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A hippocampal network for spatial coding during immobility and sleep

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 been unresolved. Here we report that a distinct population of hippocampal neurons, located in the CA2 subregion, signals current location during immobility, and does so in association with a previously unidentified hippocampus-wide network pattern. In addition, signalling 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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Figure 1: Distinct hippocampal neuron population at CA2.
Figure 2: N units fire more at low speeds and during immobility.
Figure 3: N units signal current location during immobility.
Figure 4: A novel hippocampal network pattern marks spatial coding during immobility.
Figure 5: Hippocampal spatial coding in desynchronized sleep.

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Acknowledgements

We thank G. Rothschild, D. Liu, J. Yu, S. Jadhav, E. Anderson, P. Sabes, C. Schreiner, M. Stryker, R. Knight, J. O’Doherty, E. Phillips, K. Kay, and B. Mensh for discussion and suggestions, and I. Grossrubatscher, C. Lykken, and S. Harris for technical assistance. This work was supported by the Howard Hughes Medical Institute, an NIH grant (R01 MH090188) and a McKnight Foundation Cognitive and Memory Disorders Award (L.M.F.). K.K. is supported by a Ruth L. Kirchstein National Research Service Award Fellowship (NIH/NIMH) and the UCSF Medical Scientist Training Program.

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Authors

Contributions

K.K. and L.M.F. conceived the study. K.K., M.S., J.E.C., M.P.K., and M.C.L., conducted the experiments. K.K. analysed the data. K.K. and L.M.F. wrote the paper.

Corresponding authors

Correspondence to Kenneth Kay or Loren M. Frank.

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Competing interests

The authors declare no competing financial interests.

Extended data figures and tables

Extended Data Figure 1 Behavioural task and hippocampal recording sites.

a, Continuous spatial alternation task21,24,65,70. The task environment is a W-shaped maze with a centre arm and two outer arms. Reward (~0.3 ml of sweetened evaporated milk) is dispensed through 3-cm diameter wells (yellow circles; designated ‘A’, ‘B’, and ‘C’ for reference in data plots), located at the end of each arm. Rats are rewarded for performing the trajectory sequence shown (numbered 1–4), in which the correct destination after visiting the centre well is the less recently visited outer well. All subjects stopped locomoting upon reaching the reward wells to check for (by licking) and consume reward. Subjects also stopped intermittently elsewhere in the maze (most frequently at maze junctions), particularly in earlier exposures to the task. b, c, Example hippocampal histological sections showing tetrode tracks and electrolytic lesions in CA1, CA2, CA3, and DG. Nissl-stained sections show neuronal cell bodies in dark blue, while sections stained with Neurotrace show neuronal cell bodies in light grey. Panel b shows example sections with sites overlapping with the CA2 cytoarchitectural locus28,29,30,36,50,50,54,55,56,57 (enclosed by dotted lines; characterized by dispersion of the hippocampal cell layer in the region between CA1 and CA3). Filled arrowheads indicate sites overlapping with CA2, while empty arrowheads indicate non-CA2 recording sites. The CA2 site assignment was deliberately inclusive to maximize detection of units at CA2 with novel physiological responses (N units, Fig. 1 and Extended Data Fig. 3). Scale bars: 500 μm. d, Coronal hippocampal section stained with a neuronal cell body marker (light grey; NeuroTrace) and CA2 marker (yellow; RGS1436,47,71). Bottom, magnified view of a track left by a CA2 site tetrode. Scale bars: 500 μm. e, Survey of recording sites included in the study data set. Diagrammed in a representative hippocampal section are recording site locations (circles) of seven subjects from which coronal hippocampal sections were taken (CA1: 41 sites, CA2: 9 sites, CA3: 30 sites, DG: 7 sites; two additional CA2 sites near the septal pole of hippocampus not shown). Dotted lines enclose the CA2 anatomical locus, with overlapping recording sites shown as filled circles. The majority of CA1 recordings were in CA1c, while the majority of CA3 recordings were in CA3b.

Extended Data Figure 2 Observation of firing during immobility.

a, Non-SWR immobility firing in three example principal units recorded in CA1, CA2, and CA3. Each firing raster is shown as vertical lines overlaid on a plot of the subject’s head speed (grey trace). Top traces: wide-band LFP (0.5–400 Hz, scale bar: 800 μV) and ripple-band LFP (150–250 Hz, scale bar: 100 μV) traces from a simultaneous recording in CA1, to show hippocampal network state. SWR periods are plotted as pink zones. Note that substantial firing occurs in the absence of (i) locomotion, (ii) detectable SWRs, and (iii) detectable theta (regular ~8 Hz rhythm visible in the LFP during moving periods). b, Proportions of time spent in different period types over all task recording epochs (n = 222 task recording epochs, 8 subjects) in the data set. During the performance of the task, a substantial proportion of time was spent at low speeds and immobility, moreover when SWRs were not detected. Transitional low speed periods were times when the subject’s speed was < 4 cm s−1 and within 2 s (earlier or later) of periods of movement > 4 cm s−1, while immobility periods were times when the speed was < 4 cm s−1 and separated more than 2 s (earlier or later) from periods of movement > 4 cm s−1. Note that SWR periods comprised only a minority of time spent at low speeds, consistent with past observations17,72,73.

Extended Data Figure 3 Firing properties of CA1, CA2, and CA3 units.

a, Peri-SWR time histograms (PSTHs; SWR onset at t = 0) of firing for all principal units in the task unit set. SWRs from both task and rest epochs were used to calculate PSTHs (1-ms bins), which were smoothed with a Gaussian kernel (σ = 10 ms). Each unit’s mean PSTH was then z-scored (colour bar) and plotted in a row. Units are sorted by the time of the maximum z-scored rate from 0 to +100 ms. b, PSTHs for the four hippocampal unit populations (mean ± s.e.m.; number of units: CA1: 478 units; CA3: 271; CA2 P: 142; CA2 N: 84) analysed in this study. Using formal criteria (described in Methods), units that were inhibited during SWRs constituted a majority subset (56 of 84) of N units, and were observed in every subject with CA2 site recordings (5 subjects, inhibition apparent in examples in Fig. 1d and N unit PSTHs in a). Here, the reduction of firing in these neurons manifests in the N unit population response as a dip in firing rate at the time of SWRs (N unit population in blue), in contrast to the CA1, CA3, and CA2 P unit populations, all of which showed sharp increases in firing during SWRs19. Time bins: 5 ms. c, Proportion of N units in CA2 site recordings. Upper plots: spike amplitudes measured on two channels of a tetrode for two example CA2 site recordings (left and right). Colours indicate spikes of N (blue-based tones) and P (red-based tones) units. The number of well-isolated principal units of each type is reported at upper right. Scale bars (x and y), 100 μV. Lower plot: proportion of N units across CA2 site recordings with at least four clustered putative principal units. CA2 recording sites typically reported N and P units concurrently, indicating that the spiking of two distinct hippocampal principal cell types was detectable at a single CA2 recording site. d, Unit spike counts in 15-min task epochs for each principal unit population. The counts were taken from each unit’s highest mean rate task epoch. Spikes that occurred during SWR periods were not included in these counts. e, Mean firing rate for each principal unit population (mean ± s.e.m.). The mean rates were calculated from the highest rate epoch for each unit, either among task (top, TASK) or rest (bottom, REST) epochs. TASK number units (task unit set): CA1: 478 units; CA2 P: 142; CA2 N: 84; CA3: 271. REST number units (subset of task unit set with available rest epoch data): CA1: 454 units; CA2 P: 142; CA2 N: 84; CA3: 252. All spikes and epoch times were included. f, Peak firing rate for each principal unit population (mean ± s.e.m.). The peak rates were estimated from the highest rate epochs for each unit, either among task (top, TASK) or rest (bottom, REST) epochs. The peak rate was the maximum instantaneous firing rate (IFR) exhibited by the unit. Here, the IFR was estimated by convolving each unit’s spike train (1-ms bins) with Gaussian kernels of different sizes (x-axis, times refer to s.d. of the kernel). TASK number units (task unit set): CA1: 478 units; CA2 P: 142; CA2 N: 84; CA3: 271. REST number units (subset of task unit set with available rest epoch data and at least 100 spikes in a rest epoch): CA1: 421, CA2 P: 138, CA2 N: 82, CA3: 197 units. All spikes and epoch times were included. g, Burst firing in each principal unit population. The burst index of a unit was defined as the proportion of inter-spike intervals (ISI) less than 6 ms74,75. Burst indices were calculated separately for three conditions: locomotion (left panels) and immobility (centre) in task epochs, and also for rest epochs (right). In a given condition, a minimum of 100 spikes was required for a unit to be analysed. Moreover, for locomotor and immobility periods from task epochs, only ISIs of spikes that were successive within single uninterrupted periods of a given type were included. Lastly, in this analysis, SWR periods were not excluded. Notably, CA2 N units showed high levels of bursting, suggesting that these units correspond to hippocampal principal (pyramidal) neurons59,60,62,76,77,78,79.

Extended Data Figure 4 Spatial firing of CA1, CA2, and CA3 units.

For the analyses in a and b, unit sample sizes are the same as in Fig. 3b. a, Spatial coverage at different speed cutoffs (mean ± s.e.m.), in which only data from periods satisfying the speed condition were analysed. For each speed cutoff, a firing rate threshold of 2 Hz was used. The all speeds condition is the same as in Fig. 3b. CA2 P > each other unit population, Kruskal–Wallis ANOVA, Tukey’s post hoc tests, P = 0.0015 for all speeds, P = 0.0021 for >4 cm s−1, and P < 10−5 for >20 cm s−1. CA2 N < each other unit population, Kruskal–Wallis ANOVA, Tukey’s post hoc tests, P < 10−6 for all speeds, P < 10−7 for >4 cm s−1, and P < 10−8 for >20 cm s−1. **P < 0.01; ***P < 0.001 . b, Spatial coverage at different firing rate thresholds (mean ± s.e.m.). For each threshold level, spikes at all speeds were analysed. CA2 P > each other unit population, Kruskal–Wallis ANOVA, Tukey’s post hoc tests, P < 10−5 for >0.5 Hz, P = 0.0015 for >2 Hz, and P = 0.11 for >5 Hz. CA2 N < each other unit population, Kruskal–Wallis ANOVA, Tukey’s post hoc tests, P < 10−4 for >0.5 Hz, P < 10−6 for >2 Hz, and P < 10−7 for >5 Hz. **P < 0.01; ***P < 0.001, n.s., not significant at P < 0.05. c, Example spatial firing maps for CA1, CA3, CA2 P, and CA2 N units. Each column corresponds to data from an individual unit from a single 15-min task epoch. Upper row: raw maps showing positions visited by the subject (grey) and positions where the unit fired (coloured opaque points, plotted chronologically and with darker colour values at lower speeds). The total number of spikes (outside of SWR periods) in the epoch is reported at upper right. Lower two rows: occupancy-normalized firing maps, with the first row showing maps generated from data from outbound trajectories (centre to left or right arms) and the second row inbound trajectories (left or right to centre arm; Extended Data Fig. 1a). The spatial peak firing rate (highest rate for a occupancy-normalized bin) is shown at upper right. Shown are data from each unit’s highest mean firing rate task epoch. Data from SWR periods were excluded from all plots. Notably, N units could show substantial firing at locations distinct from the reward wells (N unit examples with spike counts of 534, 497, 957, 1819, 668, 1,016 and 372).

Extended Data Figure 5 N unit spatial coding.

a, Reward well firing rasters of 20 example N units. For each unit, data from the final ten (if available) entries of the subject’s head into each of the three task reward wells (A, B, C) from a single task epoch are shown. The time of well entry (t = 0) is plotted as a grey line. SWR periods are plotted in the background as pink zones. Note that firing for a given N unit was typically specific to one of the three reward wells. b, Non-reward well firing in three example N units. The rightmost example is the same as the third example in Fig. 2a. Upper row: spatial firing maps. Locations visited by the subject are plotted in grey, while locations at which the unit fired are plotted as coloured opaque points (in blue) plotted chronologically and with darker colour values at lower speeds. Total spike counts are indicated at upper right. In the task (Methods and Extended Data Fig. 1a), reward was delivered to the subjects only at the ends of the maze arms, thus locations elsewhere in the maze were not directly associated with reward. Lower row: firing rate versus speed of distinct visits to specific maze junctions (indicated with a square on spatial firing maps). Junction visits were identified as periods during which the subject’s linear position (Methods) was within 10 cm of a maze junction. Firing rate was the total number of spikes divided by the visit duration. Mean speed was the average instantaneous head speed during the visit. To limit analysis to discrete traversals through a junction, visits that were both less than 1 s in duration and also had mean speeds <10 cm s−1 were disregarded. Note that N units tended to fire at lower speed junction visits, and that some junction visits at higher speeds elicited no firing. c, Firing rate dependence on speed at non-reward task locations. Distribution of correlations (Pearson’s r) between firing rate and log speed for each unit population. This analysis is the same as in Fig. 2b, except restricted to periods when the subject was located >30 cm from reward wells, moreover including only units that fired at least 50 spikes at these locations (outside of SWR periods). As in the location-inclusive case (Fig. 2b), the N unit population uniquely showed an anti-correlation (r < 0) of firing rate with speed. Pearson’s r, mean ± s.d.; CA1: 0.12 ± 0.20, CA1 versus 0, P < 10−23, signed-rank; CA3: 0.11 ± 0.18, CA3 versus 0, P < 10−13, signed-rank; CA2 P: 0.12 ± 0.16, CA2 P versus 0, P < 10−10, signed-rank; CA2 N: −0.09 ± 0.20, CA2 N versus 0, P = 0.0056, signed-rank; CA2 N versus CA2 P, P < 10−8, rank-sum. Only units with significant correlations (P < 0.05) were included (CA1: 386/393 units, CA3: 195/196 units, CA2 P: 121/121 units, CA2 N: 42/42 units). **P < 0.01; ***P < 0.001. d, Same analysis as c, except with an additional restriction to periods when the subject was located in linear positions where a unit had occupancy-normalized spatial coverage >2 Hz. Pearson’s r, mean ± s.d.; CA1: 0.14 ± 0.30, CA1 versus 0, P < 10−16, signed-rank; CA3: 0.17 ± 0.30, CA3 versus 0, P < 10−10, signed-rank; CA2 P: 0.22 ± 0.23, CA2 P versus 0, P < 10−12, signed-rank; CA2 N: −0.17 ± 0.33, CA2 N versus 0, P = 0.031, signed-rank; CA2 N versus CA2 P, P < 10−6, rank-sum. Only units with significant correlations (P < 0.05) were included (CA1: 358/364 units, CA3: 168/168 units, CA2 P: 111/111 units, CA2 N: 23/24 units). *P < 0.05; ***P < 0.001.

Extended Data Figure 6 Locomotor STAs and theta analysis.

Unit spiking at speeds > 4 cm s−1 was analysed. a, Locomotor STAs. Plotted are mean STAs of hippocampal LFP for each principal unit population. LFP from four distinct recording sites (REF, CA2, CA3, DG) are plotted in rows. Vertical lines correspond to the time of spiking. The width of the trace indicates ± s.e.m. across individual unit STAs. The total trace length is 2 s. REF: reference electrode located in corpus callosum overlying dorsal hippocampus, reporting signals relative to a cerebellar ground screw. Scale bars, x, 250 ms; y, 50 μV. b, Theta phase locking analysis of each principal unit population. For comparison of theta phase preferences between unit populations in simultaneously recorded data, analysis was restricted to subjects in which all four unit types (CA1, CA3, CA2 N and CA2 P) were recorded. First row: mean circular distribution of spikes for each unit population. Error bars: ± s.e.m. across individual units. Second row: the distribution of mean circular phases for significantly modulated units (P < 0.05, Rayleigh tests, total number of significant units reported at upper right). Bottom row: the distribution of modulation depths (resultant length) for all units. In plots with theta phase (bin size: 15°; troughs at 180°, indicated in dotted lines), two cycles are shown to aid visual comparison. Surprisingly, we did not observe a ~90° phase lead of CA3 relative to CA1 as reported in a previous study31, perhaps due to differences in CA3 recording locations.

Extended Data Figure 7 N wave: a novel hippocampal network pattern at 1–4 Hz.

a, Non-SWR immobility STAs of wide-band (0.5–400 Hz, upper section) and low frequency-band (1–4 Hz, lower section) filtered LFP. Plotted are mean STAs of hippocampal LFP for each principal unit population (first four columns). LFP from four distinct recording sites (REF, CA2, CA3, DG) are plotted in rows. The mean RTA (fifth column) was calculated from individual RTAs that were matched (same recording epochs) to each CA2 N unit, and thus have the same sample sizes as N units. Vertical lines correspond to the time of spiking (STAs) or SWRs (RTA). The width of the trace indicates ± s.e.m. over individual unit STAs or RTAs. The total trace length is 2 s. REF: reference electrode located in corpus callosum overlying dorsal hippocampus, reporting signals relative to a cerebellar ground screw. Scale bars, x, 250 ms; y, 50 μV. b, All CA2 N unit STAs for spiking during non-SWR immobility. Unit STAs are grouped by polarity at the time of spiking (t = 0) and sorted by the time of the extremum (peak for positive; trough for negative) nearest the time of spiking. For each unit, LFP (1–4 Hz) from CA2, CA3, or DG (in increasing order of preference when available) was used. Colours indicate voltage (colour bar). STAs are plotted on the left, while RTAs are plotted on the right. The centre bar indicates the voltage polarity of the STA (orange: positive, black: negative) at the time of spiking (STAs) or SWRs (RTAs), with a dot indicating significance versus 0 μV (P < 0.05, rank-sum). The STA of an unclassified unit (see Methods) is indicated with an empty box. c, STA versus matched RTA voltage amplitudes (1–4 Hz LFP measured at t = 0; STA: time of spike, RTA: time of peak ripple power) for individual CA2 N units (n = 58). CA2 N unit STA amplitudes (black circles) were larger than that of their matched RTAs (pink circles) (mean ± s.e.m., STA: 47 ± 6 μV, RTA: −168 ± 10 μV; P < 10−10, signed-rank) and also 0 μV (P < 10−7, signed-rank). ***P < 0.001. d, All interneuronal unit STAs for spiking during non-SWR immobility periods. Interneuronal units were analysed for coupling to LFP since hippocampal interneurons show temporally precise firing relationships with all canonical hippocampal network patterns80. Seventy-eight putative interneuronal units were recorded in or near the cell layers of CA1, CA2, CA3, and DG; of these units, 63 were recorded when valid CA2, CA3, or DG LFP recordings were simultaneously available and reporting SWR sharp waves as negative transients. Of the 63 units, 27 fired in association with the N wave (criteria in Methods; CA1: 10, CA2: 4, CA3: 7, and DG: 6). In the plot, unit STAs are grouped by polarity at the time of spiking (t = 0) and sorted by the time of the extremum (peak for positive; trough for negative) nearest the time of spiking. For each unit, LFP (1–4 Hz) from CA2, CA3, or DG (in increasing order of preference when available) was used. Colours indicate voltage (colour bar). STAs are plotted on the left, while RTAs are plotted on the right. The centre bar indicates the voltage polarity of the STA (orange: positive, black: negative) at the time of spiking (t = 0), with a dot indicating significance versus 0 μV (P < 0.05, signed-rank). Unit STAs left unclassified (see Methods) are indicated with an empty box. e, Mean firing rate of interneuronal units (mean ± s.e.m.) with negative (black; n = 36) versus positive (orange; n = 27) STAs. f, Firing rate versus speed correlation (Pearson’s r) of interneuronal units with negative (black) versus positive (orange) STAs. Task epochs were analysed. g, Peri-SWR time histograms (PSTHs) of firing for interneuronal units with negative (left) and positive (right) STAs. Negative STA units uniformly exhibited a sharp peak in firing at the time of SWRs while positive STA units showed instances in which unit firing decreased from baseline levels (unit numbers 1–4, 6 and 8) or showed an increase in firing that was less sharp (unit numbers 23–25)80,81,82.

Extended Data Figure 8 CA1 and CA3 principal neurons fire in association with the N wave.

Units showing positive STAs for spiking during non-SWR immobility periods were identified as firing in association with the N wave (N wave-coupled). a, All CA1 and CA3 principal unit STAs for spiking during non-SWR immobility periods. Only units with >100 spikes during these periods were analysed. Unit STAs are grouped by polarity at the time of spiking (t = 0) and sorted by the time of the extremum (peak for positive; trough for negative) nearest the time of spiking. For each unit, LFP (1–4 Hz) from CA2, CA3, or DG (in increasing order of preference when available) was used. Colours indicate voltage (colour bar at upper right). STAs are plotted on the left, while RTAs are plotted on the right. The centre bar indicates the voltage polarity of the STA (orange: positive, black: negative) at the time of spiking (t = 0), with a dot indicating significance versus 0 μV (P < 0.05, signed-rank). Unit STAs left unclassified (see Methods) are plotted at bottom and indicated with an empty box. b, Firing rates for STA-classified unit populations during task epochs (mean ± s.e.m.; number of units: CA1 negative: 86, CA1 positive: 50, CA3 negative: 100, CA3 positive: 34). In both CA1 and CA3, units with positive STAs showed higher firing rates during non-SWR immobility (CA1 positive versus CA1 negative, P < 10−9, rank-sum; CA3 positive versus CA3 negative, P < 10−5, rank-sum), similar to CA2 N units (Fig. 2c). c, Spatial coverage in CA1 and CA3 units with negative versus positive STAs (mean ± s.e.m.; number of units: CA1 negative: 86, CA1 positive: 50, CA3 negative: 100, CA3 positive: 34). CA1 units with positive STAs showed somewhat lower spatial coverage than units with negative STAs (CA1 negative versus CA1 positive, P = 0.046, rank-sum), while an analogous difference in CA3 was not statistically significant (CA3 negative versus CA3 positive, P = 0.12, rank-sum). d, Well specificity distributions in CA1 and CA3 units that had STA amplitudes (at time of spiking) significantly different from 0 μV (the units marked as significant in a and with available well data). For both CA1 and CA3, units with positive STAs showed higher well specificity (mean ± s.e.m., CA1 negative: 0.66 ± 0.04, CA1 positive: 0.86 ± 0.03; CA1 negative versus CA1 positive, P < 10−4, rank-sum; CA3 negative: 0.49 ± 0.04, CA3 positive: 0.79 ± 0.04, CA3 negative versus CA3 positive, P < 10−4, rank-sum). e, Well specificity distributions in CA1 and CA3 units with theta power cutoff. For each task epoch, the distribution of power in the theta band (5–11 Hz), averaged over CA1 recording sites, was calculated for immobility non-SWR periods. Spikes occurring during times in which the theta band power was in the upper quartile of this distribution were then excluded from well specificity calculations. For both CA1 and CA3, units with positive STAs showed higher well specificity (mean ± s.e.m., CA1 negative: 0.73 ± 0.05, CA1 positive: 0.87 ± 0.04; CA1 positive versus CA1 negative, P < 0.002, rank-sum; CA3 negative: 0.58 ± 0.04, CA3 positive: 0.80 ± 0.04; CA3 negative versus CA3 positive, P < 0.004, rank-sum).

Extended Data Figure 9 N wave-coupled CA1 and CA3 principal neurons.

Examples of CA1 and CA3 principal units with negative versus positive STAs during non-SWR immobility. Units with positive STAs were defined as N wave-coupled. Each column corresponds to data from an individual unit. Upper sections: non-SWR immobility STA (black trace, ± s.e.m. over individual LFP traces) and RTA (pink trace, ± 2 s.e.m. over individual LFP traces). Vertical lines correspond to the time of spiking (for STAs) or time of SWRs (for RTAs). The total number of spikes (for STAs) and SWRs (for RTAs) averaged is reported at upper left. The region in which the LFP (at 1–4 Hz) was recorded is indicated at lower right. STAs with amplitudes (measured at the time of spiking) significantly different from 0 μV (P < 0.05, rank-sum) are marked by an asterisk at upper right. The total trace length is 1 s. A horizontal bar centred at the time of spiking indicates 0 μV and corresponds to 200 ms. Scale bars, x, 200 ms; y, 50 μV for STA (black trace); 100 μV for RTA (pink trace). Middle sections: spatial firing maps. Positions visited by the subject are plotted in grey while positions at which the unit fired are shown as coloured opaque points (in green) plotted chronologically and with darker colour values at lower speeds. Shown is the 15-min task epoch in which the unit had the highest mean firing rate. The total number of spikes in the epoch is reported at upper right. Spikes occurring during SWR periods are omitted from the plots. Lower sections: well firing rasters. The time of well entry (t = 0) is plotted as a grey line. SWR periods are plotted in the background as pink zones.

Extended Data Figure 10 Hippocampal spatial coding in the rest environment.

a, 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 versus 0, P < 10−17, signed-rank; CA3 (n = 75): 0.05 ± 0.08, CA3 versus 0, P < 10−6, signed-rank; CA2 P (n = 74): 0.01 ± 0.07, CA2 P versus 0, P = 0.55, signed-rank; CA2 N (n = 64): 0.00 ± 0.07, CA2 N versus 0, P = 0.77, signed-rank, CA2 N versus 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 (coloured opaque points, plotted chronologically and with darker colour values at lower speeds). Total number of spikes (outside of SWR periods) 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. cg, 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 centred 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 information83 of N units in awake periods outside of immobility periods (upper plot, 1.12 ± 0.59 bits per 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 per 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 signalled 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 versus 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 Methods) for nesting position coding, while the CA3 unit population did not. *P < 0.05; **P < 0.01; ***P < 0.001; n.s., not significant at P < 0.05. k, SIA firing rate versus 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. *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 and 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 SWR periods 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 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 left and upper right 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 the 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. Lower right: contingency table for CA1 and CA3 units found active in both task and rest epochs (fired >100 spikes outside of SWR periods 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 versus 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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Kay, K., Sosa, M., Chung, J. et al. A hippocampal network for spatial coding during immobility and sleep. Nature 531, 185–190 (2016). https://doi.org/10.1038/nature17144

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