Brain-wide interactions during hippocampal sharp wave ripples

Abstract

During periods of disengagement from the environment, transient population bursts, known as sharp wave ripples (SPW-Rs), occur sporadically. While numerous experiments have characterized the bidirectional relationship between SPW-Rs and activity in chosen brain areas, the topographic relationship between different segments of the hippocampus and brain-wide target areas has not been studied at high temporal and spatial resolution. Yet, such knowledge is necessary to infer the direction of communication. We analyzed two publicly available datasets with simultaneous high-density silicon probe recordings from across the mouse forebrain. We found that SPW-Rs coincide with a transient brain-wide increase in functional connectivity. In addition, we show that the diversity in SPW-R features, such as their incidence, magnitude, and intrahippocampal topography in the septotemporal axis, are correlated with slower excitability fluctuations in cortical and subcortical areas. Further, variations in SPW-R features correlated with the timing, sign, and magnitude of downstream responses with large-amplitude SPW-Rs followed by transient silence in extrahippocampal structures. Our findings expand on previous results and demonstrate that the activity patterns in extrahippocampal structures depend both on the intrahippocampal topographic origin and magnitude of hippocampal SPW-Rs.

Keywords: memory; replay; sleep.

Fig. 1.

Ripple features vary along the hippocampal longitudinal axis. (A) Locations of Neuropixels probes from all sessions, color-coded according to probe identity. In each experiment, probes were positioned in a stereotypic manner (15). Probes A–C spanned the dorsal CA1, and D and E were placed in intermediate (posterior) CA1. Probe S was either in the subiculum (19 sessions) or distal CA1 bordering the subiculum (13 sessions). Middle and Right: The recording sites in the CA1 pyramidal layer, shown in the septotemporal and the mediolateral projections, color-coded as in the Left panel. Purple Xs depict the position of individual units. A, anterior; D, dorsal; P, posterior; V, ventral; M, medial; L, lateral; CSD, Current Source Density; SW, Sharp Wave. (B) From Left to Right: Distributions of ripple amplitude, sharp wave amplitude, ripple frequency, ripple duration, and fraction of SPW-Rs in which a given neuron fired at least once (n = 347,525 SPW-R events from 50 sessions). Bottom: Effect size estimates depicted as the distribution of differences between the medians of a given probe computed from 5,000 bootstrapped resamples and the median of the values after shuffling the probe labels. Black bars depict 95% CIs. (C) Distribution of spiking peak lags referenced to probe A obtained from cross-correlations between CA1/subiculum spikes on other probes. (D) Averaged (mean ± SEM) cross-correlograms between CA1/subiculum units on different probes used to calculate the distributions in C, ordered from left to right according to the distance from probe A. Red dot depicts average peak lag.

Fig. 2.

Ripple features vary as a function of intrahippocampal synchronization. (A) Cartoon showing probe locations in one example session. Hippocampus, green; visual cortex, cyan; thalamus, red. (B) Example raw traces (Top) and average spectrograms (Bottom) for SPW-Rs detected on 1→6 probes from one session. (C) Ripple power peak correlation from all pairs of electrodes averaged across all sessions where all six probes were available (n = 224,083 events from 26 sessions). (D–I) Distribution of various SPW-R parameters for SPW-Rs detected on 1→6 probes. Data are displayed as box plots representing median, lower, and upper quartiles and whiskers representing most extreme data points. (J–L) Same as D–I but for various behavioral parameters and brain-state estimators. a.u., arbitrary units; CSD, Current Source Density; SW, Sharp Wave.

Fig. 3.

Brain-wide firing rate modulation with SPW-Rs. (A) Locations of the 36,516 units (blue dots) recorded in Siegle et al. (15) (n = 50 mice, one session per animal). Shaded areas in cyan, green, and red depict visual cortex, hippocampus, and thalamus, respectively. (B) Same as in A for 17,354 units recorded in Steinmetz et al. (16) (n = 19 sessions from eight mice). (C) Average (mean ± SEM) SPW-R–related activity for the four major extrahippocampal areas. CNU, cerebral nuclei; MB, midbrain; TH, thalamus. Shaded area corresponds to time windows within which spike responses were used to calculate SPW-R–related strengths and modulation direction (D). (D) SPW-R responses across data from both datasets combined (see also SI Appendix, Table S1). Left: Z-scored average peri–SPW-R histograms centered on SPW-R peaks. Dashed boxes show four peri–SPW-R histograms (±1 s) from selected structures (mean ± SEM). Middle: Bar graph showing the average response magnitude ±30 ms around SPW-R peak, ranked separately by modulation magnitude in each brain region. Pink shaded area, SEM (not visible in most bars due to small values). Right: Fraction of significantly positively (blue) and negatively (red) modulated neurons in each structure (for neuron numbers and sessions, SI Appendix, Table S1). Note that these effects may not correspond to excitation and inhibition because the occurrence of SPW-R is often embedded in brain-state changes. HPF, hippocampal formation; SUB, subiculum; DG, dentate gyrus; misc., miscellaneous. (E) Probability distributions of the COM of principal neuron firing in the four hippocampal subregions. (F) Distributions of the COM for the four major extrahippocampal areas. misc., miscellaneous. Data are displayed as box plots representing median, lower, and upper quartiles and whiskers representing most extreme data points.

Fig. 4.

SPW-Rs reorganize thalamo-cortical functional network topology. (A) Left: Adjacency matrix showing the increase in MI following drifting grating visual stimulation (stim.) computed between the MUA from pairs of brain areas (n = 23 sessions). Right: The corresponding undirected graph; edge thickness denotes weights. Right Bottom: Shows an example MI time series between LGd and a visual cortical area. (B) Same as A, but for MUA around ripple peaks (n = 50 sessions). (C) Distributions of ΔMI values for cortical and thalamic node pairs during either visual stimulation or SPW-Rs. Data are displayed as box plots representing median, lower and upper quartiles and whiskers representing most extreme data points (n = 135 and 251 pairs, respectively; *** P = 2.5 × 10⁻³³, rank-sum test). (D) Example adjacency matrix (t = 0) of pairwise ΔMI during ripples between single units (n = 685) from one session. (E) Change in path length around ripples. Note the decrease across all brain areas. (F) Same as E, but for clustering coefficient. MB, midbrain; HPF, hippocampal formation; DG, dentate gyrus; SUB, subiculum; PO, posterior nucleus of the thalamus; LGd, dorsal part of the lateral geniculate nucleus; LP, lateral posterior nucleus of the thalamus; APN, anterior pretectal nucleus; Eth, Ethmoid nucleus of the thalamus; VIS, visual cortex unspecific; VISl, lateral visual area; VISli, laterointermediate area; VISam, anteromedial visual area; VISrl, rostrolateral visual area; VISpm, posteromedial visual area; VISp, primary visual area; VISal, anterolateral visual area; VISmma, mediomedial anterior visual area; VISmmp, mediomedial posterior visual area; POL, posterior limiting nucleus of the thalamus; SGN, suprageniculate nucleus; TH, thalamus.

Fig. 5.

SPW-R correlations with spiking activity in extrahippocampal areas vary as a function SPW-R magnitude. (A) Average peri–SPW-R spike responses from the four major brain regions, centered on the peak of ripple power. Responses for ripples of increasing power detected on the subicular probe (probe S; see green illustration on the right; values for first, third, fifth, and seventh octiles (octs.) are shown; n = 28,568 units from 38 sessions where probe S was available) are shown by different colors. Shaded areas in lower Left: time windows within which spike counts in partner regions were counted before and after SPW-R. (B) Similar plot to A, but here the magnitude of spatial synchrony of SPW-Rs across the hippocampal six recording sites are shown. (C) Distributions of pre-SPW-R modulations (left shaded brown area in A) across the six recording sites, averaged across all units from the same area and session. Data are displayed as box plots representing median, lower, and upper quartiles and whiskers representing most extreme data points. Linear regression lines are shown in black. Pearson's rho and p-values are indicated on top of each panel. (D) Same as C for post–SPW-R activity (right shaded brown area in A). 1st, first; oct., octile.

Fig. 6.

SPW-R correlations with spiking activity in extrahippocampal areas vary as a function of the intrahippocampal origin of SPW-Rs. (A) Average peri–SPW-R spike responses (mean ± SEM) from the four major brain regions, triggered on the peak of ripple power detected on different probes (illustrated by green cartoon on the right). Analysis was restricted to isolated SPW-R events (i.e., those detected on a single probe only; Top Right cartoon). See Fig. 1A for anatomical probe locations (n = 36,516 units from 50 sessions). (B) Similar display to A, but here the reference electrode was the site with the largest ripple power, irrespective of whether SPW-Rs were detected at other hippocampal sites or not. (C) Distributions of session-averaged SPW-R modulation scores across all probes for the three main areas included in the dataset (n = 26 sessions where all probes were available; *P < 0.05; **P < 0.01; ***P < 0.001; Kruskal-Wallis test followed by Tukey-Kramer post hoc tests). Data are displayed as box plots representing median, lower and upper quartiles and whiskers representing most extreme data points. (D) Firing rate modulations of all extrahippocampal units for SPW-R detected on probe A (most dorsal probe), plotted against SPW-Rs detected on probe D (most posterior). Each dot is one unit from visual cortex (magenta), thalamus (green), or midbrain (blue). Only units that are significantly modulated on either probe A or D are shown. Red line depicts linear least square regression slope with CIs obtained from 5,000 bootstraps. Regression lines for individual areas are shown separately as dotted lines in the respective color. Gray dotted line is the unity line (n = 10,587 units from 34 sessions where both probes A and D were available; P < 0.001). SI Appendix, Fig. S7 shows individual sessions. (E) Performance of cross-validated SVM decoder (mean ± SEM, gray shaded area) trained to classify isolated dorsal and posterior SPW-Rs based on peri–SPW-R normalized firing rates from all extrahippocampal units in a given session (n = 29 sessions where probes A, B, D, and E were all simultaneously available). Red dashed line, upper 95% confidence bound obtained after 1,000 shuffles of SPW-R location labels. MB, midbrain; TH, thalamus.