© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Montreal, Montreal, Quebec, Canada. should Correspondence be addressed to G.B. ( New York, New York, USA. 1 to linked hippocampus, the dorsal the that are functionally episodes before and sleep after training. Toand identify the subpopulationstraining of during in hippocampus dorsal and gdala amy the in simultaneously ensembles neuronal large Werecorded puff). (air element aversive location-specific a with task spatial sical sleep. non-REM (NREM) of SPW-Rs during BLA the in representation threat the with associated be may hippocampus dorsal the from information dorso-ventral axis of the hippocampus entire the throughout information neuronal of combination the tate synchronous discharges of populations during SPW-Rs facili because More sleep. specifically, during circuit pocampus–amygdala hip interconnected the in replayed is experience emotional textual explored partially been only have son, the consolidation mechanisms of amygdala-dependent stabilization of newly formed spatial representations the and consolidation spatial for instrumental are SPW-Rs valence. emotional associated and context the of representation tual stimuli are combined and consolidated to form a stable, integrated gdala outputs entorhinal amythe BLA and central including to the amygdala, directly project associated and hippocampus ventral the only hippocampus ventral the a from contribution with limited associations, context–threat including memory, contextual repre hippocampus dorsal the spatial in sentation fine that shown have experiments other and Lesion respectively circuits, by hippocampal and dorsal the amygdala the and emotional components spatial of are an processed experience pus is for critical contextual emotional memory Cooperation between amygdala, particularly the BLA, and hippocam of consolidation contextual emotional memory occurs during of circuits. ripple-reactivation hippocampus–amygdala patterns representing the run direction that involved the air puff than for the ‘safe’ direction. These findings suggest that positively modulated during hippocampal SPW-Rs. Notably training. These peaked reactivations during hippocampal sharp wave–ripples (SPW-Rs) and involved a subgroup of BLA cells and after training. We found coordinated between reactivations the hippocampus and the BLA during non-REM sleep following hippocampus and BLA while rats learned the location of an aversive air puff on a linear track (BLA) The of consolidation emotional memory context-dependent requires between communication the hippocampus and the Gabrielle Girardeau hippocampus–amygdala system during sleep Reactivations of emotional memory in the nature nature Received 21 February; accepted 2 August; published online 11 September 2017; New New York University Institute, New York University, New York, New York, USA. To study hippocampus–amygdala interactions, we combined a clas hippocampal during cells place of sequences wake of replay Sleep 10 , 22 NEUR , 2 3 , it remains to be determined how emotional and contex how , emotional it to remains be determined OSCI EN C 3 Center Center for Neural Science, New York University, New York, New York, USA. E

1 , , Ingrid Inema advance online publication online advance , but the mechanisms of this process are unknown. We recorded neuronal ensembles in the 1 , 27 14 , 2 2 8 9 , 1 . We hypothesized that con that Wehypothesized . , , we hypothesized that spatial 5 is required for spatial and and spatial for required is 1 , 4 & György Buzsáki 1– 1 0 . . It is that believed 24– 11 2 , 6 16– . By compari 2 1

. Because Because . 8 [email protected] , 11– , reactivation was stronger for the correlation hippocampus–BLA 1 3 ------. d 1 o – i in the speed ratio (previous/current danger zone) between pre- and and pre- between zone) danger (previous/current ratio speed the in reversal systematic the Therefore, nature. aversive its loses zone ger dan the previous while training, during an acquires aversive valence 1a Fig. speed the at the with previous day’slocation) danger puff zone air ( the preceding cm 20 the current as the of (defined day zone danger the in rat the of speed running the ing compar by epochs test post-run and pre-run the from performance memory quantified we location, its remember they if location puff without session ( puff air test the post-run a and post-NREM) or post-REM as (‘post-sleep’, sleep categorized post-learning puff, air (‘run’)the with (‘pre-sleep’, categorized as pre-REM or pre-NREM), a training session cage home in the sleep by pre-learning followed puff, air the without on test session the track of consisted a behavioral ing session pre-run large neuronal ensembles in freely moving animals. Each daily record of and recordings training behavioral to daily task allow this adapted learning fear relies learning on both the amygdala and the hippocampus contextual air-puff-induced that shown has work Previous manner. pseudo-random a in daily changed was puff air the of direction and of the track on each lap in one of The the directions. location running an air at aversive puff we location same the introduced was achieved, performance steady After rewards. water for track linear a on forth ( Rats neurons. BLA recruit to component aversive an with task spatial classical a combining by task a designed we reactivations, hippocampal–amygdala Tostudy Rats learn the daily location of an aversive airRESULTS puff on a linear track sleep. SPW-Rs NREM of during reactivated are threat tigated whether joint hippocampus–BLA representations of space and we examined their discharge patterns during SPW-Rs. We then inves : 3 1

0 . 1

0 3 2 ). The current danger zone, initially neutral during pre-run, pre-run, during neutral initially zone, danger current The ). 8 Department Department of , Medical Center, New York University, / n n . 4 Fig. 1 Fig. ). 6 3 4 7 Present Present address: Douglas Institute, McGill University, a ). Because rats slow down before crossing the air air the crossing before down slow rats Because ). , n as well as during sleep before = 4) were pretrained to run back and and back run to pretrained were 4) = Fig. 1a , b and t r a Supplementary Supplementary C I

e l 3 0 . . We s  - - - - © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. days ( days training with diminished gradually puff air the of valence aversive ( pre-run to compared post-run in zone danger rent cur the in speed slower significantly the by reflected quantitatively ( pre-run during track the throughout smoothly increased speed whereas post-run, during maintained was change speed similar A zone. danger the through passing after acceleration an by followed puff, air the before speed reduced a was run during 1b Fig. Supplementary ( location puff air new the of learning indicates post-run pre-run. to compared post-run DZ the in speed slower the bar. Note pink shaded the by indicated is DZ current The epochs. puff) air (no post-test and training puff), air (no pre-test the in direction puff air the ( correction. ** outliers). excluding values maximum and minimum whiskers, quartiles; last and first boxes, outliers; post-run vs. pre-run effect, session significant ANOVA; measure ( post-run and pre-run between DZ current the for ( post-run and run pre-run, for speed DZ current F post-run, or run (pre-run, effect session ANOVA; measures repeated (two-way epochs run three the during sessions and animals across DZ previous and ( (blue). day previous the on and (pink) day current the on puff air the of location the preceding cm 20 the as defined are (DZ) zones danger The post-run). (pre-run, delivered is puff air no where sessions run test two and post-sleep) (pre-sleep, epochs sleep two by flanked is epoch day. run The every changed is location puff air The epoch. run the during direction running one in track the on location same the at delivered is puff air An 4 animals). in sessions 55 of out animal one in session (one session a representative in time over track the on animal the of position 1 Figure t r a  in zone danger current the in speed the with correlate not did track = 11.81) and interaction, ( interaction, and = 11.81)

a

Post-run Post-sleep Run (air puff) Pre-sleep Pre-run

Supplementary Fig. 1c Fig. Supplementary

min 2 W

C I ater Rats learn the daily location of an aversive air puff. ( puff. air aversive an of location daily the learn Rats c Danger zone ) Air-puff-centered mean speed ( speed mean ) Air-puff-centered e l Current day s P = 5.3 × 10 = 5.3 A ir puff(current) ). The typical behavioral pattern on track the pattern behavioral ). The typical P = 4.46 × 10 = 4.46 ). The location of the air puff on the the on puff air the of location The ). −6 Air puff(previous) , , t (51) = −5.08; run vs. post-run post-run vs. run = −5.08; (51) P = 7.48 × 10 = 7.48 −11 P = 1.31 × 10 = 1.31 Previous day Danger zone ± , d.f. = 2, = 2, , d.f. s.e.m., pre-run: pre-run: s.e.m., P = 0.0011, = 0.0011, P = 1.21 × 10 = 1.21 Fig. 1 Fig. −14 F , d.f. = 2, = 2, , d.f. Fig. 1b Fig. = 30.53). = 30.53). −13 W a c t t , d.f. = 2, = 2, , d.f. e (52) = 3.45; = 3.45; (52) a Fig. 1 Fig. ). This was was This ). r ) Rats run back and forth on a linear track for water rewards. Gray line: one-dimensional one-dimensional line: Gray rewards. water for track a linear on forth and back run ) Rats −6 n = 52 sessions in 4 animals; run and post-run: post-run: and run 4 animals; in sessions = 52 , , , c t ). The The ). F (53) = 5.47). Right: speed ratios across sessions and animals (one-way repeated repeated (one-way animals and sessions across ratios speed Right: = 5.47). (53) b P c b = 41.51), air puff location effect (current vs. previous, previous, vs. (current effect location puff air = 41.51), Post hoc Post and and = 5.1 × 10 = 5.1 Speed (cm/s) Speed (cm/s) F 100 110 = 40.48; = 40.48; 60 70 80 90 10 2 30 40 5 - 10 2 30 4 50 60 7 80 90 0 0 0 0 0 0 P –1 = 9.70 × 10 = 9.70 paired paired we recorded 7,390 well-isolated units (rat 1, 2,444; rat 2, 1,294; rat rat 1,294; 2, rat 2,444; 1, (rat units well-isolated 7,390 recorded we ( rat each in cortex piriform the and amygdala the of areas large from recording allowed This experiment. behavioral each between steps 2a ( task the during region hippocampal CA1 amy dorsal the and right gdala and left both from neurons of ensembles recorded We physiology sleep and recordings BLA results. the on location puff air the of bias systematic a out ruling post-run, or training pre-run, C P Supplementary Fig. 2 Fig. Supplementary rev urrent dangerzon P , b re-ru −5 i ** ). Eight-shank silicon probes were moved downward by were downward moved probes 140- silicon ). Eight-shank ous post hoc t hoc post , , t t n (50) = 4.43; white line, median; black line, mean; black dots, dots, black mean; line, black median; line, white = 4.43; (50) R P P d -tests showed significant differences between previous and and previous between differences significant showed -tests anger zon ost-run (noairpuff re-run un advance online publication online advance −9 ( air puff , , A ( t no airpuff -tests, pre-run vs. run: run: vs. pre-run -tests, ir-puff-centered normalizedpositiononthetrac (51) = −6.84; = −6.84; (51) e e Ru *** ) *** n ) ) P ). Over the course of a total of 61 sessions, sessions, 61 of total a of course the Over ). < 0.01, *** < 0.01, P ost-ru P ** = 0.00307, = 0.00307, n 0 n n = 55 sessions in 4 animals; significant significant 4 animals; in sessions = 55 = 53 sessions in 4 animals) curves in curves 4 animals) in sessions = 53 P P = 2.5 × 10 = 2.5 < 0.001 with Bonferroni Bonferroni with < 0.001 b ) Left: speed in the current current the in speed ) Left:

t Speed ratios

(51) = −3.10), as well as well as = −3.10), (51) –0. –0. – P nature nature 0 0 0 0 0 = 0.0012, d.f. = 1, d.f. = 0.0012, . . . . . 0 2 4 6 8 6 4 2 −11 k P r , , u re- n t (51) = −8.49; = −8.49; (51) *** NEUR Ru *** n *** OSCI P r ost u n - EN 1

Fig. Fig. µ C m E - © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Reactivations across the hippocampus–amygdala network as well as as well as network hippocampus–amygdala the across Reactivations BLA–hippocampus coordinated reactivations during NREM sleep ( types cell two the for ratios rate firing NREM/wake or REM/wake of distributions the by as shown to relative wakefulness, sleep NREM and, to extent, a lesser sleep REM during but not , cells, rate of pyramidal BLA a ness wakeful and REM) followed and (NREM cells sleep during pyramidal distribution of skewed rates firing The Methods). Online ( criteria physiological and waveform by interneurons and cells pyramidal putative as characterized further cortex piriform the ( in hippocampus the and in 1,210 1,560 nuclei, central the in 782 BLA, the in were these of 2,038 record, movement probe and placement probe of reconstruction histological of basis the On 2,514). 4, rat 1,138; 3, (NREM/wake: to wake compared NREM during rates firing decrease interneurons, identified monosynaptically (blue, wake and REM between rates firing change not = 8 × 10 cells; pyramidal identified monosynaptically (orange, cells pyramidal 1 for toward skewed is (bottom) ratios rate firing NREM/wake and REM/wake of distribution The right). (top wake vs. REM and left) (top wake vs. NREM during BLA (orange, cells ( (high)). red to (low) green from units, arbitrary in power represent colors sleep; (out of 29 sessions in 3 rats with simultaneous BLA and hippocampus recordings). Spectrograms were used to define ( in by sleep. lines NREM gray SPW-R brainare indicated times Hippocampal blue). (BLA; states amygdala right (wake, NREM REM or and left and red) (Hpc; hippocampus the in plots) (raster units and (LFPs) potentials field local example and channels) 160 total probes; (eight-shank 2 Figure nature nature ( networks within-structure b a NREM 3 Wake 1 RE Frequency Frequency ( 20 40 60 20 40 60 M Fig. Fig. 2 0 0

−42 NEUR 0 0 Physiological characterization of BLA. ( BLA. of characterization Physiological , , z n c = 13.54; Wilcoxon signed rank = 13.54; tests), do indicating an increase in firing rate during both sleep Interneurons stages compared to wake. = 675 cells; see Online Methods and and Methods Online see cells; = 675 OSCI ). In addition, we found a specific increase ). in In we the firing increase addition, found a specific 1 1 EN C Fig. 2 Fig. E advance online publication online advance 2 2 c Supplementary Fig. 4 Fig. Supplementary and Online Methods). Online and

Supplementary Table 1 Supplementary Units LFPs Time (h Time (h) BLA 3 3 0 BLA Hpc Right Left Hpc NREM slee ) Supplementary Fig. 3 Fig. Supplementary p a 4 4 ) Silicon probe recordings from the dorsal hippocampal CA1 (four-shank probe) and bilateral amygdala amygdala bilateral and probe) (four-shank CA1 hippocampal dorsal the from recordings probe ) Silicon 1 Supplementary Fig. 3 Fig. Supplementary ) were quantified quantified were ) 5 5 ). ). Units were 2 Time (s

P ) = 1.97 × 10 = 1.97 and and 6 6 3 - c

), interneurons (blue, (blue, interneurons ), NREM rate (Hz) No. cells

Normalized cell count 0.00 0.01 10 the previously described decay forthe previously described pairs of neuronshippocampal n Neurons in the showed weaker experience-induced experience-induced weaker showed cortex piriform the in Neurons ( calculation EV the in included were rons Reactivations were maintained when both pyramidal cells and interneu 2.89 ( sleep hour of NREM first over the reactivations in decay gradual The tions between the hippocampus and BLA during post-NREM ( reactiva showed significant pairs, cell pyramidal hippocampus–BLA REV, and EV using The value. control calculated a as used is epochs, post-sleep and pre-sleep the switching by calculated (REV), variance or NREM (REM pre-sleep during correlations pre-existing account into taking NREM) that can be explained by run correlations (‘reactivation’) while or (REM correlations post-sleep during ofpopulation pairwise the in variance of percentage the is EV (EV). variance explained the using 0. 0. 10 20 40 60 80 0.00 Fig. 3 Fig. 5 0 1 = 19 sessions, 1 0 1 1 0

c –1 ) Distributions of firing rates for monosynaptically identified pyramidal pyramidal identified monosynaptically for rates firing of ) Distributions 0 1 4 −9

n –0.8 = 675; NREM/wake: NREM/wake: = 675; ± .0 Wake rate(Hz) , , –0.6 0.47%; 20–40 min, 1.72 1.72 min, 20–40 0.47%; c 0 1 z ; mean differences between EV and REV, and EV between differences mean ; = −6.00; Wilcoxon signed rank tests; dotted lines: medians). lines: dotted tests; rank signed Wilcoxon = −6.00; –0.4 .1 32– Firing raterati –0.2 1 3 5 4 10 ; ; P 0 0 Fig. Fig. 3a = 0.014, d.f. = 2, REM slee 0.2 10 n 0 n = 175; REM/wake: REM/wake: = 175; 8 0 = 175 cells) and other cells (gray, cells other and cells) = 175

b 0.4 o No. cell ) CA1 and BLA spectrograms for an example session example an for spectrograms BLA and ) CA1 40 0.6 , p b

0.8 0 and Online Methods). The reverse explained 1 12 P s = 4.07 × 10 = 4.07 1 0 χ ± 2

0.00 REM rate (Hz) No. cells

= 8.53; Kruskal-Wallis test) paralleled Normalized cell count 0.01 0.44%; 40–60 min, 1.31 1.31 min, 40–60 0.44%; 10 0. 2 0. 0.00 10 20 40 60 80 5 0 1 1 1 0 1 0

P –1 Time (s 0 1 = 0.21, = 0.21, –0.8 −46 .0 Wake rate(Hz)

–0.6 0 1 , , ) z

–0.4 .1 = 14.25; REM/wake: REM/wake: = 14.25; 3 Supplementary Fig. 5 Fig. Supplementary Firing raterati –0.2 1 z = 1.25) and slightly slightly and = 1.25) 10 0 ± t r a 10

s.e.m.: 0–20 min, min, 0–20 s.e.m.: 0.2 n 0 = 1,188 cells) in cells) = 1,188

0.4 8 0 o 4 No. cell 0.6 40

0.8 C I 0 s ± 12 Fig. 3 0.60%; 0.60%; 1 0 e l 5 P 35

, c 3 s 6 ). ). ).  - - .

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. BLA neurons receive direct input from ventral, but not dorsal, CA1 CA1 dorsal, not but ventral, from input direct receive neurons BLA A subset of BLA cells are modulated during hippocampal SPW-Rs REM- rates robust ( firing cells the pyramidal putative despite BLA in structure, increase any sleep-specific in significant not were ( hippocampus the there while were no reactivations at the all between central nuclei and cortex ( sions, mean EV – REV 3.13 rank sum tailed test on EV – REV for ( hippocampus–BLA neurons ( partner CA1 their with reactivation dots). (black outliers (whiskers), outliers excluding values maximum and minimum and (box), quartiles pairs; ( ( pairs; (pyr–pyr epoch NREM 20-min first the in > REV EV where sessions for NREM of epochs min 20 successive for REV and EV Right: pairs). pyr–pyr rats; a ( sleep). NREM for sessions 25 and 3 animals of out session and animal (1 session example an in cells (pyr) pyramidal hippocampal multiple with neuron pyramidal BLA a single of coactivations strong arrows: Red (REV). variance explained reverse value, control its and (EV) variance explained the calculate to used were matrices These bins. time 50-ms in epochs post-NREM and run pre-NREM, 3 Figure t r a  neurons e d Figs. Figs. 2c . . (

) Same as as ) Same ) Hippocampus–piriform cortex EV and REV (NREM: (NREM: REV and EV cortex ) Hippocampus–piriform c c a ) Left: EV and REV across all sessions for NREM ( NREM for sessions all across REV and EV ) Left: EV REV (%) n n 10 12

= 3 rats). All tests are Wilcoxon signed rank tests, *** tests, rank signed Wilcoxon are tests All = 3 rats). min: 0–20 3 rats, in sessions = 19 Hippocampal cells n 0 2 4 6 8

C I 2 = 14, mean EV – REV 0.85 40 35 30 25 20 15 10 Hippocampus–BLA ensembles reactivate during NREM sleep. ( sleep. NREM during reactivate ensembles Hippocampus–BLA 2 and 5 . . However, spatial location is more precisely coded by dorsal d e l but for central nuclei (CeN) (NREM: (NREM: (CeN) nuclei central for but 3c NREM 5 *** – s e 10 and Fig. 3 Fig. Pre-NREM BLA cells 15 Supplementary Fig. 5a Supplementary RE e 20 M ). Reactivations during REM sleep REM during Reactivations ). ± 0.73%, s.e.m.) vs. hippocampus–piriform 25 30 ± 0.34%, s.e.m.), 0–20 min 15 10 40 35 30 25 20 P *** 5 = 0.00013, = 0.00013, 5 Fig. 3 Fig. ). n = 19 sessions, sessions, = 19 20–40 min Hp 10 P n NREM n = 0.0092, c = 25, = 25, *** d = 17 sessions, sessions, = 17 BLA cells ; ; Wilcoxon one- 15 z = 0.38; 20–40 min: min: 20–40 = 0.38; Run 20 P BLA P n < 0.001, ** < 0.001, = 0.00019, = 0.00019, B 40–60 mi L = 25 ses A z 25 = 2.38), * 27 P = 0.717, = 0.717, , 37 30 n P , a 3 = 0.0052; REM: REM: = 0.0052; 8 - ) Correlation matrices were calculated for hippocampus–BLA cell pairs for the the for pairs cell hippocampus–BLA for calculated were matrices ) Correlation

P z 40 35 30 25 20 15 10 < 0.01, * < 0.01, d = 3.72; = 3.72; nonmodulated pairs ( pairs nonmodulated for than larger were cells BLA SPW-R-modulated using calculated of SPW-Rsdorsal hippocampal on BLA Moreover,cells. reactivations SPW-Rs hippocampal ( 163 interneurons (14.7%), 102 of 1,233 pyramidal cells (8.3%)) during of 24 (‘downmodulation’; modulated negatively or (11.1%)) cells dal (‘upmodulation’; 42 of 163 interneurons (25.8%), 137 of 1,233 pyrami A modulated and positively of were neurons BLA significantly fraction neurons. BLA and SPW-Rs between relationship functional the examined we hypothesis, this test To amygdala. and dorsal the hippocampus between connections functional establish may SPW-Rs hippocampal neurons fire together during large-amplitude SPW-Rs ones ventral than neurons CA1 EV REV (%) 5 z P 10 12 = 0.36 and REM: REM: and = 0.36 8 0 2 4 6 = 0.00046, = 0.00046, 5 n 10 P NREM = 3 rats) and REM sleep ( sleep REM and = 3 rats) advance online publication online advance < 0.05. All box plots show the median (red line), first and last last and first line), (red median the show plots box All < 0.05. ** Post-NREM Hpc BLA cells n 15 = 15 sessions in 3 rats, 3 rats, in sessions = 15 b z 20 ) NREM EV and REV for the example session shown in shown session example the for REV and EV ) NREM = 3.5; 40–60 min: min: 40–60 = 3.5; REM n 25 = 19 sessions, sessions, = 19 i P Supplementary Fig. 5b Fig. Supplementary B L A r Fig. Fig. 30 4 ). This confirmed the indirect influence influence the indirect ). This confirmed e

14 EV REV (%) –0.04 –0.02 0 0.02 0.04 , 10 12 n 1 8 0 2 4 6 5 = 23, = 23, . Because both dorsal and ventral and ventral dorsal both . Because P

P

P = 0.0312, = 0.0312, = 0.687, = 0.687, Correlation = 0.301; pyr–pyr pairs). pairs). pyr–pyr = 0.301; NREM P Hpc

= 0.377, = 0.377, b nature nature EV REV (%) 0 2 4 6 8 ). z z = −0.40; all cell cell all = −0.40; = 2.15). = 2.15). CeN REM B z L A NEUR = 0.88; = 0.88;

OSCI

n = 3 EN C 2 9 E - , © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. the largest pre-NREM to post-NREM change (one-way ANOVA, (one-way change post-NREM to pre-NREM largest the showed partner BLA the of upmodulation SPW-R and correlations 2 Table ( partner BLA the of modulation SPW-R and correlation run of combination a on based subgroups nine into pairs separated we reactivations, sleep in involved To of was preferentially subgroup pairs a selective whether test 17,768). 4, rat 3,836; 3, rat 16,056; 1, rat 37,660: pairs pus–BLA hippocam of pyramidal–pyramidal number total Methods; (Online correlated reliably not was 89.96%) 37,660; of (33,881 majority ing percentage small Another the remain while 6.69%). correlated, was negatively 3.34%) of 37,660; (1,258 37,660; of (2,521 trains correlated spike positively significantly showed pairs neuron pyramidal of hippocampal–BLA values a fraction run, During to ripples. related reactivation were their how examined and correlates their ripple of LFP irrespective cell each for reactivations quantified we First, direction. opposite the from worked approach second The vations. reacti influenced properties to such how relative examined neurons then and ripples individual of properties firing the defined we In approaches. approach, the first sleep, we two complementary used during dynamics In attemptthe reactivation a to further characterize reactivations in involved preferentially are cells BLA Ripple-modulated (LFP). ripples hippocampal example Top traces: black panels). (bottom interneurons and panels) (top cells pyramidal putative BLA right) (top downmodulated and left) (top in asterisks colored respective the by indicated are neurons These downmodulated). bottom, upmodulated; top, (blue: interneurons and downmodulated) bottom, upmodulated; top, (red: cells pyramidal BLA putative two for gain event n (Hpc: SPW-Rs during blue) light or red light (down-mod; downmodulated or blue) dark or red dark (up-mod; upmodulated significantly are that blue) (int; interneurons and red) (pyr; cells pyramidal putative BLA ( SPW-Rs. hippocampal 4 Figure nature nature P a = 41 sessions, sessions, = 41 = 1.1 × 10 = 1.1 b Ripple-modulated cells (%)

Gain Gain Gain Gain 100 10 20 30 40 50 60 70 80 90 0 1 1 1 0 1 2 3 0 2 0 2 –0. 0 5

Hpc Pyr ). Hippocampus–BLA pairs with significant, positive run run positive significant, with pairs Hippocampus–BLA ). NEUR Subsets of BLA cells are up- or downmodulated during during downmodulated or up- are cells BLA of Subsets Time (s) Int Down-mod Up-mod 0 −45

BLA Pyr OSCI Fig. 5 Fig. , d.f. = 8, = 8, , d.f. Int n 0 * * * * = 3 rats; BLA: BLA: = 3 rats; .5 c . . ( EN c a c a C , ,

) Normalized peri-event gain for all upmodulated upmodulated all for gain peri-event ) Normalized No. ripple-modulated pyr ) Percentages of hippocampal (Hpc) and and (Hpc) hippocampal of ) Percentages No. ripple-modulated int Supplementary Fig. 6 Fig. Supplementary E 120 100 F

40 30 20 10 80 60 40 20 = 29.09; = 29.09; 1 –0.5 –0.5 * * advance online publication online advance n Time (s = 29 sessions, sessions, = 29 0 0 0 0 post hoc post ) .5 .5 comparisons, comparisons, 100 20 10 80 60 40 20 –0.5 –0.5 1 and and n * * = 3 rats). ( = 3 rats). Supplementary Supplementary Time (s 0 0 0 0 P b

) < 0.001). < 0.001). ) ) Peri- .5 .5

0 1 Normalized gain Normalized - - -

calculated EVs and REVs for pairs pooled according to their firing firing their to according pooled pairs for REVs and EVs calculated P quartile: high-contribution in averaged around a peak; window ripple 500-ms ( quartiles and low-contribution three, upmodulated the remaining the to of compared cells post-NREM to SPW-R) outside pre-NREM versus from during rate firing is, (that gain SPW-R increase in specific a showed quartile contributing strongly most the in neurons BLA upmodulated that We indi found their contributions. of vidual magnitude the to according quartiles into cells BLA Wedivided in. then aver participated were cell the that pairs the all contributions over aged measure, contribution per-cell a obtain EV, in decrease pair; the of the contribution the larger larger the (the pair removed the of contribution one. by one (EV EV in pairs change The hippocampus–BLA removing by sessions) animals and across pairs all with (calculated EV overall the to pair cell sessions; across and EVs animals 6b the Fig. across Supplementary grouped calculating (pairs by subgroups nine confirmed the was pairs reactivations cell of to subgroup specific this of contribution dominant The ban oe iet upr, e sd ratvto srnt ( strength reactivation a used we support, direct more To obtain reactivations. sleep in threat of not role do critical the alone address directly findings these during Furthermore, reactivations SPW-Rs. for hippocampal support indirect only these offer However, training. observations after modulation their of gain increased an through reactivations, coordinated in involvement show preferential a ripples hippocampal during upmodulated are that cells BLA SPW-Rs during reactivated is trajectory aversive The ( rates firing on depend not did EV that showed control This rate). firing combined or rate firing cell hippocampal rate, firing cell BLA (individual rates lc–het ersnain uig aeuns. as ere a learned Rats the to wakefulness. new air puff location every day linked during during the training session ( are representation reactivations place–threat sleep how examined we Finally, representations place–threat new of reinstatement to contributes NREM sleep. during reinstated is association place–threat the which within windows time SPW-Rs are specific sleep NREM that confirm test; rank signed ( epochs NREM and the pre-NREM post- between different not was also significantly SPW-R of rate occurrence by The increase. rate explained firing be air-puff-induced cannot results reactivation the tests), rank signed cells: dal ( safe between and differ not air (pyrami significantly puff trajectories direction safe the for 11b Fig. Supplementary not but direction puff air SPW-Rs SPW-R for to pre-NREM the compared post-NREM during joint hippocampus–BLA neuron the representation of was significantly enhanced reinstatement the that Wefound direction. safe the vs. of correlation patterns the pairwise of hippocampus–BLA the air puff strengths reactivation the compared we Therefore, safe. considered on a day, given (air or puff trajectory) danger can run be the opposite track the on run of direction one only during presented was puff air firing patterns separately during the two directions of travel. Since the measure ( = 0.991, 0.991, = In the second approach, we evaluated the contribution of each each of contribution the evaluated we approach, second the In Supplementary Fig. 8 Fig. Supplementary P Supplementary Fig. 10 Supplementary P = 0.270, = 0.270, 45 × 10 × 4.57 = z = 2.40). To control for the effects of firing rates, we we rates, firing of effects the for control To 2.40). = Supplementary Fig. 9 Fig. Supplementary P Supplementary Fig. 11d Fig. Supplementary = 0.192; 0.192; = z = 1.101; all cells: cells: all = 1.101; all ). – EV – , −5 c ). Because the firing rates of BLA cells did cells of rates BLA firing the ). Because ; Wilcoxon one-tail sign-rank test on test gain sign-rank ; one-tail Wilcoxon , , z z = −1.289, −1.289, = = 3.91; low-contribution quartiles: quartiles: low-contribution 3.91; = minus one pair one minus and Online Methods) and analyzed P ). = 0.763, = 0.763, Supplementary Fig. 7a Fig. Supplementary n ). These observations thus observations These ). = 41 sessions; Wilcoxon Wilcoxon sessions; 41 = ) indicates the individual individual the indicates ) z = 0.302, Wilcoxon = 0.302, t r a i. 6a Fig. C I Fig. Fig. 1a Fig. 5 Fig. , b e l and and ). To). , b R s ). ). b  - - - )

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Notably, the reactivation of hippocampus–BLA coactivity during during coactivity hippocampus–BLA of reactivation the Notably, SPW-Rs. hippocampal with in association rons in and BLA occurred neu hippocampus-responsive of subgroup a involved Reactivations sleep following experience in a spatially anchored threat model threat anchored spatially a in experience following sleep of NREM neurons during strengthened was between BLA and hippocampus activity dorsal the neuronal correlated that found We DISCUSSION representation. space–threat new the of stabilization the in role a play sleep during reactivations ( compared were distribution the of percentiles) 2.5th of (instead quartiles tributing con weakly most the and strongly most the when maintained ( was post-NREM coac and in pre-NREM increase the between post-run with tivity and correlated pre-run significantly was between coactivity increase the pairs contributing, 7b Fig. contribution; lowest of percentile 2.5th contributing (the strongly pairs least the and of distribution) percentile contribution 2.5th the highest the by (represented pairs contributing strongly most the separately we examined relationship, this quantify of Toan air puff. absence in the test post-run in the were maintained and training during developed patterns coordinated These ampus). (hippoc fields place and air-puff-related (BLA) activity puff-related air- showed that pairs cell BLA–hippocampus contributing of highly sleep. during been replayed and has it when experienced test, post-run the and has yet, location new experienced the been to not when test, expected pre-run thus the is between threat different and be space of representation joint The quartiles: contribution quartiles: contribution high peak; ripple around window a 500-ms in averaged gain on tests rank signed one-tail (Wilcoxon cells upmodulated BLA contributing strongly for SPWRs post-NREM and pre-NREM between gain in increase significant a is There (bottom). quartiles remaining the for and (top) quartile contributing strongly the of cells upmodulated for SPW-Rs (red) post-NREM and ( mean Right: epoch). pre-sleep the during gain highest with bin the of timing by sorted are cells cell; per gain 6. (b different from all others ( ANOVA s.e.m.; bars: error (blue; group correlation run negative significantly downmodulated, and (red) group correlation run positive significantly upmodulated, the for difference correlation – pre-NREM post-NREM the of distributions cumulative normalized the shows Inset negative. significantly or nonsignificant positive, run—significantly the during correlation the (ii) (down-mod)—and downmodulation or mod) (no modulation no (up-mod), cell—upmodulation BLA the of type ripple-modulation the (i) to according classified pairs cell of group each for correlations NREM ( training. following SPW-Rs during gain their increase selectively cells BLA modulated contributing 5 Figure t r a 

a

) Left: peri-ripple gains for upmodulated cells of the highly contributing quartile for pre-NREM SPW-Rs and post-NREM SPW-Rs (color: normalized normalized (color: SPW-Rs post-NREM and SPW-Rs pre-NREM for quartile contributing highly the of cells upmodulated for gains peri-ripple ) Left: Mean pre/post NREM correlation difference –3 –2 –1 × 0 1 2 3 4 5 ). We found that for strongly contributing, but not for weakly but not for weakly ). We contributing, for that strongly found P 10

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Reactivations rely on pairs with correlated activity during run and a BLA partner that is upmodulated during hippocampal SPW-Rs. Strongly Strongly SPW-Rs. hippocampal during upmodulated is that partner a BLA and run during activity correlated with pairs on rely Reactivations –3 ** e l Up-mod s Fig. 7 Fig. −45 n BLA-cell ripplemodulation , d.f. = 8, = 8, , d.f. = 73 cells, cells, = 73 post hoc

c Proportion of cells ). These coordinated changes indicate that that indicate changes coordinated These ). 1 0 Training –0.1

No mod corr Tukey–Kramer multiple comparison test with ** Significantly negative Nonsignificant Significantly positive F Correlation difference = 29.09, = 29.09, P = 0.992, = 0.992, 0 Figure 7 Figure Down-mod n = 3 rats). The upmodulated, significantly positive correlation group is the only one to be significantly significantly be to one only the is group correlation positive significantly upmodulated, The = 3 rats). z = 2.408; = 2.408; Fig. 7 Fig. a shows examples examples shows Supplementary Supplementary 0.1 b n ). This result result This ). = 3 rats). 60 40 20 b 1 –2 –1 39 SPW-Rs, Pre , 4 0 - - - - . 2 1 0 correlated with the changes in the coactivations on the test sessions on were by training induced sleep during of coactivation in strength the changes only,the pairs reactivated the the For of association. place–threat learning during correlations strongest the showed also that those were sleep post-experience to sleep pre-experience from correla tion in increase strongest the showed that BLA and pocampus hip the across pairs neuron Furthermore, sleep. post-experience to pre-experience from partners neuron hippocampal with correlation during SPW-Rsactivity their did not change show in significant their change not did or decreased that neurons BLA contrast, In SPW-Rs. hippocampal during rates firing increased they because responding of as pairs hippocampus- members these the amygdala characterized We reactivations. further to cross-structure the and thus contributed sleep to post-experience from pre-experience significantly increased coactivation whose subset relevant the identified we cross-structure pairs, of neuron number large the Of daily. neurons of sample sets and new amygdala the of structure full the through probes our advance slowly could we that so day every associations place–threat new generate to us allowed that design experimental an and probes silicon in multi-shank using by this simultaneously We achieved structures. two neurons these individual of number large edentedly from an recording unprec inputs required hippocampal that receive in active is neurons amygdala and of hippocampus the set small a only learning threat contextual direction. safe the zone, representing patterns danger pairwise the of the reactivations to through compared travel the during dominating relations cor pairwise of patterns the for stronger was sleep post-experience P Previous works have shown that in both tasks and tasks memory spatial both in that have shown works Previous < 0.01). Details of all distributions are shown in Time (s) –2 advance online publication online advance –1 SPW-Rs, Post n = 63 cells, *** cells, = 63 2 1 0 a ) Mean differences between pre-NREM and post- and pre-NREM between differences ) Mean ±

s.e.m.) gain during pre-NREM (blue) (blue) pre-NREM during gain s.e.m.) Normalized gain Normalized 7– P 9 = 4.57 × 10 = 4.57 , 3

5 Mean gain Mean gain . Identifying amygdala neurons neurons amygdala . Identifying 1 2 1 2 –2

Top contributionquartile n nature nature = 37,660 pairs, one-way one-way pairs, = 37,660 Remaining quartiles –1 −5 Supplementary Figure , , Time (s) z = −3.913; low low = −3.913; *** 1 0 NEUR Post-NREM Pre-NREM OSCI EN 2 C E - - - - © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. ventral neurons projecting to the amygdala the to projecting neurons ventral involving likely hippocampus, SPW-Rs ventral and dorsal amplitude the of populations large during because possible is this that esize We hypoth hippocampus. dorsal the of SPW-Rs by entrained tively effec were interneurons and cells pyramidal of BLA a fraction BLA, to hippocampus dorsal from connections direct of lack the despite tial representation of ventral hippocampal neurons is debated processing contextual ing to memories spatial consolidate known SPW-Rs, hippocampal sleep of suppression indirect the that information spatial specific highly carry hippocampus dorsal the in neurons that observations associations context–threat classical including threat. the of in absence session test the during on track the and is reinstated sleep during or reconsolidated consolidated that is amygdala subsequently the and hippocampus the between representation joint novel a ates our suggest findings that training on the cre association place–threat the aversive air puff, compared to travel in Overall, the safe direction. involved that travel during correlated pairs hippocampus–BLA for were stronger reactivations Moreover,track. the experience-induced outliers). excluding (whiskers) values maximum and minimum and (box), quartiles last and z ** rank-test; signed one-tail (Wilcoxon trajectory to safe compared trajectory puff air the for higher significantly is peak ripple the at (RS) strength reactivation in difference post-NREM vs. pre-NREM ( sessions. single indicate post-NREM to pre-NREM from lines ( (*** trajectory puff air for pre-NREM to compared post-NREM in higher significantly was bars) (gray peaks ripple around window 500-ms a in strength reactivation Right: SPW-Rs. hippocampal (red) post-NREM and (blue) ( animals over trajectories (bottom) safe versus (top) puff air the of strength reactivation ripple ( SPW-Rs. hippocampal during peak 6 Figure nature nature Indeed, one postulated role of SPW-Rs is to combine neuronal activity P a = −2.798, −2.798, = = 0.217, 0.217, =

The dorsal hippocampus is crucially involved in spatial memory, memory, spatial in involved crucially is hippocampus dorsal The Safe trajectory Air puff trajectory 2

5 Mean reactivation strength Mean reactivation strength . . By the of comparison, importance the ventral hippocampus for –0.01 –0.01 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.01 0.02 0.03 0.04 0.05 0.06 0.07

NEUR 0 0 Hippocampus–BLA reactivations of the air puff trajectory trajectory puff air the of reactivations Hippocampus–BLA –2 –2 Time fromripplepeak(s) Time fromripplepeak(s) z n = −0.780; Wilcoxon one-tail signed rank tests). Gray Gray tests). rank signed one-tail Wilcoxon −0.780; = = 25 sessions; box plots show the median (red line), first first line), (red median the show plots box sessions; 25 = P OSCI –1 –1 = 7.42 × 10 × 7.42 = EN – 0 – 0 Post-NREM Pre-NREM C E n

= 3) and sessions ( sessions and 3) = – 1 – 1 advance online publication online advance −5 1 , , 3 . More specifically, it has been shown shown been has it specifically, More . z 2 = −3.793), but not for safe trajectory trajectory safe for not but −3.793), = 2 2 4 4 2 , , impairs fear contextual condition a , , again in spa line with the coarser b ) Mean ( Mean ) Mean reactivation in –250 to +250 ms Mean reactivation in –250 to +250 ms window around ripple peak window around ripple peak –0.04 –0.04 0.16 0.04 0.08 0.12 0.16 0.04 0.08 0.12 ± 0 0 4

s.e.m.) s.e.m.) n

3 = 25) for pre-NREM pre-NREM for 25) = , robustly synchronize. synchronize. robustly , *** 19 , 4 P 14 1 = 0.00257, 0.00257, = , in line with the the with line in , z , 1 -scored peri- -scored

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after learning compared to sleep before learning. Overall, our find our Overall, learning. before sleep to compared sleep learning after during SPW-R with association their increase to likely more found that neurons BLA contribution were to with high reactivations significant a sleep. Conversely, we to post-experience change from pre-experience showed neurons BLA SPW-R-excited only Third, R. responded with suppression of firing rates during hippocampal SPW- neurons amygdala the of fraction large a contrast, In rates. firing in expected. Second, DOWN-UP shift inducesbe would increases responses but rate notfiring decreasesprolonged more spindles, or sleep of diate and short. If firing correlations were driven by UP-DOWN states First, neuronal responses in BLA to hippocampal SPW-Rs were imme possibility. this against argue findings However,several oscillations. ronal populations are simply responding to a third party, such as slow neu both that is replay sleep hippocampus–amygdala the for nation neurons also respond robustly to SPW-Rs contextual threat conditioning BLA–entorhinal connections have been implicated in the acquisition of pus––amygdala route may also be involved,hippocam a given projections, that hippocampus–amygdala ventral direct the structures subcortical and amygdala , of the parts to different projections receive hippocampus the of segments different across t the in available are references, and codes accession statements of including Methods, and data availability any associated M neurons BLA SPW-Rs. of during specifically perturbation dynamic as such experiments, ther fur require will hypothesis this for support Direct fear. contextual of consolidation the for thus and sleep NREM during resentations rep emotional and spatial/contextual combining for responsible is SPW-Rs during cells BLA and hippocampal of activation concerted We that in amygdala. the neurons hypothesize and threat-responsive physiological hippocampus in dorsal the a activity cell place to integrate mechanism provides replay SPW-R that suggests finding training. This after SPW-Rs during rate firing their increase and SPW-Rs selectively during upmodulated preferentially partners are BLA pairs The these task. of association follow place–threat SPW-Rs a in sleep training during ing reactivated are that pairs neuronal investigations. by future answered be to remain questions These amygdala. and hippocampus between exchange of as mediator cortex a information the entorhinal possible subcortical of neurotransmittersrole in memory replay potential and consolidation the address not did work our Finally, representation. of hippocampus–BLA joint the reinstatement offline an not involve does that memories of emotional consolidation in the role or complementary a plays different sleep REM that possible also It sleep. is REM during reactivations of significant lack to the tribute con may performed we analyses the for available spikes of number low consequently the and episodes sleep of REM duration short The hypothesis. However, REM during sleep. this we reactivations did not significant find with line in are sleep REM during cells pyramidal tion that REM sleep is for critical the of consolidation informa emotional associations. place–threat consolidate to BLA and hippocampus dorsal between connections ings suggest that SPW-Rs are for instrumental functional establishing h et e Alternative explanations should also be considered. In addition to to addition In considered. be also should explanations Alternative In summary, we identified a small subset of hippocampus–BLA hippocampus–BLA of subset small a identified we summary, In suggested have animals other and in findings Previous

p 27 h a , p 36 ods e , r 37 . , 48 , 4 9 . Our results showing an elevated firing rate of BLA BLA of rate firing elevated an showing results Our . 4 5 . 4 6 and given that entorhinal deep-layer 4 7 . . Another expla potential 29 t r a , 4 o 4 n that send and and send that 5 l 0 i n or the role of e C I

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© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. jurisdictional claims jurisdictional in published maps and affiliations. institutional reprints/index.htm at online available is information permissions and Reprints The authors declare no competing interests.financial G.G. analyzed the data and G.B. and G.G. wrote the manuscript. G.G. and G.B. the designed study, G.G. and I.I. performed the experiments, 090583 and the Simons Foundations (G.B.). Fellowship in Biomedical (G.G.), Science NIH MH54671 and MH107396, NS Recherche Médicale (FRM), the Fyssen Foundation, a Charles H. Revson Senior laboratory for their support. This work was supported by the Fondation pour la discussions on the analyses and manuscript and all the members of the Buzsáki We thank J. LeDoux, C. Léna, E. Stark, A. Peyrache and L. Roux for comments and on Note: Any Supplementary Information and Source Data files are available in the r ( difference. correlation diff, Corr (Pearson pairs contributing strongly for correlated are changes run and NREM contributions). lowest 2.5% (blue, pairs contributing weakly and contributions) ( hertz. in are bars Color trajectory’). puff (‘air applied is puff air the which in direction running arrows: Black location. puff air line: Red run. for histogram rate firing and bottom) to (top epochs post-run and run pre-run, for shown are maps Firing triangles). green and blue right; and (center ( 7 Figure t r a  COM AU Acknowled = 0.013, = 0.013, b a

) Behavioral correlates of an example BLA (left; red triangle) that forms highly contributing pairs with two hippocampal place cells cells place hippocampal two with pairs contributing highly forms that triangle) red (left; cell pyramidal BLA example an of correlates ) Behavioral ) Correlation between changes in pre vs. post-NREM correlations and pre- vs. post-run correlations for strongly contributing pairs (red, 2.5% highest highest 2.5% (red, pairs contributing strongly for correlations post-run vs. pre- and correlations post-NREM vs. pre in changes between ) Correlation line version of the pape T H P O ET R R

C I r I Contributing pairs form a representation during the run that is reactivated during sleep and reinstated during post-run without the air puff. puff. air the without post-run during reinstated and sleep during reactivated is that run the during a representation form pairs Contributing CONT = 0.27, = 0.27, N P a G G FI

= 0.22; = 0.22; Post-run Run Pre-run e l

g Rate Rate Rate Rate 10 20 10 15 10 N ments l RIBU b 2 6 5 0 . . Publisher’s with neutral Nature remains regard to note: Springer 20 10 A 0 Pre/post-run corr diff s n NC –0.2 All track = 866 pairs, pairs, = 866 0.2 n T –0.1 0 r IA = 3 rats) contributing quartiles (25% highest and lowest contributions). lowest and highest (25% quartiles contributing = 3 rats) . I ONS L I Pre/post-NREM NTE corr diff Position ontrack R 0 c ESTS P ) Same as as ) Same = 2.11 × 10 = 2.11 B LA 0.1 b but for strong ( strong for but –0.2 0.2 −16 0 –0.1 ; ; n http://www.natur Pre/post-NREM = 3 rats), but not for weakly contributing pairs ( pairs contributing weakly for not but = 3 rats), corr diff 0 4 8 1 2 3 0 1 2 0 2 4 0 n = 9,415 pairs, pairs, = 9,415

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r Run = 0.13, = 0.13,

Post- Phillips,LeDoux,R.G.& J.E.Differential contribution amygdalaof andhippocampus C. Xu, H.-L.L. Hsiang, R.L. Redondo, stable a of Localization M. Mayford, & N. Matsuo, B.L., Perkins, L.G., Reijmers, I. Goshen, basolateral the of stimulation High-frequency K. Abe, & H. Saito, Y., Ikegaya, in potentiation long-term hippocampal Attenuated K. Abe, & H. Y.,Saito, Ikegaya, Maren, S. & Fanselow, M.S. in the basolateral amygdala induced consolidation the and oscillations Amygdala Pelletier,J.G. & D.R. Collins, D., Paré, modulating in involved is amygdala Basolateral J.L. McGaugh, & A. Vazdarjanova, to cued and contextual .contextualfearand cued to retrieval. memory in (2014). 14115–14127 . memory contextual hippocampal memory. associative of correlate neural (2011). 678–689 vivo. in gyrus dentate the in potentiation long-term of induction the facilitates amygdala rats. amygdala-lesioned basolateral vivo. in (1995). stimulation formation hippocampal by memories. emotional of (1999). consolidation of memory for classical fear conditioning. NREM Neurosci. Res. Neurosci. c t al. et P

advance online publication online advance Pre/post-run corr diff –0.2 = 1.07 × 10 = 1.07 0.2 t al. et itnt ipcma ptwy mdae iscal rls f context of roles dissociable mediate pathways hippocampal Distinct –0.1 0 et al. et yais f erea srtge fr eoe memories. remote for strategies retrieval of Dynamics t al. et Pre/post-NREM

22 Cell 10 20 10 15 Manipulating a “cocaine engram” in mice. in engram” “cocaine a Manipulating 0 0 5 0 2 4 corr diff iietoa sic o te aec ascae wt a with associated valence the of switch Bidirectional 0 4 8 , 203–207 (1995). 203–207 , Trends Cogn. Sci. TrendsCogn.

r −32 0 167 = 0.03, = 0.03, ; ; , 961–972 (2016). 961–972 , n = 3 rats) and weak ( weak and = 3 rats) 0.1 Res. Brain n Pairwise corr = 845 pairs, pairs, = 845 0.1 0.2 Position ontrack 0 Science Behav.Neurosci. –0.2

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ezl L, pomkr VI, ord BN & rse, . h rl o rpd eye rapid of role The M. Dresler, & B.N. Konrad, V.I., Spoormaker, L., Genzel, of Reactivation C.A. Barnes, & B.L. McNaughton, H.S., Kudrimoti, J., Shen, memories ensemble hippocampal of Reactivation B. McNaughton, & M. Wilson, memory distributed of reactivation Coordinated B.L. McNaughton, & K.L. Hoffman, Lansink, C.S., Goltstein, P.M., Lankelma, J.V., McNaughton, B.L. & Pennartz, C.M.A. hippocampal of Reactivation B.L. McNaughton, & C.A. Barnes, H.S., Kudrimoti, behavioral and dynamics Activity G. Buzsáki, & K. Diba, S., Royer, K., Mizuseki, ich, . Psekr J, aao-ia H, iu, . Kasegr T Brain T. Klausberger, & N. Mikus, H., Malagon-Vina, J., Passecker, S., Ciocchi, D.M. Bannerman, Wang, M.E. Y.,Zhou, S., Rosis, M.A., Moita, Blair,& J.E. LeDoux, H.T. place: its in fear Putting LeDoux, J.E. Coming to terms with emotional fear. in activity theta sleep REM of role The S. Rathore, & I.C. Hutchison, Atherton, L.A., Dupret, D. & Mellor, J.R. Memory trace replay: the shaping of memory Maquet, P. the for evidence Causal A. Adamantidis, & S. Williams, S.D., Glasgow, R., Boyce, of networks output the in oscillations High-frequency G. Buzsáki, & J.J. Chrobak, D.R. Sparta, Logothetis, N.K. episodic for biomarker cognitive a wave-ripple: sharp Hippocampal G. Buzsáki, movement sleep for amygdala-related memory processing. memory amygdala-related for sleep movement spatial after sleep during gyrus dentate experience. hippocampal in ensembles neuronal sleep. during neocortex. in traces information. Biol. place-reward of replay in ventral leads Hippocampus dynamics. EEG and experience, state, Neurosci. behavioral of effects assemblies: cell neurons. pyramidal (2012). hippocampal 1659–1680 CA1 and CA3 of correlates computation. Selective information routing by ventral hippocampal CA1 projection CA1 hippocampal ventral by routing information Selective computation. . and conditioning. fear contextual odor (2004). 7015–7023 conditioning. fear during cells place hippocampal of remapping (2014). memory. 122 consolidation by . by consolidation sleep. REM 23 consolidation. memory contextual in rhythm theta sleep REM of role (1996). the hippocampal-entorhinal axis of the freely behaving rat. 8 entorhinal cortex disrupts the acquisition of contextual fear. silence. planning. and memory neurons. , 129 (2014). 129 , , 812 (2016). 812 , , 110–121 (2015). 110–121 ,

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© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. rections or Tukey–Kramer test for multiple comparisons. All dataolds are* represented in the equality of variance (Bartlett’sand testtest) (Kolmogorov–Smirnovfor normality equal variance).for For criteria multiple the comparisons satisfied data the ( not predetermined, but our sample sizes are similar to ( All tests used are specified in the figure legends or in the text. Sample sizes were paper.throughoutthe used were tests specified) otherwise unless (two-tailed, analysis. Statistical theta waves. ratioamygdala).(in sleepwasREMcharacterized by sleepposture and regular (in hippocampus) or gamma (45–65 Hz)/broad low frequency (1–12 Hz) band ratio theta/delta high and immobility with associated were NREM of Periods customscoringprogramaccelerometervisual TheStateEditor. theusing signal through visual inspection of the hippocampus and amygdala spectrograms and seconds) of the mean waveform of the spikes. Sleep stages were manually scored duration;(thatis,milli Fourier fasttransform)(in peak-to-troughvaluesand cells were sorted using monosynaptic connections ( using interneuronsputative and cells pyramidal putative into classified were s ( Neuroscope using preprocessed and visualized were Data lowedby manual clustering using Klusters ( then clustered using Klustakwik ( Spikes were extracted by high-pass filtering (800 Hz) and thresholding the Preprocessing.signal, was adjusted daily to optimize ripple and unit recording. the amygdala region over the course of the experiment. The hippocampal probe 140 and the associated Amplirec software. The amygdala electrodes were lowered by at 20 kHz using an Amplipex recording system (Amplipex Inc.,ceiling andSzeged, a red LED attachedHungary) to the head of the animal. Signals were recorded mountedthecamera on a using tracked was animal the ofposition The track. on water restriction to >85% of their normal weight and re-exposed to the linear superior limit of BLA, respectively. During this period, the the ratsand layerwere pyramidal placedCA1 hippocampal back reaching when started recordings probesthe recovery Aftertheperiod, were slowly lowered brainthe in and the to access regained surgery, they before days Three rewards( on water restriction and trained to run back and forth on a linear track for water being included in the study. After a week of daily handling, animals were placed Recordings and behavior. analysis we not performed blind to the conditions of the experiments. intra-piriformcortex physiology and reactivation analysis. Data collection and andintra-amygdala for used was coordination,buthippocampus–BLA about during the course of the experiment. This animal was hence not used for analysis5 d with the probe connectors were attached. Animals were allowed to recover for at least probes were protected by a cement-covered copper-mesh Faraday cage on which screws above the cerebellum were used as ground and reference. The drives and ML from bregma) and in the dorsal hippocampus (left or right, CA1, AP −3.5 mm, ML mm −2.5 (AP bilaterallyamygdalae implantedthe above layout)movable64mountedindividual andmicrodriveson Buzsaki32 with 4 shanks, 160 recording channels total, 1 NeuroNexusshanks, 8 H32 with and (2 H62, probesA-style, silicon Three isoflurane. with anesthetized deeply were surgery) of time at old months 3 g, (300 study.Animals the throughout experiment,andmaintained 12h:12hlight-darkona (lightscycle onata.m.) 7 Medical Center. Four individually housed male Long-Evans rats were Institutionalused in Animal this Care and Use Committee (IACUC) at New Yorkimplantation. electrode Universityand Subjects ONLINE MET nature nature with box plots showing the median with central and dispersion statistics. Some n o u cells) those generally employed in the field. When parametric tests were used, r ± µ c e P 2.5 mm). The drives were secured to the skull using dental cement. Skull m at the end of each recordingcompleteensureeach aof tosessionspanning ofend theat m post hoc f < 0.05, ** o ad libitum r g Fig. NEUR e . n e 1 tests, the original t ). All experimentswere All dayperformedduring). (light thecycle). 20-kHz signals were resampled at 1,250 Hz to extract LFP data. / ) and NDManager ( OSCI P H < 0.01, *** food and water. In one animal, the hippocampus probe failed ODS Non-parametric Wilcoxon rank sum or signed rank sum rank signed or sum Non-parametricWilcoxonrank k EN -means clustering (two clusters) on the inverse frequency C All animals were free from prior manipulation before E Supplementary Fig. 3 P < 0.001 are indicated with either a Bonferroni cor P h t -values are shown but the significance thresh t p h : / t / t s p All experiments were approved by the the approvedby were experiments All o : u / / r n c e e h u f t o r t r o p g s : e / u ). The remaining, unidentified / . n i n t e e e ad libitumad t . u / s n p r o o animals) or higher than r u o s r u j c e i e c t f e t o s . h s / r food and water.and food t ± o k g t u 3.6 to 5.5 mm 5.5 to 3.6 p l e u . r : n s / c / t e e a n t f k / e o ) w u r 5 g r 2 i 5 k o e . Units 1 / . were s n ) fol u e i t t / e - - - - ) .

Analysis. is available for an overview of ethics and statistics. in CA1 pyramidal layer. SPW-Rs were defined as events starting at 1 s.d., peak recordedpotential field the ofthresholding by followed normalizing, and ing FR). Positive ratios indicate REM FR > wake FR. using the REM/wake ratios, calculated as (REM FR – wake FR)/(REM FR + wake sessions are missing due to corruption of the animal position data. ( plotthis Insession. each forlocation puff air the to aligned and obtainair-puff-centeredthe trackthe positions curves, speed were normalized To100. × maze the on spent time total the by divided laps back-and-forth of tion index was calculated for each training session and animal Because asrats the run more totaland fasternumber laps when habituated to the air puff, a habitua danger zone (20 cm preceding the air puff location of the current training day). preceding the air puff location of the previous training day) and cDZ the currentpreviouscm thedanger zone(20 pDZ with speed), cDZ + speed speed)/(pDZ Inc., Natick, MA, USA) built-in functions and custom-written scripts. FMAToolbox ( the correlation (Matlab “corr” function). A correlations are computed using a Student’s distributions( full the with tion ( plots Bar analyses. the in includedwere pointsdata all butclarityfor figures the in shownnotare points data extreme formed on the difference EV – REV (Wilcoxon rank sum tests). sign rank test). Comparisons of reactivation across time or structures were per considered significant when EV was significantly different from REV (WilcoxonwereReactivationsexcluded).were REV > EV with sessions 6 epochs; NREM used to calculate the decay of reactivationssession (EV/REV in first and subsequentpost-sleep and pre- the of order temporal the switching20-minby obtained is (REV) ( sleep where (EV): session pre-sleep the in correlations pre-existing for controlling while training during patterns established the by explained be could that period post-sleep the in variance percentage of the assess to used were and calculated then were matrices three these of combinations all between correlations The matrices. correlation into assembled and periods REM) or (NREM post-sleep and training, REM), or (NREM pre-sleep for calculated separately were coefficients The trains. 50-ms-binned spike on coefficient correlation Pearson the using calculated were both pre- were and correlations post-sleep included. Pairwise for EV and REV in together) pooled were epochs sleep REM (all sleep REM total of min 3 of (pyramidal cell only vs. all cells). For REM sleep, only sessions with a minimum on ofof the subset depending the EV sessions cells and REV forare calculated included in the analysis. This criterion accounts for the variation in the number est. Only sessions with a minimum of 1 shank and 6 cells in each structure were lated per session using subsets of cell pairs selected from the structures of inter after each ripple were also excluded. contamination of rate changes around SPW-Rs, the 100-ms periods before and ing rate was computed during NREM sleep epochs excluding SPW-Rs. To avoid program Matlabcalling the “poiscdf” function). The baseline (inter-ripple) fir SPW-Rs(custom during function cumulativePoisson the for as same the are SPW-Rsoutsidespikes(baseline) of Poisson cumulativedistributionfunction a Poisson test with example, muscular noise) were removed. Ripple modulation was assessed using events simultaneously recorded from the hippocampal and control channels (for peak. the A controlaround ms detection was >20 performed onand a nonhippocampalms channel<130 andfor all s.d. >1 at remaining and s.d., >4 at ing Ripple detection was performed by band-pass filtering (~100–200 Hz), squar Firing rate (FR) changes between wakefulness and REM sleep were evaluated Forbehavioral measures,ratioscDZ – werespeed speed calculated(pDZas Explained variance (EV) and reverse explained variance (REV) were (REV) calcu variance explained (EV) and reverse variance Explained S R 17 1) and post-sleep ( andpost-sleep1) variables are the correlation coefficients between training ( training between coefficients correlation the are variables , 1 All analyses were performed using Chronux ( 8 . Only sessions with EV > REV for the first 20 min NREM epoch were h t t EV p : P / / < 0.001. This approach tests whether the parameters for the = = f m R a S T 2 t o , o S 1 2 2) pairwise correlation pairwise 2)matrices. controlThe value l ∨ b S o x . Supplementary Fig. 6 SupplementaryFig. s o      u R R r ) ( c S T 1 1 e , , f − o 1 2 R R r Fig. 5 Fig. g × − S T 2 t e Life Sciences Reporting Summary distribution for a transformation of , , . n 1 S T e t ) ( a / ) and Matlab (The MathWorks, ) are shown only in combinain onlyshown are ) − R S S 2 S S 1 2 h 1 2 ). , t t P p -values for Pearson’sfor-values doi: : /      / 2 c h 10.1038/nn.4637 r o n Fig. 1 Fig. u x . o T r g c ), pre- ), ), two ), / ), the ------

© 2017 Nature America, Inc., part of Springer Nature. All rights reserved. SPW-Rs occurring during pre-NREM and SPW-Rs occurring or post-NREMduring epochs. The peri-ripple reactivationpost-NREM strength was calculated for reactivation strength the time bin z strength relations at each time point of the pre-sleep and post-sleep epochs (reactivation training correlation matrix (whole run, safe or air puff trajectories) and the cor puff runs) was calculated as correlation matrix scored spike count matrices for hippocampus and BLA. The hippocampus–BLA and bins) (50-ms binned experience sleep epochs, BLA and hippocampal pyramidal cell spike trains were window) gain in a Gaussian(20-mssmoothedone-sidedmeanWilcoxon the ontest rank signed a using gains mean ripple post-NREM and pre- on performed were statistics and averaged across cells. The data are shown for cell each for calculated then was gain peri-ripple mean The intervals). NREM SPW-Rsoutsiderate (inter-ripple firing baseline the by bin each in rate firing between pre- and post-NREM was calculated for each 10-ms bin by dividing the rippledistribution).upmodulationin thegain of The tails right and left the of using percentiles of the distribution of contributions (quartiles contributions,magnitudetheiraccording oforthe to pooled werethen pairs cell 2.5th percentile averaging the contributions of all pairs in which the cell participated. Cells and by calculated also was cell per contribution a pairs, several in participate can without that pair indicates a positive contribution of that pair. Since a single cell recalculated EV without that pair ( a global EV (all pairs) and then taking the difference between the global EV and each subgroup, where the contribution of each pair was evaluated by calculating followed by Bonferroni corrected multiple comparisons, and (ii) EV andgroup,each groupsin pairs thewerewhere compared tionsfor all ANOVA byREV for correla post-NREM and pre-NREM between difference the computed(i) we pairs in each of these groups are summarized in ( Pearson correlation during training (positively correlated, negatively correlated the of significance the (ii) and none) or down(up, pair the of cell BLA the of intomals)naturegroups the9on (i) based ofhippocampal ripple-modulation pairs to replay. For this analysis, cell pairs were pooled (across sessions and ani doi: P hpc < 0.01) or uncorrelated ( To calculate the reactivation strength reactivation the Tocalculate An alternative approach was used to assess the contribution of individual cell 10.1038/nn.4637 ( t ) are the population firing rate vectors of BLA and hippocampus neurons for R ) was then calculated as t of either pre-experience sleep and post-experience sleep epoch. The C ± 250-ms window centered at the ripple peak. bla-hpc R over time was then for the training epoch (whole epoch or safe runs or air z -scored. This gives This -scored. P C > 0.01) pairs). The nine groups and the number of hpc–bla R Supplementary Fig. 10a = ( t ) = Z bla z Z bla R hpc z in pre-experience sleep and post- and sleep pre-experience in ( -scored over the whole pre-NREM t T ) C / Z n bla–hpc Supplementary Table 2 bla Bins ± and 2-s windows for . The . The similarity between the z hpc Z hpc ( t ) ). A decrease in EV , the , T , where n Pyr z × bla ( n . Next, t Bins ) and z - - - - B publicly available on the CRCNS server ( Dataavailability. to specific amygdala nuclei. and ihb ( Github Code availability. the putative recorded location for each shank and each recording day ( recordingday each and shank each forputativelocationrecorded the showingmaps histology of construction the recordingday.allowed each This the final position of the probe and the expected depth of the probe location for tions of the electrodes were reconstructed for all shanks from extracted, slicedadjacent (70 slices using were The paraformaldehyde. 10% then and saline using perfused and positionmark final ofprobes.the the wereRats euthanized withpentobarbital Histology. tions strength. reactiva calculate to correlationmatrix training the componentsof principal directly be applied, wetheraw used correlation matrix instead of individual or not could methods used previously these andreactivations cross-structure in matrixcorrelation the on PCA or ICA an followingcomponents individual of reactivation the for described These methods used for evaluation of the reactivation strength were previously 500-ms window centered on the ripple peak using a Wilcoxon signed rank test. NREM and post-experience NREM SPW-Rs was calculated on the mean in difference the of significance The sessions. and Finally, the mean peri-ripple reactivation strength as the average 54. 53. 52. 51. L A

Lopes-dos-Santos, V., Ribeiro, S. & Tort, A.B.L. Detecting cell assemblies in large in assemblies cell Detecting A.B.L. Tort, & S. V.,Ribeiro, Lopes-dos-Santos, F.P.Battaglia, & Wiener,S.I. Replay K., Benchenane, M., Khamassi, A., Peyrache, free a NDManager: NeuroScope, Klusters, G. Buzsáki, & M. Zugaro, L., Hazan, Vandecasteele,M. of rule-learning related neural patterns in the during sleep. during cortex prefrontal the in patterns neural related rule-learning of Methods visualization. and processing data neurophysiological for suite software . behaving in neuronal populations. neuronal Neurosci. Supplementary Fig. 2 H p c I n At the end of experiments, small electrolytic lesions were made to made werelesions electrolytic small experiments, of end the At t h

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t r 12 t a R p c , 919–926 (2009). 919–926 , s in a , 207–216 (2006). 207–216 , t : i / o The data that support mainthe findings of thisstudy be will / All custom code is freely available on the Buzsáki Laboratory n g s ± i µ et al. et t - 2-s window around ripple peaks ( h P m), DAPI-stained and coverslipped. The sequential posi J. Vis. Exp. Vis. J. u a J. Neurosci. Methods Neurosci. J. c b Large-scale recording of neurons by movable silicon probes silicon movable by neurons of recording Large-scale k . c a ). These maps were then used to restrict the analyses o g e m ). / 26 b u ,

53 3568 z , s 5 a 4 . Because we were specifically interested specifically were we Because . k , e3568 (2012). e3568 , i l h a t b t / p

p 220 : / a / p c r , 149–166 (2013). 149–166 , e c r n s R nature nature / s was computed over all rats t R . o r between pre-experience between e r Supplementary Fig. 10 g e / / ). m a s NEUR t e r / G OSCI G J. Neurosci. J. i r a r Fig. 1 Fig. d EN R e in a Nat. a C u E - - - ) f

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