Overdispersion: Navigating Noise, Learning and Remembering.

A Quarter of a Century of Place Cells

Temporal Encoding of Place Sequences by Hippocampal Cell Assemblies

Decision letter: ‘Fearful-place’ coding in the amygdala-hippocampal network

Increased Size and Stability of CA1 and CA3 Place Fields in HCN1 Knockout Mice

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.

Bob Muller, friend, colleague, and place-cell pioneer, died following a heart attack on Sept 16, 2013. He was 71 years old. Figure 1 shows Bob at the early stages of place cell recording. FIGURE 1 Bob and John Kubie (approx. 1985) in the “large rectangle” recording chamber. [Color figure can be viewed in the online issue, which is available at http://wileyonlinelibrary.com.]

Hippocampal Place Cells Acquire Location-Specific Responses to the Conditioned Stimulus during Auditory Fear Conditioning

On the linear track, the recent firing sequences of CA1 place cells recur during sharp wave/ripple patterns (SWRs) in a reverse temporal order [Foster & Wilson (2006) Nature, 440, 680–683]. We have found similar reverse-order reactivation during SWRs in open-field exploration where the firing sequence of cells varied before each SWR. Both the onset times and the firing patterns of cells showed a tendency for reversed sequences during SWRs. These effects were observed for SWRs that occurred during exploration, but not for those during longer immobility periods. Additionally, reverse reactivation was stronger when it was preceded by higher speed (> 5 cm/s) run periods. The trend for reverse-order SWR reactivation was not significantly different in familiar and novel environments, even though SWR-associated firing rates of both pyramidal cells and interneurons were reduced in novel environments as compared with familiar. During exploration-associated SWRs (eSWR) place cells retain place-selective firing [O'Neill et al. (2006) Neuron, 49, 143–155]. Here, we have shown that each cell's firing onset was more delayed and firing probability more reduced during eSWRs the further the rat was from the middle of the cell's place field; that is, cells receiving less momentary place-related excitatory drive fired later during SWR events. However, even controlling for place field distance, the recent firing of cells was still significantly correlated with SWR reactivation sequences. We therefore propose that both place-related drive and the firing history of cells contribute to reverse reactivation during eSWRs.

The firing of hippocampal place cells encodes instantaneous location but can also reflect where the animal is heading (prospective firing), or where it has just come from (retrospective firing). The current experiment sought to explicitly control the prospective firing of place cells with a visual discriminada in a T-maze. Rats were trained to associate a specific visual stimulus (e.g., a flashing light) with the occurrence of reward in a specific location (e.g., the left arm of the T). A different visual stimulus (e.g., a constant light) signaled the availability of reward in the opposite arm of the T. After this discrimination had been acquired, rats were implanted with electrodes in the CA1 layer of the hippocampus. Place cells were then identified and recorded as the animals performed the discrimination task, and the presentation of the visual stimulus was manipulated. A subset of CA1 place cells fired at different rates on the central stem of the T depending on the animal's intended destination, but this conditional or prospective firing was independent of the visual discriminative stimulus. The firing rate of some place cells was, however, modulated by changes in the timing of presentation of the visual stimulus. Thus, place cells fired prospectively, but this firing did not appear to be controlled, directly, by a salient visual stimulus that controlled behavior.

Most of our cognitive life depends on our brain's ability to generate internal representations of the external world. The hippocampus is a brain structure that supports the formation of internal representations of the spatial environment (O'Keefe and Nadel, 1978) as well as the formation (Scoville and Milner, 1957) and consolidation (Squire and Alvarez, 1995) of episodic memories. In rodents, hippocampal pyramidal cells are active at discrete places along the trajectory of the animal in linear and two-dimensional spatial environments, and therefore are called place cells (O'Keefe and Dostrovsky, 1971). During exploratory behavior, the firing rates of individual place cells are thought to encode the moment-to-moment location of the animal in space (O'Keefe and Dostrovsky, 1971; Wilson and McNaughton, 1993). With reference to the background local field potential theta oscillation (~8 Hz), individual place cells oscillate at slightly faster frequency (~10 Hz) and fire at more advanced theta phases the further the animal travels through the cell's place field, a phenomenon called phase precession (O'Keefe and Recce, 1993; Skaggs et al., 1996; Huxter et al., 2008). Since most place cells go through almost a full 360° cycle of precession from the beginning to the end of their place field (O'Keefe and Recce, 1993), the theta phase of firing is thought to encode the distance of the animal relative to the beginning of the place field (Huxter et al., 2003).

There are two prominent features for place cells in rat hippocampus. The firing rate remarkably increases when rat enters the cell's place field and reaches a maximum around the center of place field, and it decreases when the animal approaches the end of the place field. Simultaneously the spikes gradually and monotonically advance to earlier phase relative to hippocampal theta rhythm as the rat traverses along the cell's place field, known as temporal coding. In this paper, we investigate whether two main characteristics of place cell firing are independent or not by mainly focusing on the generation mechanism of the unimodal tuning of firing rate by using a reduced CA1 two-compartment neuron model. Based on recent evidences, we hypothesize that the coupling of dendritic with the somatic compartment is not constant but dynamically regulated as the animal moves further along the place field, in contrast to previous two-compartment modeling. Simulations show that the regulable coupling is critically responsible for the generation of unimodal firing rate profile in place cells, independent of phase precession. Predictions of our model accord well with recent observations like occurrence of phase precession with very low as well as high firing rate (Huxter et al. Nature 425:828-832, 2003) and persistency of phase precession after transient silence of hippocampus activity (Zugaro et al. Nat Neurosci 8:67-71, 2005.

The hippocampal formation contains the head direction cells, the grid cells and the place cells which work as an internal GPS for the brain. The head directions cells can sense the direction in which the animal is moving, based on which the entorhinal grid cells fire at regular intervals as the animal is at the corners of an equilateral triangle and the hippocampal place cells [1] fire when the animal is at a place in the environment. Several mathematical models [2] have been proposed to explain firing pattern of the place cells, most of which consider place cell firing to be the result of integration of either sensory or processed motor inputs (received via the grid cells). Only the oscillatory interference model mentions the role of both sensory and motor inputs in place cell firing but does not explain how this information is remembered. However, empirical observations [2-6] indicate a role for both the sensory and the grid cell inputs in place cell firing and a one to one correspondence between the grid and the place cell firing patterns. Anatomical evidence [7] indicates that an area of the medial entorhinal cortex is primarily connected to a similar area of the hippocampus along the dorso-ventral axis. All the above is not possible if the place cell firing depended on integration of inputs from several grid cells or on integration of either sensory or motor inputs alone as proposed by the current models. Moreover, the animals without binocular vision, in whom most place cell recordings have been done, ought to have different mechanism for mapping the environment than those with binocular vision. Due to lack of depth perception, the former could be using the matrix formed by grid cells to hang the objects as seen by their eyes to get an accurate estimate of position. Therefore, we propose that the place cells integrate both sensory and motor inputs to them in a Bayes' optimal manner (Fig. ​(Fig.1).1). Also each place cell is connected to only one grid cell. As the animal enters an environment, the place cell resets. While the animal moves around in the environment, the grid cell firing causes movement along the ring of intermediate cells which wraps around. As soon as the sensory inputs identify the place to be of significance and cause a place cell to fire, by Hebbian learning, synapses develop between the place cell and the intermediate neuron which is firing concurrently in the ring. These synaptic connections help the animal to retrieve the location correctly during future encounters. This model offers improvements over the prior models as it explains the empirical observations more closely. Figure 1 Sensorimotor model of the hippocampal place cells. A) Hexagonal grid cell firing gets integrated on to B) the ring of intermediate neurons. C) Together sensory and motor inputs are integrated in a Bayes' optimal manner on the place cell.

The hippocampus

The properties of hippocampal place cells are reviewed, with particular attention to the nature of the internal and external signals that support their firing. A neuronal simulation of the firing of place cells in open-field environments of varying shape is presented. This simulation is coupled with an existing model of how place-cell firing can be used to drive navigation, and is tested by implementation as a miniature mobile robot. The sensors on the robot provide visual, odometric and short-range proximity data, which are combined to estimate the distance of the walls of the enclosure from the robot and the robot's current heading direction. These inputs drive the hippocampal simulation, in which the robot's location is represented as the firing of place cells. If a goal location is encountered, learning occurs in connections from the concurrently active place cells to a set of 'goal cells', which guide subsequent navigation, allowing the robot to return to an unmarked location. The system shows good agreement with actual place-cell firing, and makes predictions regarding the firing of cells in the subiculum, the effect of blocking long-term synaptic changes, and the locus of search of rats after deformation of their environment.

Hippocampal "place cells" fire when a freely moving rat is in a given location. The firing of these cells is controlled by visual and nonvisual environmental cues. The effects of darkness on the firing of place cells was studied using the task of Muller et al. (1987), in which rats were trained to chase randomly scattered food pellets in a cylindrical drum with a white cue-card attached to the wall. The position of the rats was tracked via an infrared LED on the headstage with a video system linked to computer. Two experimental protocols were used: in the first, lights were turned off after the rat had already been placed in the chamber; in the second, the rat was placed in the darkened chamber. The dark segments produced by these 2 methods were identical with respect to light and other cues but differed with respect to the rat's experience. The firing patterns of 24 of 28 cells were unaffected by darkness when it was preceded by a light period. In contrast, the firing patterns of 14 of 22 cells changed dramatically when the rats were put into the darkened chamber. Furthermore, the majority of cells that changed their firing pattern in initial darkness maintained that change when the lights were turned on. These results show that place cells can fire differently in identical cue situations and that the best predictor of firing pattern is a combination of current cues and the rat's recent experience. The results are discussed in terms of mnemonic properties of hippocampal cells and "remapping" of place cell representations.