both spatial location and the phase of the theta rhythm in healthy young and old rats performing a simple spatial task on a rectangular track. The old rats had previously been found to be deficient on the Morris spatial learning task. Age effects on the theta rhythm per se were minimal. Theta amplitude and frequency during rapid eye movement sleep were virtually identical. During behavior, theta frequency was slightly reduced with age. In both groups, cell firing occurred at progressively earlier phases of the theta rhythm as the rat traversed the place field of the cell (i. e., there was "phase precession," as reported by others). The net phase shift did not differ between age groups. The main finding of the study was a loss of experience-dependent plasticity in the place fields of old rats. During the first lap around the track on each day, the initial sizes of the place fields were the same between ages; however, place fields of young rats, but not old, expanded significantly during the first few laps around the track in a given recording session. As the place fields expanded, the rate of change of firing with phase slowed accordingly, so that the net phase change remained constant. Thus changes in field size and phase precession are coupled. A deficit in plasticity of place fields in old rats may lead to a less accurate population code for spatial location.

Paradoxical effects of external modulation of inhibitory interneurons.

The neocortex, hippocampus, and several other brain regions contain populations of excitatory principal cells with recurrent connections and strong interactions with local inhibitory interneurons. To improve our understanding of the interactions among these cell types, we modeled the dynamic behavior of this type of network, including external inputs. A surprising finding was that increasing the direct external inhibitory input to the inhibitory interneurons, without directly affecting any other part of the network, can, in some circumstances, cause the interneurons to increase their firing rates. The main prerequisite for this paradoxical response to external input is that the recurrent connections among the excitatory cells are strong enough to make the excitatory network unstable when feedback inhibition is removed. Because this requirement is met in the neocortex and several regions of the hippocampus, these observations have important implications for understanding the responses of interneurons to a variety of pharmacological and electrical manipulations. The analysis can be extended to a scenario with periodically varying external input, where it predicts a systematic relationship between the phase shift and depth of modulation for each interneuron. This prediction was tested by recording from interneurons in the CA1 region of the rat hippocampus in vivo, and the results broadly confirmed the model. These findings have further implications for the function of inhibitory and neuromodulatory circuits, which can be tested experimentally.

Dynamics of mismatch correction in the hippocampal ensemble code for space: interaction between path integration and environmental cues.

Populations of hippocampal neurons were recorded simultaneously in rats shuttling on a track between a fixed reward site at one end and a movable reward site, mounted in a sliding box, at the opposite end. While the rat ran toward the fixed site, the box was moved. The rat returned to the box in its new position. On the initial part of all journeys, cells fired at fixed distances from the origin, whereas on the final part, cells fired at fixed distances from the destination. Thus, on outward journeys from the box, with the box behind the rat, the position representation must have been updated by path integration. Farther along the journey, the place field map became aligned on the basis of external stimuli. The spatial representation was quantified in terms of population vectors. During shortened journeys, the vector shifted from an alignment with the origin to an alignment with the destination. The dynamics depended on the degree of mismatch with respect to the full-length journey. For small mismatches, the vector moved smoothly through intervening coordinates until the mismatch was corrected. For large mismatches, it jumped abruptly to the new coordinate. Thus, when mismatches occur, path integration and external cues interact competitively to control place-cell firing. When the same box was used in a different environment, it controlled the alignment of a different set of place cells. These data suggest that although map alignment can be controlled by landmarks, hippocampal neurons do not explicitly represent objects or events.

Speed, noise, information and the graded nature of neuronal responses.

How the firing rate of a neuron carries information depends on the time over which rates are measured. For very short times, the amount of information conveyed depends, in a universal way, on the mean rates only (trial-to-trial variability is irrelevant) and the cell response can be taken to be binary (although an ideal binary response would convey more). For longer times, noise as well as the graded nature of the response come into play, with opposite effects. Which times can be considered 'short' varies with the brain area considered and, possibly, with the processing speed it is required to operate at.

Replay of neuronal firing sequences in rat hippocampus during sleep following spatial experience.

The correlated activity of rat hippocampal pyramidal cells during sleep reflects the activity of those cells during earlier spatial exploration. Now the patterns of activity during sleep have also been found to reflect the order in which the cells fired during spatial exploration. This relation was reliably stronger for sleep after the behavioral session than before it; thus, the activity during sleep reflects changes produced by experience. This memory for temporal order of neuronal firing could be produced by an interaction between the temporal integration properties of long-term potentiation and the phase shifting of spike activity with respect to the hippocampal theta rhythm.

Binding of hippocampal CA1 neural activity to multiple reference frames in a landmark-based navigation task.

The behavioral correlates of rat hippocampal CA1 cells were examined in a spatial navigation task in which two cylindrical landmarks predicted the location of food. The landmarks were maintained at a constant distance from each other but were moved from trial to trial within a large arena surrounded by static background cues. On each trial, the rats were released from a box to which they returned for additional food after locating the goal. The box also was located variably from trial to trial and was moved to a new location while the animals were searching for the goal site. The discharge characteristics of multiple, simultaneously recorded cells were examined with respect to the landmarks, the static background cues, and the box in which each trial started and ended. Three clear categories of cells were observed: (1) cells with location-specific firing (place cells); (2) goal/landmark-related cells that fired in the vicinity of the goal or landmarks, regardless of their location in the arena; and (3) box-related cells that fired either when the rat was in the box or as it was leaving or entering the box, regardless of its location in the arena. Disjunctive cells with separate firing fields in more than one reference frame also were observed. These results suggest that in this task a subpopulation of hippocampal cells encodes location in the fixed spatial frame, whereas other subpopulations encode location with respect to different reference frames associated with the task-relevant, mobile objects.

Population dynamics and theta rhythm phase precession of hippocampal place cell firing: a spiking neuron model.

O'Keefe and Recce ([1993] Hippocampus 68:317-330) have observed that the spatially selective firing of pyramidal cells in the CA1 field of the rat hippocampus tends to advance to earlier phases of the electroencephalogram theta rhythm as a rat passes through the place field of a cell. We present here a neural network model based on integrate- and-fire neurons that accounts for this effect. In this model, place selectivity in the hippocampus is a consequence of synaptic interactions between pyramidal neurons together with weakly selective external input. The phase shift of neuronal spiking arises in the model as result of asymmetric spread of activation through the network, caused by asymmetry in the synaptic interactions. Several experimentally observed properties of the phase shift effect follow naturally from the model, including 1) the observation that the first spikes a cell fires appear near the theta phase corresponding to minimal population activity, 2) the overall advance is less than 360 degrees, and 3) the location of the rat within the place field of the cell is the primary correlate of the firing phase, not the time the rat has been in the field. The model makes several predictions concerning the emergence of place fields during the earliest stages of exploration in a novel environment. It also suggests new experiments that could provide further constraints on a possible explanation of the phase precession effect.

Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences.

O'Keefe and Recce [1993] Hippocampus 3:317-330 described an interaction between the hippocampal theta rhythm and the spatial firing of pyramidal cells in the CA1 region of the rat hippocampus: they found that a cell's spike activity advances to earlier phases of the theta cycle as the rat passes through the cell's place field. The present study makes use of large-scale parallel recordings to clarify and extend this finding in several ways: 1) Most CA1 pyramidal cells show maximal activity at the same phase of the theta cycle. Although individual units exhibit deeper modulation, the depth of modulation of CA1 population activity is about 50%. The peak firing of inhibitory interneurons in CA1 occurs about 60 degrees in advance of the peak firing of pyramidal cells, but different interneurons vary widely in their peak phases. 2) The first spikes, as the rat enters a pyramidal cell's place field, come 90 degrees-120 degrees after the phase of maximal pyramidal cell population activity, near the phase where inhibition is least. 3) The phase advance is typically an accelerating, rather than linear, function of position within the place field. 4) These phenomena occur both on linear tracks and in two-dimensional environments where locomotion is not constrained to specific paths. 5) In two-dimensional environments, place-related firing is more spatially specific during the early part of the theta cycle than during the late part. This is also true, to a lesser extent, on a linear track. Thus, spatial selectivity waxes and wanes over the theta cycle. 6) Granule cells of the fascia dentata are also modulated by theta. The depth of modulation for the granule cell population approaches 100%, and the peak activity of the granule cell population comes about 90 degrees earlier in the theta cycle than the peak firing of CA1 pyramidal cells. 7) Granule cells, like pyramidal cells, show robust phase precession. 8) Cross-correlation analysis shows that portions of the temporal sequence of CA1 pyramidal cell place fields are replicated repeatedly within individual theta cycles, in highly compressed form. The compression ratio can be as much as 10:1. These findings indicate that phase precession is a very robust effect, distributed across the entire hippocampal population, and that it is likely to be inherited from the fascia dentata or an earlier stage in the hippocampal circuit, rather than generated intrinsically within CA1. It is hypothesized that the compression of temporal sequences of place fields within individual theta cycles permits the use of long-term potentiation for learning of sequential structure, thereby giving a temporal dimension to hippocampal memory traces.

Deciphering the hippocampal polyglot: the hippocampus as a path integration system.

Hippocampal 'place' cells and the head-direction cells of the dorsal presubiculum and related neocortical and thalamic areas appear to be part of a preconfigured network that generates an abstract internal representation of two-dimensional space whose metric is self-motion. It appears that viewpoint-specific visual information (e.g. landmarks) becomes secondarily bound to this structure by associative learning. These associations between landmarks and the preconfigured path integrator serve to set the origin for path integration and to correct for cumulative error. In the absence of familiar landmarks, or in darkness without a prior spatial reference, the system appears to adopt an initial reference for path integration independently of external cues. A hypothesis of how the path integration system may operate at the neuronal level is proposed.

How much of the hippocampus can be explained by functional constraints?

In the spirit of Marr, we discuss an information-theoretic approach that derives, from the role of the hippocampus in memory, constraints on its anatomical and physiological structure. The observed structure is consistent with such constraints, and, further, we relate the quantitative arguments developed in earlier analytical studies to experimental measures extracted from neuronal recordings in the behaving rat.

Interactions between location and task affect the spatial and directional firing of hippocampal neurons.

When rats forage for randomly dispersed food in a high walled cylinder the firing of their hippocampal "place" cells exhibits little dependence on the direction faced by the rat. On radial arm mazes and similar tasks, place cells are strongly directionally selective within their fields. These tasks differ in several respects, including the visual environment, configuration of the traversable space, motor behavior (e.g., linear and angular velocities), and behavioral context (e.g., presence of specific, consistent goal locations within the environment). The contributions of these factors to spatial and directional tuning of hippocampal neurons was systematically examined in rats performing several tasks in either an enriched or a sparse visual environment, and on different apparati. Place fields were more spatially and directionally selective on a radial maze than on an open, circular platform, regardless of the visual environment. On the platform, fields were more directional when the rat searched for food at fixed locations, in a stereotypic and directed manner, than when the food was scattered randomly. Thus, it seems that place fields are more directional when the animal is planning or following a route between points of special significance. This might be related to the spatial focus of the rat's attention (e.g., a particular reference point). Changing the behavioral task was also accompanied by a change in firing location in about one-third of the cells. Thus, hippocampal neuronal activity appears to encode a complex interaction between locations, their significance and the behaviors the rat is called upon to execute.

A model of the neural basis of the rat's sense of direction.

In the last decade the outlines of the neural structures subserving the sense of direction have begun to emerge. Several investigations have shed light on the effects of vestibular input and visual input on the head direction representation. In this paper, a model is formulated of the neural mechanisms underlying the head direction system. The model is built out of simple ingredients, depending on nothing more complicated than connectional specificity, attractor dynamics, Hebbian learning, and sigmoidal nonlinearities, but it behaves in a sophisticated way and is consistent with most of the observed properties of real head direction cells. In addition it makes a number of predictions that ought to be testable by reasonably straightforward experiments.

Spatial information content and reliability of hippocampal CA1 neurons: effects of visual input.

The effects of darkness on quantitative spatial firing characteristics of 235 hippocampal CA1 "complex spike" (CS) cells were studied in young and old Fischer-344 rats during food-motivated performance of a randomized, forced-choice task on an eight-arm radial maze. The room lights were turned on or off on alternate blocks of all eight arms. In the dark, a lower proportion of CS cells had "place fields," and the fields were less specific and less reliable than in the light. A small number of cells had place fields unique to the dark condition. Like CS cells, Theta cells showed a reduction in spatially related firing in the dark. The specificity and reliability of the place fields under both light and dark conditions were similar for both age groups. Increasing the salience of the environment, by increasing the light level and the number of visual cues in the light condition, did not affect the specificity or reliability of the place fields. Even though all rats had substantial prior experience with the environment, and were placed on the maze center under normal illumination before the first dark trial, the correlation between the firing pattern in the light and dark increased after the rat first traversed the maze in the light. Thus, even after considerable experience with the environment over days, experiencing the illuminated environment from different locations on a given day was a significant factor affecting subsequent location and reliability of place fields in darkness. While the task was simple and errors rare, rats that made fewer errors (i.e., re-entries into the previously visited arm) also had more reliable place cells, but no such correlation was found with place cell specificity. Thus, the reliability of spatial firing in the hippocampus may be more important for spatial navigation than the size of the place fields per se. Alternatively, both spatial memory and place field reliability may be modulated by a common variable, such as attention.

Computational approaches to hippocampal function.

The results of theoretical work have led researchers to suggest that the hippocampal formation may maximize its memory storage capacity by recoding events into patterns that are as dissimilar to one another, and which use as few neurons per event, as possible.