Control of recollection by slow gamma dominating mid-frequency gamma in hippocampus CA1

<div><p>Behavior is used to assess memory and cognitive deficits in animals like Fmr1-null mice that model Fragile X Syndrome, but behavior is a proxy for unknown neural events that define cognitive variables like recollection. We identified an electrophysiological signature of recollection in mouse dorsal Cornu Ammonis 1 (CA1) hippocampus. During a shocked-place avoidance task, slow gamma (SG) (30–50 Hz) dominates mid-frequency gamma (MG) (70–90 Hz) oscillations 2–3 s before successful avoidance, but not failures. Wild-type (WT) but not Fmr1-null mice rapidly adapt to relocating the shock; concurrently, SG/MG maxima (SG_dom) decrease in WT but not in cognitively inflexible Fmr1-null mice. During SG_dom, putative pyramidal cell ensembles represent distant locations; during place avoidance, these are avoided places. During shock relocation, WT ensembles represent distant locations near the currently correct shock zone, but Fmr1-null ensembles represent the formerly correct zone. These findings indicate that recollection occurs when CA1 SG dominates MG and that accurate recollection of inappropriate memories explains Fmr1-null cognitive inflexibility.</p></div

SG dominates MG prior to successful place avoidance.

<p>(A) Left: typical 30-min path during the third active place avoidance training session. Shocks are shown as red dots. Right: example of avoidance (success; blue line) and escape after receiving a shock (error; red line). (B) Top: time profile of the angular distance to the leading edge of the shock zone, showing a typical sawtooth avoidance pattern during approximately 60 s. Periods of stillness (green) when the mouse is passively carried towards the shock zone are interrupted by active avoidances (blue dots). Entrance to the shock zone is marked as a red dot. The horizontal blue and red lines mark time intervals of the example avoidance and escape from panel (A), right. The red dotted line marks the leading edge of the shock zone. Bottom: speed profile during the same approximately 60-s interval. The stillness threshold is shown as a green dotted line at 2 cm/s. (C) Schematic depiction of the working hypothesis—as the mouse approaches the shock zone (top), SG driven by CA3 inputs transiently dominates MG driven by ECIII inputs, causing recollection of the shock zone location. (D) Top: average power of SG (blue; 30–50 Hz) and MG (yellow; 70–90 Hz) in the LFP around the time of avoidance initiation (<i>T</i> = 0). Mean powers are displayed as dotted lines. Inset shows average of normalized power across 20–120 Hz around avoidance initiation. Representative SG and MG bands are marked by white rectangles. Bottom: the average ratio of SG to MG power (red line) around avoidance initiation. The mean power ratio is shown as a dotted line. The corresponding average speed profile is shown in green. Data are represented as average ± SEM. Gray boxes represent time intervals for statistical comparisons, *<i>p</i> < 0.05 relative to baseline (−7–−5 s). (E) The time-frequency representation of a 4-s example LFP (overlaid in black) around the initiation of an avoidance start (<i>T</i> = 0 marks avoidance initiation). Notice the relative reduction in number of MG (70–90 Hz) oscillatory events relative to SG (30–50 Hz) events prior to the avoidance (<i>T</i> = approximately −2 s) compared to times during the active avoidance (<i>T</i> > 0 s). (F) Left, top: average event rates for SG (blue; 30–50 Hz) and MG (yellow; 70–90 Hz) oscillations around the time of avoidance initiation (<i>T</i> = 0). Mean rates are displayed as dotted lines. Left, bottom: the average ratio of SG to MG event rates (red line) around avoidance initiation. The mean ratio is shown as a dotted line. The corresponding average speed profile is shown in green. Right: same as (F), left, but for avoidance errors. Data are represented as average ± SEM. Gray boxes represent time intervals for statistical comparisons, *<i>p</i> < 0.05 relative to baseline (−5–−3 s). CA3, Cornu Ammonis 3; ECIII, entorhinal cortex layer 3; LFP, local field potential; MG, mid-frequency gamma; SG, slow gamma. <i>Underlying data can be found here</i>: [<a href="https://goo.gl/oHH22A" target="_blank">https://goo.gl/oHH22A</a>].</p

Error in Bayesian decoding of location increases during SG_dom events.

<p>(A) Example firing-rate maps (top) and 2D decoded Bayesian posterior around avoidance onset. Ensemble activity vectors are shown to the right of each decoded Bayesian posterior. The mouse’s path during a 12-s segment is shown as a white line and the current position is marked by a red cross. (B) Example time series of the angular position that was observed and decoded using a 1D Bayesian estimator from ensemble discharge overlaid with the SG/MG ratio. <i>T</i> = 0 s marks avoidance onset. (C) The average of WT and Fmr1-KO z-score normalized 1D decoding error from ensemble activity that is time-locked to SG_dom events, MG_dom events, and RNDs. <i>T</i> = 0 s corresponds to the time of the events. (D) Summary of decoding error at the moments of SG_dom events, MG_dom events, and RNDs for WT and KO mice. *<i>p</i> < 0.05 relative to random. Data are represented as average ± SEM. KO, knockout; MG, mid-frequency gamma; RND, random time; SG, slow gamma; WT, wild-type. <i>Underlying data can be found here</i>: [<a href="https://goo.gl/oHH22A" target="_blank">https://goo.gl/oHH22A</a>].</p

During SG_dom events, putative pyramidal cell ensemble discharge represents the vicinity of shock.

<p>(A) Four examples of the time evolution of the Bayesian posterior probability from before to after avoiding the shock zone (white sector centered at 12 o’clock for the initial shock zone and 6 o’clock for the conflict shock zone). The mouse’s path during the episode is shown in gray, with the current location indicated by a red cross. The top row corresponds to a WT mouse, the bottom row to a Fmr1-KO mouse. The left examples illustrate training to the initial shock zone. The right examples are after the shock was relocated for conflict training. The initial shock zone location in conflict training is shown as a dotted line. (B) Average normalized posterior probability as a distance from the leading edge of the shock zone. Full gray lines mark the location of the initial shock zone; dotted lines mark the location of the conflict shock zone. Data are represented as averages ± SEM. (C) Ratio of average posterior probability at the location of the initial shock zone and the location of the conflict shock zone in 10-min intervals. (D) Top: summary of normalized posterior probability estimates obtained during SG_dom events for the initial and conflict shock zone sessions for WT (left) and Fmr1-KO (right) mice. Notice maximal decoding probability at the leading edge of the shock zone in both WT and KO mice during the initial shock zone session, and during the conflict session, maximal decoding probability is at the leading edge of the relocated shock zone in WT mice but not in Fmr1-KO mice. During conflict, Fmr1-KO ensemble discharge decodes to the vicinity of the initial shock zone that is currently incorrect for avoiding shock. Red arcs located next to angular bins indicate significantly positive (>1) normalized probability (<i>p</i> < 0.05), blue arcs indicate significantly negative (<1) normalized probability (<i>p</i> < 0.05), gray arcs indicate n.s. relative to 1. Bottom: split bar plots comparing the decoding probability distributions (color: each color corresponds to one 30° angular position) and dwell distributions (gray) for corresponding trials. Black vertical lines mark regions inside of the currently correct shock zone. Dotted vertical lines in conflict trials mark regions inside the initially correct shock zone. KO, knockout; n.s., not significant; P_int, probability at the initial shock zone location; P_con, probability at the conflict shock zone location; SG, slow gamma; WT, wild-type. <i>Underlying data can be found here</i>: [<a href="https://goo.gl/oHH22A" target="_blank">https://goo.gl/oHH22A</a>].</p

Cognitive inflexibility and associated increases of SG dominance in Fmr1-KO mice.

<p>(A) Dwell distribution during first half (0–15 min; top) and second half (15–30 min; bottom) of retention (left) and conflict (right) sessions for WT (gray) and Fmr1-KO (red) mice. Dotted lines show locations of the active shock zone during each session (red) and location of the initial shock zone during conflict sessions (gray). Insets show dwell probability distributions. (B) Behavioral performance during retention and conflict sessions for WT and Fmr1-KO mice. (C) Rates of SG_dom events during retention and conflict sessions. *<i>p</i> < 0.05 between genotypes. Data represent average ± SEM. Inset: vectors showing the time evolution from the first half (circles, 0–15 min) to the second half (arrowheads, 15–30 min) of the conflict session in the coordinate system of <i>x</i> = SG_dom rate and <i>y</i> = number of entrances. KO, knockout; rot., rotation; SG, slow gamma; WT, wild-type. <i>Underlying data can be found here</i>: [<a href="https://goo.gl/oHH22A" target="_blank">https://goo.gl/oHH22A</a>].</p