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. 2017 Feb 8;93(3):677-690.e5.
doi: 10.1016/j.neuron.2016.12.026. Epub 2017 Jan 26.

Spatial Representations of Granule Cells and Mossy Cells of the Dentate Gyrus

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Free PMC article

Spatial Representations of Granule Cells and Mossy Cells of the Dentate Gyrus

Douglas GoodSmith et al. Neuron. .
Free PMC article

Abstract

Granule cells in the dentate gyrus of the hippocampus are thought to be essential to memory function by decorrelating overlapping input patterns (pattern separation). A second excitatory cell type in the dentate gyrus, the mossy cell, forms an intricate circuit with granule cells, CA3c pyramidal cells, and local interneurons, but the influence of mossy cells on dentate function is often overlooked. Multiple tetrode recordings, supported by juxtacellular recording techniques, showed that granule cells fired very sparsely, whereas mossy cells in the hilus fired promiscuously in multiple locations and in multiple environments. The activity patterns of these cell types thus represent different environments through distinct computational mechanisms: sparse coding in granule cells and changes in firing field locations in mossy cells.

Keywords: dentate gyrus; granule cell; hilus; mossy cell; pattern separation.

Figures

Figure 1
Figure 1. DG circuit, experimental design, and example cells recorded in the GCL, hilus, and CA3
A) Schematic of the DG (left) with granule cells (blue), CA3 cells (green), and mossy cells (red) in the hilus (shaded). To the right is a simplified diagram of the numerous connections between these cell types and dentate interneurons. B) Schematic of experimental procedure including sleep sessions and four foraging sessions in 4 distinct rooms. C) Example cells recorded on the final day from tetrodes located clearly in the hilus (top), GCL (middle), and CA3 (bottom). For each cell, the deepest point of the tetrode track is shown (left, marked by arrows). In the GCL and CA3, both example cells were recorded on the same tetrode. One cluster projection is shown for each cell (middle) in both the post-behavior sleep session and during one foraging session. Note that cells in the hilus tended to be active during both sleep and behavior (dense clusters in both projections), whereas cells in the GCL and CA3 tended to be more active during sleep with only a fraction active during behavior. The firing of the cell in all four sessions is shown on the right. For each session, the grey line represents the rat’s trajectory, with the location of spikes plotted in red. The two cells in the hilus had multiple fields in multiple rooms, whereas the cells in the GCL and CA3 were mostly silent in most environments, and they had a single field in one room when they were active.
Figure 2
Figure 2. Spatial firing of cells recorded on the final day of recording and on tetrodes located clearly in the GCL, hilus, or CA3
A) Number of rooms with place fields for cells in the GCL (left), hilus (middle), and CA3 (right). B) Number of fields in each recording session. Each cell contributed four values (one for each session). C) Histogram of average sparseness ratio for each tetrode. A value of 1 means that all cells on the tetrode were active in all rooms; values near 0 mean that most cells were silent. D) Cumulative density function (CDF) of the mean firing rates of cells during sleep. Cells in the hilus had higher mean firing rates than cells in the GCL or CA3. E-F) CDF of mean firing rates (E) and peak firing rates (F) in the most active room for cells with a field in at least one environment (left) or all cells (right).
Figure 3
Figure 3. Distribution of response types recorded simultaneously from individual tetrodes
For each tetrode, the recording day with the most active cells during sleep was selected. This produced a set of 242 cells from 57 tetrodes, shown here. A) Each tetrode was sorted into anatomical regions. Tetrodes that ended clearly in the GCL, hilus, or CA3, and either were recorded on the final day or had not been moved between the recording day and perfusion, were separated from tetrodes which were estimated based on histology to be near the GCL/hilus or hilus/CA3 boundaries at the time of recording. Tetrodes were sorted within each area by the average mean firing rate during sleep of all cells on the tetrode. Tetrodes in each area are arranged from lowest to highest average firing rate or vice versa (labeled low → high or high → low). Cells silent in all environments are plotted downward and cells active in at least one room are plotted upward. Some tetrodes (marked with arrows) recorded simultaneously cells that were active in all rooms and cells that were silent or only active in a single room; these recordings were most often localized to ambiguous recording sites. B) An example tetrode (marked by red arrow in A). This tetrode ended at the border between the GCL and hilus (left, white arrow). The firing of all three cells (recorded on the final day) during the 4 foraging sessions is shown on the right. One cell had multiple fields in all environments while the other two cells were mostly silent.
Figure 4
Figure 4. Spatial firing of cells from the larger dataset classified as putative GCL, hilus, and CA3 cells by the random forests classifier
The 5 features used by the classifier were mean firing rate, burst index (proportion of all inter-spike intervals that are ≤ 6 ms), number of well-isolated units recorded simultaneously on the same tetrode, channel slope (slope of the best fit line through the normalized, sorted peak amplitudes of the average waveform on the four tetrode wires), and proximity of the tetrode tip to either the GCL or CA3 (Figure S4A). Classified cells had distributions of firing properties that were very similar to the initial training set based on histological classification (Figure 2). All p values represent the results of Dunn’s tests and are adjusted for multiple comparisons. A) Number of active rooms. The number of rooms with fields was higher for cells classified as hilus than cells classified as GCL or CA3, even when only considering active cells (Table S1). B) Number of fields in each recording session and C) number of fields excluding sessions with no fields. Cells in the hilus were more likely to have multiple firing fields in a recording session than cells in the GCL or CA3, which were silent in the majority of behavior sessions and typically had single fields when active. D) Number of fields per room (total number of fields divided by the number of active rooms, excluding silent cells). Cells classified as hilus cells had more fields per room (2.20 ± 0.13) than GCL (1.33 ± 0.09) or CA3 cells (1.35 ± 0.07).
Figure 5
Figure 5. Spatial firing properties of juxtacellularly recorded and identified granule cells
A) Left, rat’s trajectory (gray lines) superimposed by the firing locations of the neuron (red dots). Middle, rate map where red represents the highest firing rate and blue represents no firing. The peak firing rate is shown above each rate map. Right, binary image showing pixels where the firing rate was > 20% of the peak firing rate. B) Left, representative voltage traces recorded during freely moving behavior. Bandpass-filtered (300 Hz – 6 kHz) (top) and raw traces (bottom) are shown. Scale bars: 1 s (horizontal) and 1 mV (vertical). Middle, mean (black line) and standard deviation (gray lines) of spike waveforms. Right, inter-spike interval histograms. C) Fluorescent image showing the morphology and location of the labelled neuron (green, Neurobiotin; blue, DAPI). Right, camera lucida reconstructed morphology (soma and dendrite, black; axon, red; GCL border, blue). Scale bar: 50 µm. D–I) Further example granule cells located in upper blade (D–F) and lower blade (G–I) of the GCL are shown with the same conventions as (A–C). The 6 ms burst indices for these 3 granule cells were 0.16 (B), 0.16 (E) and 0.13 (H), respectively.
Figure 6
Figure 6. Spatial firing properties of juxtacellularly recorded and identified mossy cells
A–C) One mossy cell with 3 firing fields. A-B) Same convention used for Figure 5A–B. Scale bars in B: 1 sec (horizontal) and 1 mV (vertical). C) Top middle, the morphology and location of the recorded cell. The inset to the right shows a magnified view, where large spines (“thorny excrescences”) covering the soma and proximal dendrites, typical of mossy cells, can be clearly seen. The camera lucida reconstructed morphology of the mossy cell is shown at left. The boundaries of GCL and CA3 are represented with blue lines. Bottom, antibody staining of the cell (left to right: merge, Neurobiotin, GluR2/3, DAPI). The labeled cell (indicated with arrows) is positive for GluR2/3. Scale bar: 50 µm. (D–F) A mossy cell with 2 firing fields. Note that only the soma and parts of the dendritic arbor of the cell were recovered after labeling. The identity of this mossy cell was confirmed by the location of the cell body (in the hilus), the GluR2/3+ signal, as well as some large spines on the cell body (F, top right panel). (G–I) A mossy cell close to the lower blade of the GCL with a single field. Although only one labeling attempt was made, three cells were labeled in this rat. We believe that the recorded cell was a mossy cell because the deepest labeled cell was adjacent to the pipette tip, was located in the hilus (I, top), and was GluR2/3+ (I, bottom). The 6 ms burst indices for these 3 mossy cells were 0.17 (B), 0.11 (E) and 0.19 (H), respectively.
Figure 7
Figure 7. Different mechanisms to support pattern separation in putative mossy cells vs. granule cells and CA3 cells
A) For each session pair (4 rooms, 6 pairs per cell), the mean firing rate in one session is plotted against the mean rate for the other session. This was done for all cells active in at least one environment. Cells in the GCL (top) and CA3 (bottom) were usually silent in all but one room when active, causing most points to lie near an axis. Cells in the hilus (middle) were more likely to have high firing rates in multiple sessions. B) Histogram of the mean value of rate overlap for each of 100 shuffles of active cells in the GCL (top), hilus (middle), and CA3 (bottom). The red line indicates the observed mean of rate overlap values. The observed value is not significantly different from the shuffled distributions for the GCL (p = 0.45) or CA3 (p = 0.43) but the observed value is greater than all shuffles in the hilus (p < .01). C) Histogram of observed ratemap correlations between pairs of sessions (excluding pairs with no fields in either room). The shaded region represents the 95th percentile of correlation values obtained from shuffled distributions. In all three areas, the observed correlations exceed this value < 5% of the time (i.e., no more than as expected by chance).

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