Decades of research have established two central roles of the hippocampus – memory consolidation and spatial navigation. Recently, a third function of the hippocampus has been proposed: simulating future events. However, claims that the neural patterns underlying simulation occur without prior experience have come under fire in light of newly published data.

1 O’Keefe J.

Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. 2 Roumis D.K.

Frank L.M. Hippocampal sharp-wave ripples in waking and sleeping states. 2 Roumis D.K.

Frank L.M. Hippocampal sharp-wave ripples in waking and sleeping states. 3 Pfeiffer B.E.

Foster D.J. Hippocampal place-cell sequences depict future paths to remembered goals. 3 Pfeiffer B.E.

Foster D.J. Hippocampal place-cell sequences depict future paths to remembered goals. 4 Ólafsdóttir H.F.

et al. Hippocampal place cells construct reward related sequences through unexplored space. 2 Roumis D.K.

Frank L.M. Hippocampal sharp-wave ripples in waking and sleeping states. 2 Roumis D.K.

Frank L.M. Hippocampal sharp-wave ripples in waking and sleeping states. 5 Bendor D.

Wilson M.A. Biasing the content of hippocampal replay during sleep. Much of our understanding of the hippocampus comes from neural recordings in behaving rodents. Neurons within the rodent hippocampus, known as place cells, are tuned to spatial position of the animal, such that each place cell increases its neural activity when the rodent is in a specific location within its environment []. However, when the rodent stops running, the hippocampus exhibits brief high-frequency oscillations, referred to as sharp-wave-ripple (SWR) events []. SWR events typically co-occur with the sequential firing of place cells that represent a spatial trajectory. These spontaneously reactivated ‘trajectory events’ can represent the spatial path that the animal has recently taken [] or is about to begin []. Trajectory events are not limited to when the animal is awake and static; during non-REM sleep, trajectory events depicting past journeys can also be observed []. Substantial evidence supports the phenomenon of trajectory events, commonly referred to as ‘replay’ or ‘reactivation’, demonstrating that these events are coordinated with reactivation events in brain regions beyond the hippocampus, and are influenced by both rewards and external cues [].

1 O’Keefe J.

Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat. 6 Dragoi G.

Tonegawa S. Preplay of future place cell sequences by hippocampal cellular assemblies. 6 Dragoi G.

Tonegawa S. Preplay of future place cell sequences by hippocampal cellular assemblies. A common assumption about ‘trajectory events’ is that they are a byproduct of experience. During exploration of a novel environment the hippocampus is thought to create a cognitive map of that environment, which can be reactivated to recall this map []. However, in 2011 a break with this standard view occurred []. The sequential pattern of hippocampal place cells during a sleep session was recapitulated while the animal was subsequently running on a linear track (after waking up), despite no prior experience of the track []. This phenomenon of de novo ‘pre-play’ argues for the existence of pre-configured sequential patterns in the hippocampus that the hippocampus ‘maps’ onto a new environment.

7 Silva D.

et al. Trajectory events across hippocampal place cells require previous experience. In a challenge to these findings, a recent study by Silva, Feng, and Foster [] reports that, although it is possible to observe de novo pre-play events, the occurrence of these events does not happen at a frequency above what would be expected by chance. Second, while a significant increase in the number of trajectory events can be observed after the animal's spatial exploration, these effects are mitigated with pharmacological blockade of NMDA receptors (disrupting synaptic plasticity) when administered before exploration. Together, these two observations suggest that trajectory events are experience-dependent.

How can we resolve the conflicting results surrounding the existence of de novo pre-play? To answer this, we raise three main issues, which we will refer to as the good news, the bad news, and the ugly truth.

The Good News: Internal Sequences Exist in the Hippocampus 8 MacDonald C.J.

et al. Hippocampal ‘time cells’ bridge the gap in memory for discontiguous events. 9 Villette V.

et al. Internally recurring hippocampal sequences as a population template of spatiotemporal information. For de novo pre-play to exist, the hippocampus must be able to generate an internal sequence, in other words a sequential pattern of place cell activity in the absence of a spatial trajectory. Substantial evidence now supports this. Time cells in the hippocampus exhibit responses tuned to time instead of, or in addition to, space []. If time cells do not require travel, then theoretically trajectory sequences can be generated without locomotion, and may not be fully determined by the spatial tuning of cells. Recently, hippocampal cells have been observed to exhibit repeated sequences of activation linked to the distance run on a wheel in the dark, providing further support for internal representations [].

The Bad News: We Can’t Predict the Future 2 Roumis D.K.

Frank L.M. Hippocampal sharp-wave ripples in waking and sleeping states. 3 Pfeiffer B.E.

Foster D.J. Hippocampal place-cell sequences depict future paths to remembered goals. 4 Ólafsdóttir H.F.

et al. Hippocampal place cells construct reward related sequences through unexplored space. 10 Wu X.

Foster D.J. Hippocampal replay captures the unique topological structure of a novel environment. Evidence suggests trajectory events can pre-play through previously explored space [], and even through unexplored space, when the path leads to a visible reward []. However, can trajectory events occur without any experience or knowledge of the environment? To explore this we can perform the following thought experiment. Imagine we observe two different trajectory events (A and B) repeating during sleep. If trajectories A and B do not share any place cells, we can assume that they represent different trajectories, while if instead the middle of both trajectories share the same sequence of place cells, then this would imply that the trajectories intersect. This means that we can infer information about the topology of the environment. This principle has already been demonstrated for replay events [], and thus might apply to de novo pre-play trajectory events. Except that, in a pure de novo state, one cannot predict the future. Thus either de novo pre-play only works on specific topologies, limiting its overall utility, or we have identified the neural correlate of pre-cognition.

The Ugly Truth: Statistics 2 Roumis D.K.

Frank L.M. Hippocampal sharp-wave ripples in waking and sleeping states. 7 Silva D.

et al. Trajectory events across hippocampal place cells require previous experience. How do we even know that a pattern of neural activity is replaying or pre-playing a trajectory? Since the discovery of hippocampal replay we have observed a rapid evolution of statistical analyses to measure: (i) the similarity between patterns of activity, and (ii) whether a pattern occurs above chance levels. These statistical methods have moved from pairwise correlation, combinatorics of short sequences, rank-order correlation, to Bayesian inference [], and most recently to using a multidimensional analysis of sequence correlation and jump distance []. Unfortunately, with the improved use of statistics has also come their misuse. For instance, it is important to compare like with like. Firing rates in place cells, as well as the behavioural and sensory experience of the animal, vary dramatically between sleep and awake states. Comparing trajectory events between these two states can be problematic, especially given that many of the methods employed depend on neuronal firing rates. Similarly, it is incorrect to compare the best correlation scores from multiple sequence templates with a single shuffled template. Another concern is the issue of event independence. Statistical methods generally assume that each event being compared is independent. We assume that each neuron generates its activity independently of the other neurons. However, some studies have treated all spikes generated by a neuron (rather than only the first spike) as independent events. This is problematic because place cells typically fire in bursts, generating non-independent events. 6 Dragoi G.

Tonegawa S. Preplay of future place cell sequences by hippocampal cellular assemblies. Finally, it is important to note that the strongest evidence supporting de novo pre-play has only found approximately 7% of trajectory events pre-playing a single trajectory []. Thus the number of pre-play events observed in these studies is more frequent than chance levels, but not by much. Therefore ‘statistical clarity’ is more important than ever to either properly dismiss or support the view that the hippocampus maps out the future de novo.

Acknowledgments D.B. received support from an ERC starter grant and H.J.S. received support from a James S. McDonnell Foundation Scholar Award.

Article Info Publication History Identification DOI: https://doi.org/10.1016/j.tics.2016.01.003 Copyright © 2016 Published by Elsevier Inc. ScienceDirect Access this article on ScienceDirect