Ensemble Place Codes in Hippocampus: CA1, CA3, and Dentate Gyrus Place Cells Have Multiple Place Fields in Large Environments

Previously we reported that the hippocampus place code must be an ensemble code because place cells in the CA1 region of hippocampus have multiple place fields in a more natural, larger-than-standard enclosure with stairs that permitted movements in 3-D. Here, we further investigated the nature of hippocampal place codes by characterizing the spatial firing properties of place cells in the CA1, CA3, and dentate gyrus (DG) hippocampal subdivisions as rats foraged in a standard 76-cm cylinder as well as a larger-than-standard box (1.8 m×1.4 m) that did not have stairs or any internal structure to permit movements in 3-D. The rats were trained to forage continuously for 1 hour using computer-controlled food delivery. We confirmed that most place cells have single place fields in the standard cylinder and that the positional firing pattern remapped between the cylinder and the large enclosure. Importantly, place cells in the CA1, CA3 and DG areas all characteristically had multiple place fields that were irregularly spaced, as we had reported previously for CA1. We conclude that multiple place fields are a fundamental characteristic of hippocampal place cells that simplifies to a single field in sufficiently small spaces. An ensemble place code is compatible with these observations, which contradict any dedicated coding scheme

Remapping and the active subset across hippocampal subregions.

<p>In each subregion, a greater proportion of place cells were active in the box than the cylinder. Note that the proportion of DG cells that were active in both environments was higher than the proportions in the CA3 and CA1 areas (test of proportions z≥2.52, p<0.01). Only cells with an overall firing rate>0.1 AP/s in at least one environment were analyzed. The number of cells is given in parentheses.</p

An example of remapping in an ensemble of DG cells.

<p>A) The standard and B) the altered visual environments. The blue-to-red color-coded firing rate maps are shown for a 9-cell ensemble of place cells that were recorded from the region of the dentate gyrus. The maps illustrate remapping between the two environments. The number below each map is the lowest rate in the red color category.</p

Examples of A) CA1, B) CA3, and C) DG spatial firing patterns in the cylinder and box.

<p>A histological section illustrating the recording location as well as five simultaneously-recorded place cells is given for each example. The number below each firing rate map is the lowest rate in the red color category.</p

Comparison of CA1, CA3, and DG average place field properties in the cylinder and box.

<p>Place field A) number; B) size; and C) spatial organization, D) proportion of active pixels.</p

Computer-controlled foraging behavior.

<p>A) Examples of a rat's path through the box during its first 3 exposures. This rat learned to forage throughout the box rapidly. By the third 60-min session the rat was foraging throughout the box. B) Spatial exploration throughout the box improved rapidly with the computer-controlled foraging we implemented (F_7,28 = 41.7, p = 10⁻¹³).</p

Summary of single unit isolation quality and its relationship to the number of place fields.

<p>At most, only 13% of the variance in number of firing fields observed in the box is explained by single unit isolation quality. Note also that more cells are active in the box than the cylinder (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0022349#pone-0022349-t002" target="_blank">Table 2</a>; Fenton et al., 2008), making single unit isolation more difficult in the box. Significant Pearson correlations are in bold.</p

Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1

<div><p>Behavior is used to assess memory and cognitive deficits in animals like Fmr1-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal Cornu Ammonis 1 (CA1) hippocampus. During a shocked-place avoidance task, slow gamma (SG) (30–50 Hz) dominates mid-frequency gamma (MG) (70–90 Hz) oscillations 2–3 s before successful avoidance, but not failures. Wild-type (WT) but not Fmr1-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SG_dom) decrease in WT but not in cognitively inflexible Fmr1-null mice. During SG_dom, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, WT ensembles represent distant locations near the currently correct shock zone, but Fmr1-null ensembles represent the formerly correct zone. These findings indicate that recollection occurs when CA1 SG dominates MG and that accurate recollection of inappropriate memories explains Fmr1-null cognitive inflexibility.</p></div

SG dominates MG prior to successful place avoidance.

<p>(A) Left: typical 30-min path during the third active place avoidance training session. Shocks are shown as red dots. Right: example of avoidance (success; blue line) and escape after receiving a shock (error; red line). (B) Top: time profile of the angular distance to the leading edge of the shock zone, showing a typical sawtooth avoidance pattern during approximately 60 s. Periods of stillness (green) when the mouse is passively carried towards the shock zone are interrupted by active avoidances (blue dots). Entrance to the shock zone is marked as a red dot. The horizontal blue and red lines mark time intervals of the example avoidance and escape from panel (A), right. The red dotted line marks the leading edge of the shock zone. Bottom: speed profile during the same approximately 60-s interval. The stillness threshold is shown as a green dotted line at 2 cm/s. (C) Schematic depiction of the working hypothesis—as the mouse approaches the shock zone (top), SG driven by CA3 inputs transiently dominates MG driven by ECIII inputs, causing recollection of the shock zone location. (D) Top: average power of SG (blue; 30–50 Hz) and MG (yellow; 70–90 Hz) in the LFP around the time of avoidance initiation (<i>T</i> = 0). Mean powers are displayed as dotted lines. Inset shows average of normalized power across 20–120 Hz around avoidance initiation. Representative SG and MG bands are marked by white rectangles. Bottom: the average ratio of SG to MG power (red line) around avoidance initiation. The mean power ratio is shown as a dotted line. The corresponding average speed profile is shown in green. Data are represented as average ± SEM. Gray boxes represent time intervals for statistical comparisons, *<i>p</i> < 0.05 relative to baseline (−7–−5 s). (E) The time-frequency representation of a 4-s example LFP (overlaid in black) around the initiation of an avoidance start (<i>T</i> = 0 marks avoidance initiation). Notice the relative reduction in number of MG (70–90 Hz) oscillatory events relative to SG (30–50 Hz) events prior to the avoidance (<i>T</i> = approximately −2 s) compared to times during the active avoidance (<i>T</i> > 0 s). (F) Left, top: average event rates for SG (blue; 30–50 Hz) and MG (yellow; 70–90 Hz) oscillations around the time of avoidance initiation (<i>T</i> = 0). Mean rates are displayed as dotted lines. Left, bottom: the average ratio of SG to MG event rates (red line) around avoidance initiation. The mean ratio is shown as a dotted line. The corresponding average speed profile is shown in green. Right: same as (F), left, but for avoidance errors. Data are represented as average ± SEM. Gray boxes represent time intervals for statistical comparisons, *<i>p</i> < 0.05 relative to baseline (−5–−3 s). CA3, Cornu Ammonis 3; ECIII, entorhinal cortex layer 3; LFP, local field potential; MG, mid-frequency gamma; SG, slow gamma. <i>Underlying data can be found here</i>: [<a href="https://goo.gl/oHH22A" target="_blank">https://goo.gl/oHH22A</a>].</p

Error in Bayesian decoding of location increases during SG_dom events.

<p>(A) Example firing-rate maps (top) and 2D decoded Bayesian posterior around avoidance onset. Ensemble activity vectors are shown to the right of each decoded Bayesian posterior. The mouse’s path during a 12-s segment is shown as a white line and the current position is marked by a red cross. (B) Example time series of the angular position that was observed and decoded using a 1D Bayesian estimator from ensemble discharge overlaid with the SG/MG ratio. <i>T</i> = 0 s marks avoidance onset. (C) The average of WT and Fmr1-KO z-score normalized 1D decoding error from ensemble activity that is time-locked to SG_dom events, MG_dom events, and RNDs. <i>T</i> = 0 s corresponds to the time of the events. (D) Summary of decoding error at the moments of SG_dom events, MG_dom events, and RNDs for WT and KO mice. *<i>p</i> < 0.05 relative to random. Data are represented as average ± SEM. KO, knockout; MG, mid-frequency gamma; RND, random time; SG, slow gamma; WT, wild-type. <i>Underlying data can be found here</i>: [<a href="https://goo.gl/oHH22A" target="_blank">https://goo.gl/oHH22A</a>].</p