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Cited by 1,865Memory and Neural MechanismsSpatial Cognition and NavigationNeuroscience and Neuropharmacology Research

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Perineuronal nets stabilize the grid cell network

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Christensen, Ane Charlotte, Lensjø, Kristian Kinden, Lepperød, Mikkel Elle, Dragly, Svenn-Arne, Sutterud, Halvard, Blackstad, Jan Sigurd, Fyhn, Marianne, Hafting, Torkel·2021·Nature Communications
DOI 10.1038/s41467-020-20241-wPMC PMC7801665

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Abstract

Grid cells are part of a widespread network which supports navigation and spatial memory. Stable grid patterns appear late in development, in concert with extracellular matrix aggregates termed perineuronal nets (PNNs) that condense around inhibitory neurons. It has been suggested that PNNs stabilize synaptic connections and long-term memories, but their role in the grid cell network remains elusive. We show that removal of PNNs leads to lower inhibitory spiking activity, and reduces grid cells' ability to create stable representations of a novel environment. Furthermore, in animals with disrupted PNNs, exposure to a novel arena corrupted the spatiotemporal relationships within grid cell modules, and the stored representations of a familiar arena. Finally, we show that PNN removal in entorhinal cortex distorted spatial representations in downstream hippocampal neurons. Together this work suggests that PNNs provide a key stabilizing element for the grid cell network.

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Fig. 1 Degradation of perineuronal nets alters synaptic connections and neuron spiking activity. a Schematic outline of parahippocampal areas. Sagittal section from rat brain stained for WFA+ PNNs (cyan) and PV+ neurons (red). PNNs are strongly expressed in MEC and parasubiculum (PaS), while there is weaker staining in presubiculum (PrS) and postrhinal cortex (POR). The overlap between PNNs and PV+ neurons is high. Right, high-magnification image of PV+ neuron in MEC, note that PNN enwrap the cell soma and large parts of proximal dendrites. b Histological verification of chABC activity. Anti-chondroitin sulfate (3B3) antibody (magenta) label 6-sulfated unsaturated disaccharide (C-6-S) stubs left from enzymatic degradation of PNNs by chABC. Intact PNN staining (cyan) is greatly reduced after chABC injection and C-6-S stubs shows the full extent of the injection area. c VGAT expressing puncta on a PV+ cell in MEC 5 days after injection of aCSF (control, top panel) or chABC (lower panel). d The number of VGAT expressing puncta on PV soma is reduced after local chABC treatment in MEC (VGAT: mean ± s.e.m.; Control (n = 31 cells) 63.29 ± 4.038; chABC (n = 32) 46.34 ± 2.48, p = 0.002; VGLUT1: Control (n = 18) 60.94 ± 5.48; chABC (n = 32) 49.44 ± 3.13, p = 0.078; VGLUT2: Control (n = 27) 20.54 ± 2.64; chABC (n = 32) 20.74 ± 2.35, p = 0.67. N = 3 animals, Mann–Whitney U test (two sided). e Illustration of open field recording setup and timeline for experiments. f Cumulative distribution of mean spike rates for broad- and narrow-spiking units from controls and chABC-treated rats. Both unit types showed reduced spike rates in animals with disrupted PNNs (median (n); control broad spiking 1.16 Hz (296); chABC broad spiking 1.01 Hz (287), p = 0.01, U = 47688; control narrow spiking 2.46 Hz (73); chABC narrow spiking 1.52 Hz (177), p = 0.03, U = 7586, Mann–Whitney U test (two sided). Insets: violin plot shows min to max and median (large black line). ns = not significant, *p < 0.05, **p < 0.01. Source data are provided as a Source Data file.
Fig. 1 Degradation of perineuronal nets alters synaptic connections and neuron spiking activity. a Schematic outline of parahippocampal areas. Sagittal section from rat brain stained for WFA+ PNNs (cyan) and PV+ neurons (red). PNNs are strongly expressed in MEC and parasubiculum (PaS), while there is weaker staining in presubiculum (PrS) and postrhinal cortex (POR). The overlap between PNNs and PV+ neurons is high. Right, high-magnification image of PV+ neuron in MEC, note that PNN enwrap the cell soma and large parts of proximal dendrites. b Histological verification of chABC activity. Anti-chondroitin sulfate (3B3) antibody (magenta) label 6-sulfated unsaturated disaccharide (C-6-S) stubs left from enzymatic degradation of PNNs by chABC. Intact PNN staining (cyan) is greatly reduced after chABC injection and C-6-S stubs shows the full extent of the injection area. c VGAT expressing puncta on a PV+ cell in MEC 5 days after injection of aCSF (control, top panel) or chABC (lower panel). d The number of VGAT expressing puncta on PV soma is reduced after local chABC treatment in MEC (VGAT: mean ± s.e.m.; Control (n = 31 cells) 63.29 ± 4.038; chABC (n = 32) 46.34 ± 2.48, p = 0.002; VGLUT1: Control (n = 18) 60.94 ± 5.48; chABC (n = 32) 49.44 ± 3.13, p = 0.078; VGLUT2: Control (n = 27) 20.54 ± 2.64; chABC (n = 32) 20.74 ± 2.35, p = 0.67. N = 3 animals, Mann–Whitney U test (two sided). e Illustration of open field recording setup and timeline for experiments. f Cumulative distribution of mean spike rates for broad- and narrow-spiking units from controls and chABC-treated rats. Both unit types showed reduced spike rates in animals with disrupted PNNs (median (n); control broad spiking 1.16 Hz (296); chABC broad spiking 1.01 Hz (287), p = 0.01, U = 47688; control narrow spiking 2.46 Hz (73); chABC narrow spiking 1.52 Hz (177), p = 0.03, U = 7586, Mann–Whitney U test (two sided). Insets: violin plot shows min to max and median (large black line). ns = not significant, *p < 0.05, **p < 0.01. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 2 Grid cells show reduced spatial coding after PNN removal. a, b Example grid cells from control and chABC-treated rats. Color-coded rate maps (top), running path with spikes superimposed (middle) and spatial autocorrelation maps (bottom) for four grid cells in controls (a) and four grid cells in chABC-treated rats (b). The number above the rate map is maximum firing rate and the number above the autocorrelation map is gridness score. c Removing PNNs did not reduce gridness in the familiar environment (median; Control 0.63; chABC 0.56, p = 0.694). d The dispersed spiking outside grid cell fields caused the spatial specificity of grid cells to decrease (median; Control 0.57; chABC 0.45, p < 0.0001), in addition to reducing the e spatial information (median; Control 0.36; chABC 0.2, p < 0.0001). f Maximum firing rate was reduced (median; Control 9.32; chABC 6.93, p = 0.009). g Grid cell bursting ratio was measured as the number of bursting events divided by the number of single-spike events. Rats with disrupted PNNs showed a large reduction in bursting event ratio (median; Control 0.08; chABC 0.02, p < 0.0001). h Spiking variability was measured as the coefficient of variation (CV) of interspike intervals (ISI). The method used here calculates CV of ISI using only spikes from passes though grid fields (Supplementary Fig. 5) (median; Control 0.99; chABC 0.82, p < 0.001). Violin plots show min to max and median (black line). Width of graph corresponds to number of samples for each value. Control n = 86, chABC n = 63. Mann–Whitney U test (two sided). **p < 0.01, ***p < 0.001, ****p < 0.0001. Source data are provided as a Source Data file.
Fig. 2 Grid cells show reduced spatial coding after PNN removal. a, b Example grid cells from control and chABC-treated rats. Color-coded rate maps (top), running path with spikes superimposed (middle) and spatial autocorrelation maps (bottom) for four grid cells in controls (a) and four grid cells in chABC-treated rats (b). The number above the rate map is maximum firing rate and the number above the autocorrelation map is gridness score. c Removing PNNs did not reduce gridness in the familiar environment (median; Control 0.63; chABC 0.56, p = 0.694). d The dispersed spiking outside grid cell fields caused the spatial specificity of grid cells to decrease (median; Control 0.57; chABC 0.45, p < 0.0001), in addition to reducing the e spatial information (median; Control 0.36; chABC 0.2, p < 0.0001). f Maximum firing rate was reduced (median; Control 9.32; chABC 6.93, p = 0.009). g Grid cell bursting ratio was measured as the number of bursting events divided by the number of single-spike events. Rats with disrupted PNNs showed a large reduction in bursting event ratio (median; Control 0.08; chABC 0.02, p < 0.0001). h Spiking variability was measured as the coefficient of variation (CV) of interspike intervals (ISI). The method used here calculates CV of ISI using only spikes from passes though grid fields (Supplementary Fig. 5) (median; Control 0.99; chABC 0.82, p < 0.001). Violin plots show min to max and median (black line). Width of graph corresponds to number of samples for each value. Control n = 86, chABC n = 63. Mann–Whitney U test (two sided). **p < 0.01, ***p < 0.001, ****p < 0.0001. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 3 Reduced grid cell stability in novel environment. a Rate maps of five consecutive 20 min recording sessions from six individual grid cells, recorded in control animals (top) and chABC animals (bottom) during a novel environment experiment. Color code indicates spike rate. Rows correspond to individual units and columns correspond to environment. Maximum spike rate (left) and gridness (right) is denoted above each rate map. b Gridness score is reduced in the novel environment in animals treated with chABC (median (n); Control 0.65 (35); chABC 0.44 (24); p = 0.004, U = 606, Mann–Whitney U test (two sided)). c Spatial correlation measured for blocks of 5-min recordings in the novel environment sessions I and II, measured against the novel environment session III. Only units reaching gridness threshold in Familiar I and that could be identified in all five recording sessions were included. Animals treated with chABC showed reduced spatial correlations in the novel environment (mean ± s.e.m.; Control 0.59 ± 0.03; chABC 0.37 ± 0.04; main effect of group: F(1, 30) = 14.22, p = 0.0007; interaction: F(7, 210) = 4.905, p < 0.0001, Control n = 16; chABC n = 16, two-way repeated measures ANOVA with group and time as factors). Points indicate mean; shaded area represents s.e.m. d Spatial stability of the same units as in c, measured by the within-trial spatial correlation of grid cell rate maps (0–10 min correlated with 10–20 min). Points indicate mean; shaded area represents s.e.m. Spatial stability decreased from Familiar I to Novel I in the chABC-treated group, but not in the control group (median; Control Familiar I 0.67; Control Novel I 0.54, p = 0.086; chABC Familiar I 0.65; chABC Novel I 0.45, p = 0.015, Mann–Whitney U test (two sided)). e Spatial stability was similar for both groups in Familiar I (median; Control 0.67; chABC 0.65, p = 0.629). After exploring the novel environment, chABC animals showed reduced spatial stability upon returning to the familiar environment (Familiar II) (median; Control 0.72; chABC 0.53, p = 0.018, Control n = 16; chABC n = 16, Mann–Whitney U test). f Rate maps of two grid cells when introduced to the novel environment for three consecutive days. g Spatial correlation of grid cells from chABC-treated animals was decreased in the novel environment when comparing day 1 with day 2 (median; Control 0.76, n = 12; chABC 0.41, n = 11, p = 0.004, Mann–Whitney U test (two sided)). Rate map from the third novel session (Novel III) on the first day was used for correlations with day 2. n.s. = not significant, *p < 0.05, **p < 0.01. Source data are provided as a Source Data file.
Fig. 3 Reduced grid cell stability in novel environment. a Rate maps of five consecutive 20 min recording sessions from six individual grid cells, recorded in control animals (top) and chABC animals (bottom) during a novel environment experiment. Color code indicates spike rate. Rows correspond to individual units and columns correspond to environment. Maximum spike rate (left) and gridness (right) is denoted above each rate map. b Gridness score is reduced in the novel environment in animals treated with chABC (median (n); Control 0.65 (35); chABC 0.44 (24); p = 0.004, U = 606, Mann–Whitney U test (two sided)). c Spatial correlation measured for blocks of 5-min recordings in the novel environment sessions I and II, measured against the novel environment session III. Only units reaching gridness threshold in Familiar I and that could be identified in all five recording sessions were included. Animals treated with chABC showed reduced spatial correlations in the novel environment (mean ± s.e.m.; Control 0.59 ± 0.03; chABC 0.37 ± 0.04; main effect of group: F(1, 30) = 14.22, p = 0.0007; interaction: F(7, 210) = 4.905, p < 0.0001, Control n = 16; chABC n = 16, two-way repeated measures ANOVA with group and time as factors). Points indicate mean; shaded area represents s.e.m. d Spatial stability of the same units as in c, measured by the within-trial spatial correlation of grid cell rate maps (0–10 min correlated with 10–20 min). Points indicate mean; shaded area represents s.e.m. Spatial stability decreased from Familiar I to Novel I in the chABC-treated group, but not in the control group (median; Control Familiar I 0.67; Control Novel I 0.54, p = 0.086; chABC Familiar I 0.65; chABC Novel I 0.45, p = 0.015, Mann–Whitney U test (two sided)). e Spatial stability was similar for both groups in Familiar I (median; Control 0.67; chABC 0.65, p = 0.629). After exploring the novel environment, chABC animals showed reduced spatial stability upon returning to the familiar environment (Familiar II) (median; Control 0.72; chABC 0.53, p = 0.018, Control n = 16; chABC n = 16, Mann–Whitney U test). f Rate maps of two grid cells when introduced to the novel environment for three consecutive days. g Spatial correlation of grid cells from chABC-treated animals was decreased in the novel environment when comparing day 1 with day 2 (median; Control 0.76, n = 12; chABC 0.41, n = 11, p = 0.004, Mann–Whitney U test (two sided)). Rate map from the third novel session (Novel III) on the first day was used for correlations with day 2. n.s. = not significant, *p < 0.05, **p < 0.01. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 4 Changes in theta oscillations after PNN removal. a Power spectrum of local field potential in MEC shows that theta oscillations in chABC rats have increased power (dB/Hz) (median; Control familiar 6.12; chABC familiar 4.18; Control novel 7.17; chABC novel 4.8) and lower peak frequency (median; Control familiar 8.39; chABC familiar 8.27; Control novel 8.39; chABC novel 8.09) (solid line: familiar, dotted line: novel, blue: control, red: chABC). Shaded area represents 95% confidence interval. b Mean theta frequency for all animals during recordings in familiar and novel environments (dark colored line). Note the decrease in theta frequency during first exposure to a novel environment in both groups. Dots indicate mean; error bars represent bootstrapped 95% confidence interval. c The mean theta power was similar when the animal was immobile, but the chABC group showed increased theta power during movement. d Power score shows increased correlation between theta power and running speed in animals treated with chABC for both familiar and novel environments (median familiar; Control 0.14 (n = 148 recording sessions); chABC 0.31(n = 75) (U = 2800, p < 0.0001). Novel; Control 0.10 (n = 33); chABC 0.27 (n = 24) (U = 102, p < 0.0001)). e Theta frequency increased slightly with running speed in both groups, but the peak frequency was lower in the chABC-treated group. f Frequency score shows increased correlation between theta frequency and running speed in chABC-treated animals for both familiar and novel environment (median familiar; Control 0.14 (n = 148); chABC 0.20 (n = 75) (U = 3100, p < 0.0001). Novel; Control 0.12 (n = 33); chABC 0.19 (n = 24) (U = 200, p = 0.002)). Number of animals: Control n = 7, chABC n = 7. Mann–Whitney U test (two sided) **p < 0.01, ****p < 0.0001. Source data are provided as a Source Data file.
Fig. 4 Changes in theta oscillations after PNN removal. a Power spectrum of local field potential in MEC shows that theta oscillations in chABC rats have increased power (dB/Hz) (median; Control familiar 6.12; chABC familiar 4.18; Control novel 7.17; chABC novel 4.8) and lower peak frequency (median; Control familiar 8.39; chABC familiar 8.27; Control novel 8.39; chABC novel 8.09) (solid line: familiar, dotted line: novel, blue: control, red: chABC). Shaded area represents 95% confidence interval. b Mean theta frequency for all animals during recordings in familiar and novel environments (dark colored line). Note the decrease in theta frequency during first exposure to a novel environment in both groups. Dots indicate mean; error bars represent bootstrapped 95% confidence interval. c The mean theta power was similar when the animal was immobile, but the chABC group showed increased theta power during movement. d Power score shows increased correlation between theta power and running speed in animals treated with chABC for both familiar and novel environments (median familiar; Control 0.14 (n = 148 recording sessions); chABC 0.31(n = 75) (U = 2800, p < 0.0001). Novel; Control 0.10 (n = 33); chABC 0.27 (n = 24) (U = 102, p < 0.0001)). e Theta frequency increased slightly with running speed in both groups, but the peak frequency was lower in the chABC-treated group. f Frequency score shows increased correlation between theta frequency and running speed in chABC-treated animals for both familiar and novel environment (median familiar; Control 0.14 (n = 148); chABC 0.20 (n = 75) (U = 3100, p < 0.0001). Novel; Control 0.12 (n = 33); chABC 0.19 (n = 24) (U = 200, p = 0.002)). Number of animals: Control n = 7, chABC n = 7. Mann–Whitney U test (two sided) **p < 0.01, ****p < 0.0001. Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 5 PNN removal disrupt the temporal relation between grid cells. a, b Pairwise temporal cross-correlation of grid cells with brighter color showing stronger correlation. Each line represents a cell pair, sorted by maximum value of the central peak. Values range from −1 to 1. Only cells that could be followed through the novel environment recording sessions were included. c Pairwise temporal stability calculated by correlations of pairwise correlations across recording sessions. Grid cells in the familiar environment prior to any change in environmental condition was identified and correlated with the first familiar session at the day of the novel environment experiment. This is seen in the graph as Familiar vs Familiar I. The pairwise stability is significant lower for the chABC-treated group from the familiar to the novel environment (median Familiar I vs Novel I; Control 0.36 (n = 51); chABC 0.21 (n = 45), U = 874, p = 0.045). Furthermore, grid cells from chABC-treated rats show reduced correlations in the familiar environment after the animals have explored the novel environment (median Familiar I vs Familiar II; Control 0.52 (n = 51); chABC 0.20 (n = 29), U = 529, p = 0.036) (see Supplementary Table 5 for statistics). Violin plots show median (black line); colored shades represent 95th percentile. d Pairwise spatial stability calculated across sessions as in c. The pairwise spatial correlations are significant lower in chABC-treated rats than controls when going from the familiar to the novel environment (median; Familiar I vs Novel I; Control 0.10 (n = 51); chABC 0.05 (n = 45), U = 800, p = 0.011) (Supplementary Table 6). All tests are Mann–Whitney U tests (two sided), *p < 0.05, ****p < 0.0001. Spatial pairwise correlations are also reduced in the chABC throughout all sessions in the novel environment (Supplementary Fig. 11). Source data are provided as a Source Data file.
Fig. 5 PNN removal disrupt the temporal relation between grid cells. a, b Pairwise temporal cross-correlation of grid cells with brighter color showing stronger correlation. Each line represents a cell pair, sorted by maximum value of the central peak. Values range from −1 to 1. Only cells that could be followed through the novel environment recording sessions were included. c Pairwise temporal stability calculated by correlations of pairwise correlations across recording sessions. Grid cells in the familiar environment prior to any change in environmental condition was identified and correlated with the first familiar session at the day of the novel environment experiment. This is seen in the graph as Familiar vs Familiar I. The pairwise stability is significant lower for the chABC-treated group from the familiar to the novel environment (median Familiar I vs Novel I; Control 0.36 (n = 51); chABC 0.21 (n = 45), U = 874, p = 0.045). Furthermore, grid cells from chABC-treated rats show reduced correlations in the familiar environment after the animals have explored the novel environment (median Familiar I vs Familiar II; Control 0.52 (n = 51); chABC 0.20 (n = 29), U = 529, p = 0.036) (see Supplementary Table 5 for statistics). Violin plots show median (black line); colored shades represent 95th percentile. d Pairwise spatial stability calculated across sessions as in c. The pairwise spatial correlations are significant lower in chABC-treated rats than controls when going from the familiar to the novel environment (median; Familiar I vs Novel I; Control 0.10 (n = 51); chABC 0.05 (n = 45), U = 800, p = 0.011) (Supplementary Table 6). All tests are Mann–Whitney U tests (two sided), *p < 0.05, ****p < 0.0001. Spatial pairwise correlations are also reduced in the chABC throughout all sessions in the novel environment (Supplementary Fig. 11). Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 6 Continuous attractor model of the grid cell network with altered inhibition. a Schematic outline of the model. Each excitatory unit (green) is connected to distant inhibitory neurons (dark blue), which in turn inhibit excitatory neurons locally. b A population of excitatory neurons (EX) receive external excitatory drive and feedback inhibition by a population of inhibitory neurons (IN). c PNN removal was simulated by reducing the excitatory to inhibitory synaptic strength (lower panel). Rate maps of excitatory neurons show grid pattern for both control and the reduced inhibition network. d The grid cells in the reduced inhibition network show increased out-of-field rate and thereby lower specificity than control, as seen with logarithmic color scale. Note the increased number of green spikes representing rate outside the field. e The average firing rate of both inhibitory and excitatory neurons are lower in the reduced inhibition network (median, inhibitory control: 57; inhibitory reduced inhibition: 41.7; U = 29,940,515, n = 6858 and excitatory control: 1.11; excitatory reduced inhibition: 0.82; U = 15,509,839.5, n = 5398, p < 0.0001, Mann–Whitney U test (two sided)). Source data are provided as a Source Data file.
Fig. 6 Continuous attractor model of the grid cell network with altered inhibition. a Schematic outline of the model. Each excitatory unit (green) is connected to distant inhibitory neurons (dark blue), which in turn inhibit excitatory neurons locally. b A population of excitatory neurons (EX) receive external excitatory drive and feedback inhibition by a population of inhibitory neurons (IN). c PNN removal was simulated by reducing the excitatory to inhibitory synaptic strength (lower panel). Rate maps of excitatory neurons show grid pattern for both control and the reduced inhibition network. d The grid cells in the reduced inhibition network show increased out-of-field rate and thereby lower specificity than control, as seen with logarithmic color scale. Note the increased number of green spikes representing rate outside the field. e The average firing rate of both inhibitory and excitatory neurons are lower in the reduced inhibition network (median, inhibitory control: 57; inhibitory reduced inhibition: 41.7; U = 29,940,515, n = 6858 and excitatory control: 1.11; excitatory reduced inhibition: 0.82; U = 15,509,839.5, n = 5398, p < 0.0001, Mann–Whitney U test (two sided)). Source data are provided as a Source Data file.CC BY · PubMed Central
Fig. 7 Altered hippocampal place code after PNN degradation in MEC. a Examples of place cells recorded in control and chABC-treated rats. Top row: color-coded rate maps; bottom row: running path with spikes superimposed. Maximum spike rate is denoted above the rate maps. b Place cells show reduced in-field rate (median; Control 2.97; chABC 2.03, p = 0.004) and increased out-of field rate in chABC-treated rats (median; Control 0.19; chABC 0.34, p = 0.004). Violin plots show min to max and median (black line). Width of graph corresponds to number of samples for each value. **p < 0.01, ****p < 0.0001 (Mann–Whitney U test (two sided)). c Rate maps of five consecutive 20 min recording sessions during a novel environment experiment. Rows correspond to individual units and columns to environment condition. d Spatial correlation between blocks of 5 min recordings in a novel environment (Novel I and Novel II) against the last 20 min (Novel III) (mean ± s.e.m.; Control 0.65 ± 0.03; chABC 0.46 ± 0.09; main effect of group: F(1, 40) = 6.011, p = 0.0187, Control n = 30; chABC n = 14, two-way repeated measures ANOVA with group and time as factors). Points indicate mean; shaded area represents s.e.m. e Within a session the place code is stable for both groups measured as spatial correlation between first and last 10 min of the session. f The power spectral density (PSD) plot show stronger theta oscillations in chABC-treated animals (red lines) compared to control (blue lines). Lines indicate median; shaded area represent 95% confidence interval. g Mean theta power in hippocampus correlated with running speeds from familiar and novel environment recordings. h Peak theta frequency increases with running speed. Source data are provided as a Source Data file.
Fig. 7 Altered hippocampal place code after PNN degradation in MEC. a Examples of place cells recorded in control and chABC-treated rats. Top row: color-coded rate maps; bottom row: running path with spikes superimposed. Maximum spike rate is denoted above the rate maps. b Place cells show reduced in-field rate (median; Control 2.97; chABC 2.03, p = 0.004) and increased out-of field rate in chABC-treated rats (median; Control 0.19; chABC 0.34, p = 0.004). Violin plots show min to max and median (black line). Width of graph corresponds to number of samples for each value. **p < 0.01, ****p < 0.0001 (Mann–Whitney U test (two sided)). c Rate maps of five consecutive 20 min recording sessions during a novel environment experiment. Rows correspond to individual units and columns to environment condition. d Spatial correlation between blocks of 5 min recordings in a novel environment (Novel I and Novel II) against the last 20 min (Novel III) (mean ± s.e.m.; Control 0.65 ± 0.03; chABC 0.46 ± 0.09; main effect of group: F(1, 40) = 6.011, p = 0.0187, Control n = 30; chABC n = 14, two-way repeated measures ANOVA with group and time as factors). Points indicate mean; shaded area represents s.e.m. e Within a session the place code is stable for both groups measured as spatial correlation between first and last 10 min of the session. f The power spectral density (PSD) plot show stronger theta oscillations in chABC-treated animals (red lines) compared to control (blue lines). Lines indicate median; shaded area represent 95% confidence interval. g Mean theta power in hippocampus correlated with running speeds from familiar and novel environment recordings. h Peak theta frequency increases with running speed. Source data are provided as a Source Data file.CC BY · PubMed Central

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Authors
Christensen, A. C., Lensjø, K. K., Lepperød, M. E., Dragly, S.-A., Sutterud, H., Blackstad, J. S., Fyhn, M., & Hafting, T.
Affiliations
University of Oslo (NO)
Corresponding author
Hafting, Torkel
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-01-11
Volume
12
Issue
1
Pages
253-253
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-20241-w
PMC
PMC7801665
OpenAlex
W3120392574
Cited by
1,865
References
76
Citations by year
2026: 132 · 2025: 277 · 2024: 340 · 2023: 431 · 2022: 499 · 2021: 170
FWCI
189.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • NORA - Norwegian Open Research Archives (submittedVersion, cc-by)
Funders
Norges Forskningsråd (217920, 231248)
Topics
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Spatial Cognition and Navigation
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
perineuronal nets, grid cells, extracellular matrix, inhibitory interneurons, spatial memory, navigation, entorhinal cortex, hippocampus, synaptic stability
MeSH terms
Grid Cells, Action Potentials, Animals, Computer Simulation, Hippocampus, Male, Models, Neurological, Neurons, Theta Rhythm, Time Factors, Entorhinal Cortex, Rats, Long-Evans, Rats

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