Time cells in the hippocampus: a new dimension for mapping memories

Journal name:
Nature Reviews Neuroscience
Volume:
15,
Pages:
732–744
Year published:
DOI:
doi:10.1038/nrn3827
Published online

Abstract

Recent studies have revealed the existence of hippocampal neurons that fire at successive moments in temporally structured experiences. Several studies have shown that such temporal coding is not attributable to external events, specific behaviours or spatial dimensions of an experience. Instead, these cells represent the flow of time in specific memories and have therefore been dubbed 'time cells'. The firing properties of time cells parallel those of hippocampal place cells; time cells thus provide an additional dimension that is integrated with spatial mapping. The robust representation of both time and space in the hippocampus suggests a fundamental mechanism for organizing the elements of experience into coherent memories.

At a glance

Figures

  1. Key features of time-cell firing sequences.
    Figure 1: Key features of time-cell firing sequences.

    a | A raster display of spiking activity from idealized, simultaneously recorded time cells (each shown in a different colour). For each cell, activity is shown as a raster of spikes for three example trials in which the cell fires for a brief period at approximately the same moment in each trial, with later-firing time cells being active for longer periods (indicating scalar coding of time). b | In the same recording session, when the time period is elongated (time + n), the cells shown at the top and bottom fire at the same moment relative to the beginning and end of the period, respectively (indicating that their activity is bound to those temporal boundaries), whereas the cells shown in the middle in part a have ceased firing and new cells (note the new colours in part b) fire to fill in the period, reflecting 're-timing' in these cells to represent the altered temporal dimension. These characteristics parallel those of place cells, which typically fire at adjacent locations in space and, when critical spatial cues are altered, either remain bound to cues still present or 're-map' to reflect the altered spatial dimensions.

  2. Early discoveries on temporal coding by hippocampal neurons.
    Figure 2: Early discoveries on temporal coding by hippocampal neurons.

    Aa | Design of an odour sequence memory task. In the encoding phase of each trial, rats sampled a sequence of five odours, which were presented at alternating positions on a platform. In the test phase at the end of each trial, they were presented with two odours and had to judge which of the two had been presented earlier. Ab | Recordings from CA1 neural ensembles made during the test phase revealed that an index of distance (or dissimilarity) between periods surrounding odour representations in neural populations was larger for odours that had been sampled further apart (that is, they were separated by a larger number of intervening items) than for odours sampled close together (smaller lag) — but only on trials in which the order judgement was correct and not on error trials, regardless of whether the odours appeared at the same or different positions. By contrast, the distance between population representations of positions in space did not differentiate correct trials and errors. Error bars indicate the standard error of the mean for the variability across sessions. Ba | Design of a spatial alternation T-maze task. Rats travelled along two paths in a T-maze (indicated by black and grey arrows) in alternation, and in between they ran in a running wheel. Bb | The ensemble firing-rate plot shows the normalized firing rates of 30 neurons during the wheel running period (each row shows the activity of one neuron). The plot reveals that different hippocampal neurons fired at different times during wheel running, and that together, the neurons' firing covered the entire period. These two studies revealed the existence of representations of a gradually changing temporal context signal in two very different memory tasks: one in which animals encoded unique sequences of odours and another in which they repeatedly ran on a running wheel in between memory judgements. Part A reprinted from Neuron, 56, Manns, J. R., Howard, M. W. and Eichenbaum, H. Gradual changes in hippocampal activity support remembering the order of events, 530540, © (2007), with permission from Elsevier. Part Bb from Pastalkova, E., Itskov, V., Amarasingham, A., and Buzsáki, G. Internally generated cell assembly sequences in the rat hippocampus. Science 321, 13221327 (2008). Reprinted with permission from AAAS.

  3. Time coding and spatial coding.
    Figure 3: Time coding and spatial coding.

    Aa | Design of a non-spatial task in which time cells were observed. Rats learned to associate each of two visually distinct objects with one of two cups of scented sand (for example, the green block was associated with the lemon-scented cup and the purple sphere was associated with the nutmeg-scented cup). In each trial, rats approached and sampled one of the two objects and, after a fixed (10 s or 20 s) delay, were exposed to one of the two odours. If the odour matched the object (for example, lemon odour following a green block), the rat had to dig in the scented sand to retrieve a reward. If the odour did not match the object (not shown), no reward was available in the odour cup and the rat did not dig. Ab | Two examples of cells that 're-timed'. On the left, a cell that progressively lost its time field as the delay was elongated from 5 s, to 10 s, to 20 s. On the right, a cell that did not fire when the delay period was 10 s but that did fire (at about t = 6–7 s) when the delay period was 20 s. Ac | The spatial activity pattern (place field) of the cell whose raster plot is shown on the right in part Ab. Activity is plotted for the entire delay period (top) and for the first ten successive seconds of the delay period in each trial block. Note that the cell fired at a particular location but only during the sixth to seventh second of the 20 s delay period (middle column) and not in trials with a 10 s delay period (left and right column; also see the normalized firing rates over time in the trace at the bottom). Ba | Design of a spatial alternation task. Rats ran on a treadmill in between alternating left turns and right turns on a T-maze (paths indicated by black and grey arrows). Bb,Bc | The firing patterns of a hippocampal neuron shown in raster plots (top), firing rate histograms (middle) and normalized firing rate (bottom) across a range of treadmill speeds. When firing is plotted according to time elapsed (Bb), the cell fired at about 14 s into treadmill running regardless of speed. Plotting the same data according to distance travelled (Bc) reveals that the cell fired at different distances depending upon speed. These experiments showed that hippocampal neurons can encode time and space conjointly (A) or can encode time only and not spatial dimensions (B). Parts Ab and Ac reprinted from Neuron, 71, MacDonald, C. J., Lepage, K. Q., Eden, U. T. and Eichenbaum, H. Hippocampal “time cells” bridge the gap in memory for discontiguous events, 737749, © (2011), with permission from Elsevier. Parts Bb and Bc reprinted from Neuron, 78, Kraus, B. J., Robinson II, R. J., White, J. A., Eichenbaum, H. and Hasselmo, M. E. Hippocampal 'time cells': Time versus path integration, 10901101, © (2013), with permission from Elsevier.

  4. Time cells have a role in memory.
    Figure 4: Time cells have a role in memory.

    Aa | Design of an example series of trials used in immobilized (head-fixed) rats performing an odour-cued delayed matching-to-sample task. Each trial began with the presentation of one of up to four sample odours for 1 s. Following a 2–5 s delay, a test odour was presented. In 'match' trials (that is, when the test odour was the same as the sample odour), the rat could respond to the test odour to receive a reward (indicated by '+'). In 'non-match' trials (that is, when the test odour differed from the sample odour), no reward was available (indicated by '–'). Match and non-match trials were presented in a random order. Ab | Population vectors during the delay period for time cells were well correlated between trials that began with the same sample odour, and were less strongly correlated (but still above that of control (random) conditions) between trials with different sample odours; cells that were not temporally modulated did not code for different sample odours. Error bars indicate the standard error of the mean. Ac | Population vectors were similar between trials with the same sample when the match/non-match judgement was subsequently correct during both the sample period and the ensuing delay, but these correlations were reduced on error trials. Error bars indicate the standard error of the mean. Ba | Mice were given trace classical conditioning; in each trial, a 350 ms tone (the conditioned stimulus (CS); red bar) was followed by a 250 ms delay period, then a 100 ms air puff (the unconditioned stimulus (US); blue bar). Bb,Bc | Calcium signals (ΔF/F) in six example CA1 neurons (activity patterns on three example trials are shown for each neuron) from the same mouse before (Bb) and after (Bc) learning show the emergence of successive timing signals ('*' indicates the peak signal for each cell). Specifically, after conditioning, the timing of the CS (red bar), the delay and the US (blue bar) periods are encoded by the firing sequence of the six neurons. Part A is adapted with permission from Ref. 20, Society for Neuroscience. Part B is adapted with permission from Ref. 21, eLife Sciences.

  5. The influence of temporal context on spatial coding.
    Figure 5: The influence of temporal context on spatial coding.

    Aa | Rats were required to select one of four paths towards distinct goal boxes (two paths are shown as dashed lines). Ab,Ac | Plots of spikes (Ab) and firing rate (Ac) for an example cell. This cell fired maximally at the outset of the path towards goal 1, and much less so at the outset of paths towards the other three goals, even when the rat passed though the same location in all paths. Error bars indicate the standard error of the mean across trials. Ba | Delayed spatial alternation task in which rats alternate between left-turn (black arrow) and right-turn (grey arrow) paths at a decision point on a maze. The two paths have a common arm, and both start with a 30 s delay period at the bottom of the common arm. Bb,Bc | Normalized firing-rate plots of a hippocampal neuron. The plots show that this neuron fired maximally in the common maze segment on correct right-turn trials (Bb, left) and less so on correct left turn trials (Bb, right), and hardly at all on either type of error trial, regardless of the subsequent turn direction (Bc). In both of these experiments, the broader temporal context of the entire path through the maze determined which place cells were active at specific locations on the maze. Part A is adapted with permission from Ref. 40, Society for Neuroscience. Part B reprinted from Behavioural Brain Research, 254, Robitsek, R. J., White, J. A. and Eichenbaum, H. Place cell activation predicts subsequent memory, 6572, © (2013), with permission from Elsevier.

  6. Temporal context versus chaining models.
    Figure 6: Temporal context versus chaining models.

    a | In the temporal context model, each hippocampal neuron represents a unique state of cortical activity that corresponds to moments in the stream of events processed within the cortex69. b | According to the chaining model, hippocampal neurons increase sequential connection strengths with repeated experiences to produce hippocampal neuron firing sequences67. c | A combined model might include firing chains that are generated at successive steps as the temporal context gradually evolves, and also associations between neurons that fire at the same time across chains.

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Affiliations

  1. Center for Memory and Brain, Boston University, Boston, Massachusetts 02215, USA.

    • Howard Eichenbaum

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The author declares no competing interests.

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  • Howard Eichenbaum

    Howard Eichenbaum is a professor at Boston University (Massachusetts, USA), where he is also director of the Center for Memory and Brain and the Silvio O. Conte Center for Neuroscience Research. He received a Ph.D. in psychology from the University of Michigan (Ann Arbor, Michigan, USA) and pursued a postdoctoral fellowship in neuroscience at the Massachusetts Institute of Technology (Cambridge, Massachusetts, USA). He has received the Senior Scientist Award from the US National Institute of Mental Health multiple times (1997–2002), and is a fellow of the Association for Psychological Science (2007) and of the American Association for the Advancement of Science (2008). He has served on the Council of the Society for Neuroscience, the National Advisory Mental Health Council and as chair of the Section on Neuroscience at the American Association for the Advancement of Science. He is editor-in-chief of the journal Hippocampus,and has published over 250 research papers, reviews, book chapters and books on the hippocampus and memory.

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Movies

  1. Supplementary information S1 (movie) (5.20 MB)

    Time cells in rats running on the treadmill. The firing patterns of three CA1 neurons are shown. For each, the time and location of the rat when individual spikes occur are plotted as dots (in a different colour for each neuron) on the rat's head. Note that even though the rat's head is approximately in the same location during the run, the neurons fire in sequence (pink then green then blue). Also note that each neuron additionally fires at a location on the maze outside the treadmill. The treadmill is on when a red triangle appears in bottom left corner.

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