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A hippocampal network for spatial coding during immobility and sleep

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ABSTRACT

How does an animal know where it is when it stops moving? Hippocampal place cells fire at discrete locations as subjects traverse space, thereby providing an explicit neural code for current location during locomotion. In contrast, during awake immobility, the hippocampus is thought to be dominated by neural firing representing past and possible future experience. The question of whether and how the hippocampus constructs a representation of current location in the absence of locomotion has stood unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and furthermore does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signaling of location persists into brief periods of desynchronization prevalent in slow-wave sleep. The hippocampus thus generates a distinct representation of current location during immobility, pointing to mnemonic processing specific to experience occurring in the absence of locomotion.

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Hippocampal spatial coding in the rest environmenta, Distribution of correlations (Pearson's r) between firing rate and log speed for each unit population in awake periods in the rest environment. Mean ± s.d.; CA1 (n = 162 units): 0.06 ± 0.07, CA1 vs. 0, p < 10-17, signed-rank; CA3 (n = 75): 0.05 ± 0.08, CA3 vs. 0, p < 10-6, signed-rank; CA2 P (n = 74): 0.01 ± 0.07, CA2 P vs. 0, p = 0.55, signed-rank; CA2 N (n = 64): 0.00 ± 0.07, CA2 N vs. 0, p = 0.77, signed-rank, CA2 N vs. CA2 P, p = 0.47. Only units with significant correlations (p < 0.05) were included (CA1: 162/163 units, CA3: 75/76, CA2 P: 74/76 units, CA2 N: 64/68 units). The N unit population did not show a significant relationship between firing rate and speed, unlike in the task environment (Fig. 2b). The positive correlation between firing rates and speed was also absent in the CA2 P population, suggesting a broader weakening of speed-dependent changes in hippocampal firing in the rest environment. This could be due to the restricted range of speeds in the rest environment enclosure and/or a fundamental influence of task conditions (Extended Data Fig. 1) on hippocampal neural activity. b, Three additional example N unit spatial firing maps in the rest environment. Plotted are data from awake periods. Each column corresponds to data from an individual unit. Upper row: raw maps showing positions visited by the subject (grey) and positions where the unit fired (colored opaque points, plotted chronologically and with darker color values at lower speeds). Total number of spikes (outside of SWRs) in the epoch is reported at upper right. Lower row: occupancy-normalized firing maps. Peak spatial firing rate is reported at upper right. Scale bar: 20 cm. c-g, Awake immobility spatial firing in five example co-recorded pairs of N units from single rest recording epochs. The example pair in c is the same as shown at bottom in Fig. 5d. For each example pair, a unit corresponds to a row. The leftmost two columns (raw and occupancy-normalized firing maps) correspond to data from awake periods, while the rightmost two columns (raw and occupancy-normalized firing maps) correspond to data from awake immobility periods. Reported at upper right are total spike counts (raw maps) or peak spatial rates (occupancy-normalized maps). Bin size: 2.5 cm. Scale bar: 20 cm. Here, the occupancy-normalized maps shown were generated from unsmoothed occupancy-normalized maps by taking the mean firing rate of bins of a 3×3 grid centered on the bin, disregarding bins that were not occupied by the subject. Quantification in h and i was performed on unsmoothed occupancy-normalized maps. h, Spatial information82 of N units in awake periods outside of immobility periods (upper plot, 1.12 ± 0.59 bits/spike, n = 67 units, with one unit excluded due to lack of firing outside of immobility) and awake immobility periods (lower plot, 1.17 ± 0.58 bits/spike, n = 68 units). In both conditions, data during SWR periods were excluded. Spatial information was calculated in the rest epoch in which the unit had the highest mean firing rate during awake periods. As in the task environment, N units exhibited spatially specific firing during immobility. Notably, the rest environment is an additional condition in which N units signaled location, moreover in the absence of material reward (analysis of non-reward locations in the task maze in Extended Data Fig. 5b-d). i, Correlation (Pearson's r) of N unit spatial maps between awake immobility periods and awake non-immobility periods in the rest environment. The correlation was calculated from unsmoothed occupancy-normalized firing maps, specifically for spatial bins in which the subject was immobile. Out of 67 units, 35 showed significant correlation (p < 0.05; 0.53 ± 0.03, mean ± s.e.m.), with no negative correlations observed. Correlations were calculated in the rest epoch in which the unit had the highest mean firing rate during awake periods. These positive correlations indicate that N units retained their spatial specificity into immobility periods. j, Comparison of firing rates across SIA-nesting conditions. Statistical tests (signed-rank, comparison of Nest OUT vs. IN): CA1, SIA ON (n = 18 units), p = 0.014; CA1, SIA OFF (n = 92), p < 10-5; CA3, SIA ON (n = 19), p = 0.60; CA3, SIA OFF (n = 58), p = 0.26; CA2 P, SIA ON (n = 15), p = 0.11; CA2 P, SIA OFF (n = 65), p = 0.0027; CA2 N, SIA ON (n = 18), p = 0.022; CA2 N, SIA OFF (n = 57), p = 0.027. As in the evaluation of the nesting position specificity index (Fig. 5f), these comparisons show that the CA1 and CA2 N unit populations met dual criteria (description in Supplementary Methods) for nesting position coding, while the CA3 unit population did not. Asterisks: *, p < 0.05; **, p < 0.01; ***, p < 0.001; n.s., not significant at p < 0.05. k, SIA firing rate vs. nesting position specificity index for all detected unit-sleep period samples. Here, if data was available for a unit (in the rest unit set) during a detected sleep period, then the unit's SIA firing rate during the sleep period was measured and its nesting position specificity index was calculated with respect to that sleep period's nesting position; this sample is then represented by a scatter point. In this approach, an individual unit can contribute more than one sample. CA1 (n = 312 samples from 94 units): Spearman's ρ: 0.55, p < 10-25. CA3 (n = 223 samples from 62 units): Spearman's ρ: 0.12, p = 0.065. CA2 P (n = 263 samples from 65 units): Spearman's ρ: 0.37, p < 10-9. CA2 N (n = 256 samples from 60 units): Spearman's ρ: 0.33, p < 10-7. l, CA2 P unit distribution of nesting position specificity indices. Mean ± s.e.m.: SIA ON (n = 15): 0.22 ± 0.09, p = 0.048, signed-rank; SIA OFF (n = 65): -0.16 ± 0.04, p < 0.001, signed-rank. Asterisks: *, p < 0.05; ***, p < 0.001. m, STA class proportions across conditions. In addition to STAs calculated from non-SWR immobility in task epochs (TASK, presented in Fig. 4 and Extended Data Figs. 7, 8, 9), STAs were also calculated from non-SWR immobility during awake periods in rest epochs (REST). For REST STAs, as in TASK STAs, a minimum of 100 spikes outside of SWRs during awake immobility and valid LFP reference sites were required, and units with STAs with mixed features were left unclassified (LFP reference site and unclassified STA criteria in Supplementary Methods; unclassified unit counts: CA1: 8 out of 83, CA3: 4 out of 51, CA2 N: 10 out of 58). As in TASK, N wave-coupled units in REST were detected in substantial proportions. In diagrams, STA positive (N wave-coupled) is in light orange, with a darker orange corresponding to significance in the STA voltage at t = 0 (p < 0.05, signed-rank). STA negative is in grey, with black corresponding to significance. Left (pie charts): proportions (%) of units in each of STA classes. Total unit counts (number of units with classified STAs) are reported at bottom right. Percentages are rounded to nearest whole number. Upper right: unit counts in each (non-overlapping) category (* denotes units with STAs with significance at p < 0.05). Lower right: contingency table for CA1 and CA3 units found active in both task and rest epochs (fired >100 spikes outside of SWRs during immobility in at least one task recording epoch and during awake immobility in at least one rest recording epoch) and with classifiable STAs (positive vs. negative). Notably, no units were observed that were STA positive in both conditions, suggesting that N wave-coupling for a given CA1/CA3 neuron is not a static property. In contrast, the majority of classifiable CA2 N units in both TASK (53/57, or 93%) and REST (38/48, or 79%) were N wave-coupled.
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Figure 10: Hippocampal spatial coding in the rest environmenta, Distribution of correlations (Pearson's r) between firing rate and log speed for each unit population in awake periods in the rest environment. Mean ± s.d.; CA1 (n = 162 units): 0.06 ± 0.07, CA1 vs. 0, p < 10-17, signed-rank; CA3 (n = 75): 0.05 ± 0.08, CA3 vs. 0, p < 10-6, signed-rank; CA2 P (n = 74): 0.01 ± 0.07, CA2 P vs. 0, p = 0.55, signed-rank; CA2 N (n = 64): 0.00 ± 0.07, CA2 N vs. 0, p = 0.77, signed-rank, CA2 N vs. CA2 P, p = 0.47. Only units with significant correlations (p < 0.05) were included (CA1: 162/163 units, CA3: 75/76, CA2 P: 74/76 units, CA2 N: 64/68 units). The N unit population did not show a significant relationship between firing rate and speed, unlike in the task environment (Fig. 2b). The positive correlation between firing rates and speed was also absent in the CA2 P population, suggesting a broader weakening of speed-dependent changes in hippocampal firing in the rest environment. This could be due to the restricted range of speeds in the rest environment enclosure and/or a fundamental influence of task conditions (Extended Data Fig. 1) on hippocampal neural activity. b, Three additional example N unit spatial firing maps in the rest environment. Plotted are data from awake periods. Each column corresponds to data from an individual unit. Upper row: raw maps showing positions visited by the subject (grey) and positions where the unit fired (colored opaque points, plotted chronologically and with darker color values at lower speeds). Total number of spikes (outside of SWRs) in the epoch is reported at upper right. Lower row: occupancy-normalized firing maps. Peak spatial firing rate is reported at upper right. Scale bar: 20 cm. c-g, Awake immobility spatial firing in five example co-recorded pairs of N units from single rest recording epochs. The example pair in c is the same as shown at bottom in Fig. 5d. For each example pair, a unit corresponds to a row. The leftmost two columns (raw and occupancy-normalized firing maps) correspond to data from awake periods, while the rightmost two columns (raw and occupancy-normalized firing maps) correspond to data from awake immobility periods. Reported at upper right are total spike counts (raw maps) or peak spatial rates (occupancy-normalized maps). Bin size: 2.5 cm. Scale bar: 20 cm. Here, the occupancy-normalized maps shown were generated from unsmoothed occupancy-normalized maps by taking the mean firing rate of bins of a 3×3 grid centered on the bin, disregarding bins that were not occupied by the subject. Quantification in h and i was performed on unsmoothed occupancy-normalized maps. h, Spatial information82 of N units in awake periods outside of immobility periods (upper plot, 1.12 ± 0.59 bits/spike, n = 67 units, with one unit excluded due to lack of firing outside of immobility) and awake immobility periods (lower plot, 1.17 ± 0.58 bits/spike, n = 68 units). In both conditions, data during SWR periods were excluded. Spatial information was calculated in the rest epoch in which the unit had the highest mean firing rate during awake periods. As in the task environment, N units exhibited spatially specific firing during immobility. Notably, the rest environment is an additional condition in which N units signaled location, moreover in the absence of material reward (analysis of non-reward locations in the task maze in Extended Data Fig. 5b-d). i, Correlation (Pearson's r) of N unit spatial maps between awake immobility periods and awake non-immobility periods in the rest environment. The correlation was calculated from unsmoothed occupancy-normalized firing maps, specifically for spatial bins in which the subject was immobile. Out of 67 units, 35 showed significant correlation (p < 0.05; 0.53 ± 0.03, mean ± s.e.m.), with no negative correlations observed. Correlations were calculated in the rest epoch in which the unit had the highest mean firing rate during awake periods. These positive correlations indicate that N units retained their spatial specificity into immobility periods. j, Comparison of firing rates across SIA-nesting conditions. Statistical tests (signed-rank, comparison of Nest OUT vs. IN): CA1, SIA ON (n = 18 units), p = 0.014; CA1, SIA OFF (n = 92), p < 10-5; CA3, SIA ON (n = 19), p = 0.60; CA3, SIA OFF (n = 58), p = 0.26; CA2 P, SIA ON (n = 15), p = 0.11; CA2 P, SIA OFF (n = 65), p = 0.0027; CA2 N, SIA ON (n = 18), p = 0.022; CA2 N, SIA OFF (n = 57), p = 0.027. As in the evaluation of the nesting position specificity index (Fig. 5f), these comparisons show that the CA1 and CA2 N unit populations met dual criteria (description in Supplementary Methods) for nesting position coding, while the CA3 unit population did not. Asterisks: *, p < 0.05; **, p < 0.01; ***, p < 0.001; n.s., not significant at p < 0.05. k, SIA firing rate vs. nesting position specificity index for all detected unit-sleep period samples. Here, if data was available for a unit (in the rest unit set) during a detected sleep period, then the unit's SIA firing rate during the sleep period was measured and its nesting position specificity index was calculated with respect to that sleep period's nesting position; this sample is then represented by a scatter point. In this approach, an individual unit can contribute more than one sample. CA1 (n = 312 samples from 94 units): Spearman's ρ: 0.55, p < 10-25. CA3 (n = 223 samples from 62 units): Spearman's ρ: 0.12, p = 0.065. CA2 P (n = 263 samples from 65 units): Spearman's ρ: 0.37, p < 10-9. CA2 N (n = 256 samples from 60 units): Spearman's ρ: 0.33, p < 10-7. l, CA2 P unit distribution of nesting position specificity indices. Mean ± s.e.m.: SIA ON (n = 15): 0.22 ± 0.09, p = 0.048, signed-rank; SIA OFF (n = 65): -0.16 ± 0.04, p < 0.001, signed-rank. Asterisks: *, p < 0.05; ***, p < 0.001. m, STA class proportions across conditions. In addition to STAs calculated from non-SWR immobility in task epochs (TASK, presented in Fig. 4 and Extended Data Figs. 7, 8, 9), STAs were also calculated from non-SWR immobility during awake periods in rest epochs (REST). For REST STAs, as in TASK STAs, a minimum of 100 spikes outside of SWRs during awake immobility and valid LFP reference sites were required, and units with STAs with mixed features were left unclassified (LFP reference site and unclassified STA criteria in Supplementary Methods; unclassified unit counts: CA1: 8 out of 83, CA3: 4 out of 51, CA2 N: 10 out of 58). As in TASK, N wave-coupled units in REST were detected in substantial proportions. In diagrams, STA positive (N wave-coupled) is in light orange, with a darker orange corresponding to significance in the STA voltage at t = 0 (p < 0.05, signed-rank). STA negative is in grey, with black corresponding to significance. Left (pie charts): proportions (%) of units in each of STA classes. Total unit counts (number of units with classified STAs) are reported at bottom right. Percentages are rounded to nearest whole number. Upper right: unit counts in each (non-overlapping) category (* denotes units with STAs with significance at p < 0.05). Lower right: contingency table for CA1 and CA3 units found active in both task and rest epochs (fired >100 spikes outside of SWRs during immobility in at least one task recording epoch and during awake immobility in at least one rest recording epoch) and with classifiable STAs (positive vs. negative). Notably, no units were observed that were STA positive in both conditions, suggesting that N wave-coupling for a given CA1/CA3 neuron is not a static property. In contrast, the majority of classifiable CA2 N units in both TASK (53/57, or 93%) and REST (38/48, or 79%) were N wave-coupled.

Mentions: To test this possibility, we evaluated hippocampal neural activity during rest sessions. First, during sleep, we observed periods of high-amplitude LFP, corresponding to a hippocampal sleep state dominated by SWRs (termed LIA1,18,34,35), frequently interrupted by periods of low-amplitude LFP in which the subject did not rouse, which we identified as periods of SIA (Fig. 5a). Next, in examining unit firing during sleep, we observed striking instances in which N units fired preferentially during SIA periods, falling silent during LIA (Fig. 5b). Analogously to awake immobility in the task (Fig. 2c), the N unit population fired at higher rates than all other unit populations during SIA (green, Fig. 5c) and also during awake immobility in the rest environment (dark grey, Fig. 5c). However, unlike the task condition, there was no significant overall correlation between firing rate and speed for N units during awake periods in the rest environment (Extended Data Fig. 10a), indicating that properties of the task maze or the cognitive demands of the task have essential roles in regulating N unit firing.


A hippocampal network for spatial coding during immobility and sleep
Hippocampal spatial coding in the rest environmenta, Distribution of correlations (Pearson's r) between firing rate and log speed for each unit population in awake periods in the rest environment. Mean ± s.d.; CA1 (n = 162 units): 0.06 ± 0.07, CA1 vs. 0, p < 10-17, signed-rank; CA3 (n = 75): 0.05 ± 0.08, CA3 vs. 0, p < 10-6, signed-rank; CA2 P (n = 74): 0.01 ± 0.07, CA2 P vs. 0, p = 0.55, signed-rank; CA2 N (n = 64): 0.00 ± 0.07, CA2 N vs. 0, p = 0.77, signed-rank, CA2 N vs. CA2 P, p = 0.47. Only units with significant correlations (p < 0.05) were included (CA1: 162/163 units, CA3: 75/76, CA2 P: 74/76 units, CA2 N: 64/68 units). The N unit population did not show a significant relationship between firing rate and speed, unlike in the task environment (Fig. 2b). The positive correlation between firing rates and speed was also absent in the CA2 P population, suggesting a broader weakening of speed-dependent changes in hippocampal firing in the rest environment. This could be due to the restricted range of speeds in the rest environment enclosure and/or a fundamental influence of task conditions (Extended Data Fig. 1) on hippocampal neural activity. b, Three additional example N unit spatial firing maps in the rest environment. Plotted are data from awake periods. Each column corresponds to data from an individual unit. Upper row: raw maps showing positions visited by the subject (grey) and positions where the unit fired (colored opaque points, plotted chronologically and with darker color values at lower speeds). Total number of spikes (outside of SWRs) in the epoch is reported at upper right. Lower row: occupancy-normalized firing maps. Peak spatial firing rate is reported at upper right. Scale bar: 20 cm. c-g, Awake immobility spatial firing in five example co-recorded pairs of N units from single rest recording epochs. The example pair in c is the same as shown at bottom in Fig. 5d. For each example pair, a unit corresponds to a row. The leftmost two columns (raw and occupancy-normalized firing maps) correspond to data from awake periods, while the rightmost two columns (raw and occupancy-normalized firing maps) correspond to data from awake immobility periods. Reported at upper right are total spike counts (raw maps) or peak spatial rates (occupancy-normalized maps). Bin size: 2.5 cm. Scale bar: 20 cm. Here, the occupancy-normalized maps shown were generated from unsmoothed occupancy-normalized maps by taking the mean firing rate of bins of a 3×3 grid centered on the bin, disregarding bins that were not occupied by the subject. Quantification in h and i was performed on unsmoothed occupancy-normalized maps. h, Spatial information82 of N units in awake periods outside of immobility periods (upper plot, 1.12 ± 0.59 bits/spike, n = 67 units, with one unit excluded due to lack of firing outside of immobility) and awake immobility periods (lower plot, 1.17 ± 0.58 bits/spike, n = 68 units). In both conditions, data during SWR periods were excluded. Spatial information was calculated in the rest epoch in which the unit had the highest mean firing rate during awake periods. As in the task environment, N units exhibited spatially specific firing during immobility. Notably, the rest environment is an additional condition in which N units signaled location, moreover in the absence of material reward (analysis of non-reward locations in the task maze in Extended Data Fig. 5b-d). i, Correlation (Pearson's r) of N unit spatial maps between awake immobility periods and awake non-immobility periods in the rest environment. The correlation was calculated from unsmoothed occupancy-normalized firing maps, specifically for spatial bins in which the subject was immobile. Out of 67 units, 35 showed significant correlation (p < 0.05; 0.53 ± 0.03, mean ± s.e.m.), with no negative correlations observed. Correlations were calculated in the rest epoch in which the unit had the highest mean firing rate during awake periods. These positive correlations indicate that N units retained their spatial specificity into immobility periods. j, Comparison of firing rates across SIA-nesting conditions. Statistical tests (signed-rank, comparison of Nest OUT vs. IN): CA1, SIA ON (n = 18 units), p = 0.014; CA1, SIA OFF (n = 92), p < 10-5; CA3, SIA ON (n = 19), p = 0.60; CA3, SIA OFF (n = 58), p = 0.26; CA2 P, SIA ON (n = 15), p = 0.11; CA2 P, SIA OFF (n = 65), p = 0.0027; CA2 N, SIA ON (n = 18), p = 0.022; CA2 N, SIA OFF (n = 57), p = 0.027. As in the evaluation of the nesting position specificity index (Fig. 5f), these comparisons show that the CA1 and CA2 N unit populations met dual criteria (description in Supplementary Methods) for nesting position coding, while the CA3 unit population did not. Asterisks: *, p < 0.05; **, p < 0.01; ***, p < 0.001; n.s., not significant at p < 0.05. k, SIA firing rate vs. nesting position specificity index for all detected unit-sleep period samples. Here, if data was available for a unit (in the rest unit set) during a detected sleep period, then the unit's SIA firing rate during the sleep period was measured and its nesting position specificity index was calculated with respect to that sleep period's nesting position; this sample is then represented by a scatter point. In this approach, an individual unit can contribute more than one sample. CA1 (n = 312 samples from 94 units): Spearman's ρ: 0.55, p < 10-25. CA3 (n = 223 samples from 62 units): Spearman's ρ: 0.12, p = 0.065. CA2 P (n = 263 samples from 65 units): Spearman's ρ: 0.37, p < 10-9. CA2 N (n = 256 samples from 60 units): Spearman's ρ: 0.33, p < 10-7. l, CA2 P unit distribution of nesting position specificity indices. Mean ± s.e.m.: SIA ON (n = 15): 0.22 ± 0.09, p = 0.048, signed-rank; SIA OFF (n = 65): -0.16 ± 0.04, p < 0.001, signed-rank. Asterisks: *, p < 0.05; ***, p < 0.001. m, STA class proportions across conditions. In addition to STAs calculated from non-SWR immobility in task epochs (TASK, presented in Fig. 4 and Extended Data Figs. 7, 8, 9), STAs were also calculated from non-SWR immobility during awake periods in rest epochs (REST). For REST STAs, as in TASK STAs, a minimum of 100 spikes outside of SWRs during awake immobility and valid LFP reference sites were required, and units with STAs with mixed features were left unclassified (LFP reference site and unclassified STA criteria in Supplementary Methods; unclassified unit counts: CA1: 8 out of 83, CA3: 4 out of 51, CA2 N: 10 out of 58). As in TASK, N wave-coupled units in REST were detected in substantial proportions. In diagrams, STA positive (N wave-coupled) is in light orange, with a darker orange corresponding to significance in the STA voltage at t = 0 (p < 0.05, signed-rank). STA negative is in grey, with black corresponding to significance. Left (pie charts): proportions (%) of units in each of STA classes. Total unit counts (number of units with classified STAs) are reported at bottom right. Percentages are rounded to nearest whole number. Upper right: unit counts in each (non-overlapping) category (* denotes units with STAs with significance at p < 0.05). Lower right: contingency table for CA1 and CA3 units found active in both task and rest epochs (fired >100 spikes outside of SWRs during immobility in at least one task recording epoch and during awake immobility in at least one rest recording epoch) and with classifiable STAs (positive vs. negative). Notably, no units were observed that were STA positive in both conditions, suggesting that N wave-coupling for a given CA1/CA3 neuron is not a static property. In contrast, the majority of classifiable CA2 N units in both TASK (53/57, or 93%) and REST (38/48, or 79%) were N wave-coupled.
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Figure 10: Hippocampal spatial coding in the rest environmenta, Distribution of correlations (Pearson's r) between firing rate and log speed for each unit population in awake periods in the rest environment. Mean ± s.d.; CA1 (n = 162 units): 0.06 ± 0.07, CA1 vs. 0, p < 10-17, signed-rank; CA3 (n = 75): 0.05 ± 0.08, CA3 vs. 0, p < 10-6, signed-rank; CA2 P (n = 74): 0.01 ± 0.07, CA2 P vs. 0, p = 0.55, signed-rank; CA2 N (n = 64): 0.00 ± 0.07, CA2 N vs. 0, p = 0.77, signed-rank, CA2 N vs. CA2 P, p = 0.47. Only units with significant correlations (p < 0.05) were included (CA1: 162/163 units, CA3: 75/76, CA2 P: 74/76 units, CA2 N: 64/68 units). The N unit population did not show a significant relationship between firing rate and speed, unlike in the task environment (Fig. 2b). The positive correlation between firing rates and speed was also absent in the CA2 P population, suggesting a broader weakening of speed-dependent changes in hippocampal firing in the rest environment. This could be due to the restricted range of speeds in the rest environment enclosure and/or a fundamental influence of task conditions (Extended Data Fig. 1) on hippocampal neural activity. b, Three additional example N unit spatial firing maps in the rest environment. Plotted are data from awake periods. Each column corresponds to data from an individual unit. Upper row: raw maps showing positions visited by the subject (grey) and positions where the unit fired (colored opaque points, plotted chronologically and with darker color values at lower speeds). Total number of spikes (outside of SWRs) in the epoch is reported at upper right. Lower row: occupancy-normalized firing maps. Peak spatial firing rate is reported at upper right. Scale bar: 20 cm. c-g, Awake immobility spatial firing in five example co-recorded pairs of N units from single rest recording epochs. The example pair in c is the same as shown at bottom in Fig. 5d. For each example pair, a unit corresponds to a row. The leftmost two columns (raw and occupancy-normalized firing maps) correspond to data from awake periods, while the rightmost two columns (raw and occupancy-normalized firing maps) correspond to data from awake immobility periods. Reported at upper right are total spike counts (raw maps) or peak spatial rates (occupancy-normalized maps). Bin size: 2.5 cm. Scale bar: 20 cm. Here, the occupancy-normalized maps shown were generated from unsmoothed occupancy-normalized maps by taking the mean firing rate of bins of a 3×3 grid centered on the bin, disregarding bins that were not occupied by the subject. Quantification in h and i was performed on unsmoothed occupancy-normalized maps. h, Spatial information82 of N units in awake periods outside of immobility periods (upper plot, 1.12 ± 0.59 bits/spike, n = 67 units, with one unit excluded due to lack of firing outside of immobility) and awake immobility periods (lower plot, 1.17 ± 0.58 bits/spike, n = 68 units). In both conditions, data during SWR periods were excluded. Spatial information was calculated in the rest epoch in which the unit had the highest mean firing rate during awake periods. As in the task environment, N units exhibited spatially specific firing during immobility. Notably, the rest environment is an additional condition in which N units signaled location, moreover in the absence of material reward (analysis of non-reward locations in the task maze in Extended Data Fig. 5b-d). i, Correlation (Pearson's r) of N unit spatial maps between awake immobility periods and awake non-immobility periods in the rest environment. The correlation was calculated from unsmoothed occupancy-normalized firing maps, specifically for spatial bins in which the subject was immobile. Out of 67 units, 35 showed significant correlation (p < 0.05; 0.53 ± 0.03, mean ± s.e.m.), with no negative correlations observed. Correlations were calculated in the rest epoch in which the unit had the highest mean firing rate during awake periods. These positive correlations indicate that N units retained their spatial specificity into immobility periods. j, Comparison of firing rates across SIA-nesting conditions. Statistical tests (signed-rank, comparison of Nest OUT vs. IN): CA1, SIA ON (n = 18 units), p = 0.014; CA1, SIA OFF (n = 92), p < 10-5; CA3, SIA ON (n = 19), p = 0.60; CA3, SIA OFF (n = 58), p = 0.26; CA2 P, SIA ON (n = 15), p = 0.11; CA2 P, SIA OFF (n = 65), p = 0.0027; CA2 N, SIA ON (n = 18), p = 0.022; CA2 N, SIA OFF (n = 57), p = 0.027. As in the evaluation of the nesting position specificity index (Fig. 5f), these comparisons show that the CA1 and CA2 N unit populations met dual criteria (description in Supplementary Methods) for nesting position coding, while the CA3 unit population did not. Asterisks: *, p < 0.05; **, p < 0.01; ***, p < 0.001; n.s., not significant at p < 0.05. k, SIA firing rate vs. nesting position specificity index for all detected unit-sleep period samples. Here, if data was available for a unit (in the rest unit set) during a detected sleep period, then the unit's SIA firing rate during the sleep period was measured and its nesting position specificity index was calculated with respect to that sleep period's nesting position; this sample is then represented by a scatter point. In this approach, an individual unit can contribute more than one sample. CA1 (n = 312 samples from 94 units): Spearman's ρ: 0.55, p < 10-25. CA3 (n = 223 samples from 62 units): Spearman's ρ: 0.12, p = 0.065. CA2 P (n = 263 samples from 65 units): Spearman's ρ: 0.37, p < 10-9. CA2 N (n = 256 samples from 60 units): Spearman's ρ: 0.33, p < 10-7. l, CA2 P unit distribution of nesting position specificity indices. Mean ± s.e.m.: SIA ON (n = 15): 0.22 ± 0.09, p = 0.048, signed-rank; SIA OFF (n = 65): -0.16 ± 0.04, p < 0.001, signed-rank. Asterisks: *, p < 0.05; ***, p < 0.001. m, STA class proportions across conditions. In addition to STAs calculated from non-SWR immobility in task epochs (TASK, presented in Fig. 4 and Extended Data Figs. 7, 8, 9), STAs were also calculated from non-SWR immobility during awake periods in rest epochs (REST). For REST STAs, as in TASK STAs, a minimum of 100 spikes outside of SWRs during awake immobility and valid LFP reference sites were required, and units with STAs with mixed features were left unclassified (LFP reference site and unclassified STA criteria in Supplementary Methods; unclassified unit counts: CA1: 8 out of 83, CA3: 4 out of 51, CA2 N: 10 out of 58). As in TASK, N wave-coupled units in REST were detected in substantial proportions. In diagrams, STA positive (N wave-coupled) is in light orange, with a darker orange corresponding to significance in the STA voltage at t = 0 (p < 0.05, signed-rank). STA negative is in grey, with black corresponding to significance. Left (pie charts): proportions (%) of units in each of STA classes. Total unit counts (number of units with classified STAs) are reported at bottom right. Percentages are rounded to nearest whole number. Upper right: unit counts in each (non-overlapping) category (* denotes units with STAs with significance at p < 0.05). Lower right: contingency table for CA1 and CA3 units found active in both task and rest epochs (fired >100 spikes outside of SWRs during immobility in at least one task recording epoch and during awake immobility in at least one rest recording epoch) and with classifiable STAs (positive vs. negative). Notably, no units were observed that were STA positive in both conditions, suggesting that N wave-coupling for a given CA1/CA3 neuron is not a static property. In contrast, the majority of classifiable CA2 N units in both TASK (53/57, or 93%) and REST (38/48, or 79%) were N wave-coupled.
Mentions: To test this possibility, we evaluated hippocampal neural activity during rest sessions. First, during sleep, we observed periods of high-amplitude LFP, corresponding to a hippocampal sleep state dominated by SWRs (termed LIA1,18,34,35), frequently interrupted by periods of low-amplitude LFP in which the subject did not rouse, which we identified as periods of SIA (Fig. 5a). Next, in examining unit firing during sleep, we observed striking instances in which N units fired preferentially during SIA periods, falling silent during LIA (Fig. 5b). Analogously to awake immobility in the task (Fig. 2c), the N unit population fired at higher rates than all other unit populations during SIA (green, Fig. 5c) and also during awake immobility in the rest environment (dark grey, Fig. 5c). However, unlike the task condition, there was no significant overall correlation between firing rate and speed for N units during awake periods in the rest environment (Extended Data Fig. 10a), indicating that properties of the task maze or the cognitive demands of the task have essential roles in regulating N unit firing.

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ABSTRACT

How does an animal know where it is when it stops moving? Hippocampal place cells fire at discrete locations as subjects traverse space, thereby providing an explicit neural code for current location during locomotion. In contrast, during awake immobility, the hippocampus is thought to be dominated by neural firing representing past and possible future experience. The question of whether and how the hippocampus constructs a representation of current location in the absence of locomotion has stood unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and furthermore does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signaling of location persists into brief periods of desynchronization prevalent in slow-wave sleep. The hippocampus thus generates a distinct representation of current location during immobility, pointing to mnemonic processing specific to experience occurring in the absence of locomotion.

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