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• W2651397524 abstract "•Unsupervised clustering discloses a mechanism of firing selectivity during ripples•Firing selectivity collapses in the epileptic hippocampus during fast ripples•Global and cell-specific synaptic drives are critical factors for selective firing•Tuning global and cell-specific factors allow improving recall in epileptic rats Memory traces are reactivated selectively during sharp-wave ripples. The mechanisms of selective reactivation, and how degraded reactivation affects memory, are poorly understood. We evaluated hippocampal single-cell activity during physiological and pathological sharp-wave ripples using juxtacellular and intracellular recordings in normal and epileptic rats with different memory abilities. CA1 pyramidal cells participate selectively during physiological events but fired together during epileptic fast ripples. We found that firing selectivity was dominated by an event- and cell-specific synaptic drive, modulated in single cells by changes in the excitatory/inhibitory ratio measured intracellularly. This mechanism collapses during pathological fast ripples to exacerbate and randomize neuronal firing. Acute administration of a use- and cell-type-dependent sodium channel blocker reduced neuronal collapse and randomness and improved recall in epileptic rats. We propose that cell-specific synaptic inputs govern firing selectivity of CA1 pyramidal cells during sharp-wave ripples. Memory traces are reactivated selectively during sharp-wave ripples. The mechanisms of selective reactivation, and how degraded reactivation affects memory, are poorly understood. We evaluated hippocampal single-cell activity during physiological and pathological sharp-wave ripples using juxtacellular and intracellular recordings in normal and epileptic rats with different memory abilities. CA1 pyramidal cells participate selectively during physiological events but fired together during epileptic fast ripples. We found that firing selectivity was dominated by an event- and cell-specific synaptic drive, modulated in single cells by changes in the excitatory/inhibitory ratio measured intracellularly. This mechanism collapses during pathological fast ripples to exacerbate and randomize neuronal firing. Acute administration of a use- and cell-type-dependent sodium channel blocker reduced neuronal collapse and randomness and improved recall in epileptic rats. We propose that cell-specific synaptic inputs govern firing selectivity of CA1 pyramidal cells during sharp-wave ripples. Reactivation of spatial and episodic neuronal sequences occurs offline in the hippocampus during sharp-wave ripples (100–250 Hz; Nádasdy et al., 1999Nádasdy Z. Hirase H. Czurkó A. Csicsvari J. Buzsáki G. Replay and time compression of recurring spike sequences in the hippocampus.J. Neurosci. 1999; 19: 9497-9507Crossref PubMed Google Scholar, O’Neill et al., 2006O’Neill J. Senior T. Csicsvari J. Place-selective firing of CA1 pyramidal cells during sharp wave/ripple network patterns in exploratory behavior.Neuron. 2006; 49: 143-155Abstract Full Text Full Text PDF PubMed Scopus (191) Google Scholar, Foster and Wilson, 2006Foster D.J. Wilson M.A. Reverse replay of behavioural sequences in hippocampal place cells during the awake state.Nature. 2006; 440: 680-683Crossref PubMed Scopus (1033) Google Scholar, Diba and Buzsáki, 2007Diba K. Buzsáki G. Forward and reverse hippocampal place-cell sequences during ripples.Nat. Neurosci. 2007; 10: 1241-1242Crossref PubMed Scopus (652) Google Scholar, Wang et al., 2016Wang Y. Roth Z. Pastalkova E. Synchronized excitability in a network enables generation of internal neuronal sequences.eLife. 2016; 5: 5Crossref Scopus (16) Google Scholar). Such sequences, which may also play prospectively (Gupta et al., 2010Gupta A.S. van der Meer M.A.A. Touretzky D.S. Redish A.D. Hippocampal replay is not a simple function of experience.Neuron. 2010; 65: 695-705Abstract Full Text Full Text PDF PubMed Scopus (423) Google Scholar, Pfeiffer and Foster, 2013Pfeiffer B.E. Foster D.J. Hippocampal place-cell sequences depict future paths to remembered goals.Nature. 2013; 497: 74-79Crossref PubMed Scopus (663) Google Scholar), are precisely organized in proximo-distal and deep-superficial hippocampal sub-regions (Csicsvari et al., 2000Csicsvari J. Hirase H. Mamiya A. Buzsáki G. Ensemble patterns of hippocampal CA3-CA1 neurons during sharp wave-associated population events.Neuron. 2000; 28: 585-594Abstract Full Text Full Text PDF PubMed Scopus (339) Google Scholar, Valero et al., 2015Valero M. Cid E. Averkin R.G. Aguilar J. Sanchez-Aguilera A. Viney T.J. Gomez-Dominguez D. Bellistri E. de la Prida L.M. Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples.Nat. Neurosci. 2015; 18: 1281-1290Crossref PubMed Scopus (134) Google Scholar, Oliva et al., 2016Oliva A. Fernández-Ruiz A. Buzsáki G. Berényi A. Spatial coding and physiological properties of hippocampal neurons in the Cornu Ammonis subregions.Hippocampus. 2016; 26: 1593-1607Crossref PubMed Scopus (64) Google Scholar). They depend in part on network microstructure (Stark et al., 2015Stark E. Roux L. Eichler R. Buzsáki G. Local generation of multineuronal spike sequences in the hippocampal CA1 region.Proc. Natl. Acad. Sci. USA. 2015; 112: 10521-10526Crossref PubMed Scopus (54) Google Scholar, Wang et al., 2016Wang Y. Roth Z. Pastalkova E. Synchronized excitability in a network enables generation of internal neuronal sequences.eLife. 2016; 5: 5Crossref Scopus (16) Google Scholar) and, in turn, firing sequences shape local field potentials (LFPs) associated with ripple events (Reichinnek et al., 2010Reichinnek S. Künsting T. Draguhn A. Both M. Field potential signature of distinct multicellular activity patterns in the mouse hippocampus.J. Neurosci. 2010; 30: 15441-15449Crossref PubMed Scopus (41) Google Scholar, Taxidis et al., 2015Taxidis J. Anastassiou C.A. Diba K. Koch C. Local field potentials encode place cell ensemble activation during hippocampal sharp wave ripples.Neuron. 2015; 87: 590-604Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). Global interference with sharp-wave ripples impairs memory and destabilizes the spatial code (Ego-Stengel and Wilson, 2009Ego-Stengel V. Wilson M.A. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat.Hippocampus. 2009; 20: 1-10Google Scholar, Girardeau et al., 2009Girardeau G. Benchenane K. Wiener S.I. Buzsáki G. Zugaro M.B. Selective suppression of hippocampal ripples impairs spatial memory.Nat. Neurosci. 2009; 12: 1222-1223Crossref PubMed Scopus (853) Google Scholar), while acting locally in a cell-type-specific manner results in alterations of some but not all sequences (Stark et al., 2015Stark E. Roux L. Eichler R. Buzsáki G. Local generation of multineuronal spike sequences in the hippocampal CA1 region.Proc. Natl. Acad. Sci. USA. 2015; 112: 10521-10526Crossref PubMed Scopus (54) Google Scholar, Kovács et al., 2016Kovács K.A. O’Neill J. Schoenenberger P. Penttonen M. Ranguel Guerrero D.K. Csicsvari J. Optogenetically blocking sharp wave ripple events in sleep does not interfere with the formation of stable spatial representation in the CA1 area of the hippocampus.PLoS ONE. 2016; 11: e0164675Crossref PubMed Scopus (26) Google Scholar, van de Ven et al., 2016van de Ven G.M. Trouche S. McNamara C.G. Allen K. Dupret D. Hippocampal offline reactivation consolidates recently formed cell assembly patterns during sharp wave-ripples.Neuron. 2016; 92: 968-974Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Selective reactivation of neuronal sequences is thought to stabilize an engram (Wilson and McNaughton, 1994Wilson M.A. McNaughton B.L. Reactivation of hippocampal ensemble memories during sleep.Science. 1994; 265: 676-679Crossref PubMed Scopus (2061) Google Scholar, Nakashiba et al., 2009Nakashiba T. Buhl D.L. McHugh T.J. Tonegawa S. Hippocampal CA3 output is crucial for ripple-associated reactivation and consolidation of memory.Neuron. 2009; 62: 781-787Abstract Full Text Full Text PDF PubMed Scopus (185) Google Scholar, Carr et al., 2011Carr M.F. Jadhav S.P. Frank L.M. Hippocampal replay in the awake state: a potential substrate for memory consolidation and retrieval.Nat. Neurosci. 2011; 14: 147-153Crossref PubMed Scopus (519) Google Scholar, van de Ven et al., 2016van de Ven G.M. Trouche S. McNamara C.G. Allen K. Dupret D. Hippocampal offline reactivation consolidates recently formed cell assembly patterns during sharp wave-ripples.Neuron. 2016; 92: 968-974Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar). Deficits of memory consolidation are common to many neurological diseases for which changes of sharp-wave ripples are reported (Suh et al., 2013Suh J. Foster D.J. Davoudi H. Wilson M.A. Tonegawa S. Impaired hippocampal ripple-associated replay in a mouse model of schizophrenia.Neuron. 2013; 80: 484-493Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, Born et al., 2014Born H.A. Kim J.-Y. Savjani R.R. Das P. Dabaghian Y.A. Guo Q. Yoo J.W. Schuler D.R. Cirrito J.R. Zheng H. et al.Genetic suppression of transgenic APP rescues Hypersynchronous network activity in a mouse model of Alzeimer’s disease.J. Neurosci. 2014; 34: 3826-3840Crossref PubMed Scopus (124) Google Scholar, Nicole et al., 2016Nicole O. Hadzibegovic S. Gajda J. Bontempi B. Bem T. Meyrand P. Soluble amyloid beta oligomers block the learning-induced increase in hippocampal sharp wave-ripple rate and impair spatial memory formation.Sci. Rep. 2016; 6: 22728Crossref PubMed Scopus (27) Google Scholar). Ripple activity patterns change with aging (Kanak et al., 2013Kanak D.J. Rose G.M. Zaveri H.P. Patrylo P.R. Altered network timing in the CA3-CA1 circuit of hippocampal slices from aged mice.PLoS ONE. 2013; 8: e61364Crossref PubMed Scopus (18) Google Scholar, Wiegand et al., 2016Wiegand J.-P.L. Gray D.T. Schimanski L.A. Lipa P. Barnes C.A. Cowen S.L. Age is associated with reduced sharp-wave ripple frequency and altered patterns of neuronal variability.J. Neurosci. 2016; 36: 5650-5660Crossref PubMed Scopus (21) Google Scholar), in tauopathies (Booth et al., 2016Booth C.A. Witton J. Nowacki J. Tsaneva-Atanasova K. Jones M.W. Randall A.D. Brown J.T. Altered intrinsic pyramidal neuron properties and pathway-specific synaptic dysfunction underlie aberrant hippocampal network function in a mouse model of tauopathy.J. Neurosci. 2016; 36: 350-363Crossref PubMed Scopus (53) Google Scholar), and in animal models of neuropsychiatric disorders (Suh et al., 2013Suh J. Foster D.J. Davoudi H. Wilson M.A. Tonegawa S. Impaired hippocampal ripple-associated replay in a mouse model of schizophrenia.Neuron. 2013; 80: 484-493Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar), presumably due to functional changes in underlying microcircuits. The mechanisms for selective single-cell firing during sharp-wave ripples, and those that govern memory degradation in pathological conditions remain to be clarified. In temporal lobe epilepsy (TLE), a disease affecting hippocampal and parahippocampal microcircuits, fast ripples (250–600 Hz) have been associated with both interictal discharges and sharp-wave-like events (Bragin et al., 1999Bragin A. Engel Jr., J. Wilson C.L. Fried I. Mathern G.W. Hippocampal and entorhinal cortex high-frequency oscillations (100--500 Hz) in human epileptic brain and in kainic acid--treated rats with chronic seizures.Epilepsia. 1999; 40: 127-137Crossref PubMed Scopus (564) Google Scholar, Bragin et al., 2002Bragin A. Wilson C.L. Staba R.J. Reddick M. Fried I. Engel Jr., J. Interictal high-frequency oscillations (80-500 Hz) in the human epileptic brain: entorhinal cortex.Ann. Neurol. 2002; 52: 407-415Crossref PubMed Scopus (260) Google Scholar, Worrell et al., 2008Worrell G.A. Gardner A.B. Stead S.M. Hu S. Goerss S. Cascino G.J. Meyer F.B. Marsh R. Litt B. High-frequency oscillations in human temporal lobe: simultaneous microwire and clinical macroelectrode recordings.Brain. 2008; 131: 928-937Crossref PubMed Scopus (372) Google Scholar, Ibarz et al., 2010Ibarz J.M. Foffani G. Cid E. Inostroza M. Menendez de la Prida L. Emergent dynamics of fast ripples in the epileptic hippocampus.J. Neurosci. 2010; 30: 16249-16261Crossref PubMed Scopus (132) Google Scholar, Alvarado-Rojas et al., 2015Alvarado-Rojas C. Huberfeld G. Baulac M. Clemenceau S. Charpier S. Miles R. de la Prida L.M. Le Van Quyen M. Different mechanisms of ripple-like oscillations in the human epileptic subiculum.Ann. Neurol. 2015; 77: 281-290Crossref PubMed Scopus (52) Google Scholar). Pathological fast ripples are a clinically useful biomarker in epilepsy, but their effects on cognition are not clear (Kucewicz et al., 2014Kucewicz M.T. Cimbalnik J. Matsumoto J.Y. Brinkmann B.H. Bower M.R. Vasoli V. Sulc V. Meyer F. Marsh W.R. Stead S.M. Worrell G.A. High frequency oscillations are associated with cognitive processing in human recognition memory.Brain. 2014; 137: 2231-2244Crossref PubMed Scopus (109) Google Scholar). Given difficulties in identifying ripples associated to hippocampal sharp waves in clinical settings (Staba et al., 2002Staba R.J. Wilson C.L. Bragin A. Fried I. Engel Jr., J. Quantitative analysis of high-frequency oscillations (80-500 Hz) recorded in human epileptic hippocampus and entorhinal cortex.J. Neurophysiol. 2002; 88: 1743-1752Crossref PubMed Scopus (481) Google Scholar, Menendez de la Prida et al., 2015Menendez de la Prida L. Staba R.J. Dian J.A. Conundrums of high-frequency oscillations (80-800 Hz) in the epileptic brain.J. Clin. Neurophysiol. 2015; 32: 207-219Crossref PubMed Scopus (46) Google Scholar), addressing this question in humans is challenging. Here, we took advantage of a rat model of TLE exhibiting distortion of sharp-wave ripples and different memory abilities to pursue the mechanisms for firing selectivity. We found that the spectral properties of sharp-wave ripples were correlated with increased neuronal firing and loss of selectivity typical of the epileptic hippocampus. Using unsupervised clustering of sharp-wave ripples (Reichinnek et al., 2010Reichinnek S. Künsting T. Draguhn A. Both M. Field potential signature of distinct multicellular activity patterns in the mouse hippocampus.J. Neurosci. 2010; 30: 15441-15449Crossref PubMed Scopus (41) Google Scholar, Taxidis et al., 2015Taxidis J. Anastassiou C.A. Diba K. Koch C. Local field potentials encode place cell ensemble activation during hippocampal sharp wave ripples.Neuron. 2015; 87: 590-604Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar), we disclosed a synaptic mechanism that can be used to perturb firing selectivity at the single-cell and microcircuit level. Our results demonstrate how global and cell-specific network activity are critical for hippocampal memory function. We first asked whether sharp-wave-associated ripples could be separated from interictal epileptiform events in chronically epileptic rats. In normal rats, physiological ripples (100–250 Hz) emerge in the CA1 region during immobility and slow-wave sleep. Thus, we implanted 16-channel silicon probes in the dorsal hippocampus of normal and epileptic behaving animals. Rats performed either the episodic-like “what-where-when” memory task (EP task; n = 4 control, n = 4 epileptic) or a one-trial object recognition task (OR task; n = 3 control, n = 3 epileptic; Figure 1A) (Inostroza et al., 2013Inostroza M. Brotons-Mas J.R. Laurent F. Cid E. de la Prida L.M. Specific impairment of “what-where-when” episodic-like memory in experimental models of temporal lobe epilepsy.J. Neurosci. 2013; 33: 17749-17762Crossref PubMed Scopus (78) Google Scholar). LFP signals were acquired along CA1 layers (Figure 1B). In normal rats (n = 7), characteristic sharp-wave ripples occurred during awake immobility and slow-wave sleep in periods between trials at a rate of 0.55 ± 0.18 events/s (Figure 1C, left). Sharp-wave amplitude was maximal in the stratum radiatum (1.03 ± 0.24 mV) and associated with ripples at the stratum pyramidale. Time-frequency spectra revealed that ripples contributed consistently to the 100–250 Hz band (Figure 1C). Sharp-wave-associated gamma oscillations were identified in some events (Sullivan et al., 2011Sullivan D. Csicsvari J. Mizuseki K. Montgomery S. Diba K. Buzsáki G. Relationships between hippocampal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical activity.J. Neurosci. 2011; 31: 8605-8616Crossref PubMed Scopus (183) Google Scholar), but we focused on the ripple band given its relevance for the epileptic condition (Bragin et al., 1999Bragin A. Engel Jr., J. Wilson C.L. Fried I. Mathern G.W. Hippocampal and entorhinal cortex high-frequency oscillations (100--500 Hz) in human epileptic brain and in kainic acid--treated rats with chronic seizures.Epilepsia. 1999; 40: 127-137Crossref PubMed Scopus (564) Google Scholar, Alvarado-Rojas et al., 2015Alvarado-Rojas C. Huberfeld G. Baulac M. Clemenceau S. Charpier S. Miles R. de la Prida L.M. Le Van Quyen M. Different mechanisms of ripple-like oscillations in the human epileptic subiculum.Ann. Neurol. 2015; 77: 281-290Crossref PubMed Scopus (52) Google Scholar). Similar events were recorded in epileptic rats between trials but their spectral components were remarkably variable (Figure 1C, right). In the stratum radiatum, sharp-wave amplitude (0.82 ± 0.20 mV, n = 7; p = 0.18; Student’s t test) and rate (0.37 ± 0.16 events/s, p = 0.19) were similar to records from control rats. They clearly differed from interictal discharges with larger, saturating amplitude fluctuations (Figure S1A). We thus excluded sessions with interictal or ictal events for further analysis. Are ripples recorded in normal and epileptic rats spectrally different? We defined two indices to characterize individual events. The fast ripple index was the proportion of the 100–600 Hz power spectrum above a frequency cutoff, usually 250 Hz. Ripple entropy was a measure of spectral disorganization in the 100–600 Hz band (see STAR Methods). The larger the entropy, the more disorganized the spectra; the larger the fast ripple index, the stronger the ripple contribution to the fast frequency band. Events from normal and epileptic rats could be separated statistically for cutoff thresholds of 180–350 Hz (Figure 1D for 250 Hz; Figures S1B–S1D). Overall, ripples in epileptic rats exhibited higher entropy (p = 0.017), fast ripple index (p = 0.015), and frequency (p = 0.018; Figure 1E). How do sharp-wave ripples in epileptic rats relate to their memory performance? Previously, we showed that epileptic rats failed in their ability to discriminate old and recently displaced and non-displaced objects in the “what-where-when” task (objects A1 and B2 in the EP task, Figure 1A; Inostroza et al., 2013Inostroza M. Brotons-Mas J.R. Laurent F. Cid E. de la Prida L.M. Specific impairment of “what-where-when” episodic-like memory in experimental models of temporal lobe epilepsy.J. Neurosci. 2013; 33: 17749-17762Crossref PubMed Scopus (78) Google Scholar). We confirmed a similar trend in the subset of animals used for this study (Figure 1F; effect for group F(1,10) = 15.14, p = 0.002, but not for objects nor interaction, two-way ANOVA). Importantly, we found strong correlation between spectral indices of sharp-wave ripples recorded during the inter-trial and the discrimination ratio for object A1 and B2 for both groups together (Figure 1G for the fast ripple index; for entropy: R = −0.73, p = 0.0013; frequency: R = −0.68, p = 0.003). Theta and gamma rhythmopathies were recently associated with memory deficits in TLE (Inostroza et al., 2013Inostroza M. Brotons-Mas J.R. Laurent F. Cid E. de la Prida L.M. Specific impairment of “what-where-when” episodic-like memory in experimental models of temporal lobe epilepsy.J. Neurosci. 2013; 33: 17749-17762Crossref PubMed Scopus (78) Google Scholar, Lopez-Pigozzi et al., 2016Lopez-Pigozzi D. Laurent F. Brotons-Mas J.R. Valderrama M. Valero M. Fernandez-Lamo I. Cid E. Gomez-Dominguez D. Gal B. Menendez de la Prida L. Altered oscillatory dynamics of CA1 parvalbumin basket cells during theta-gamma rhythmopathies of temporal lobe epilepsy.eNeuro. 2016; 3: 3Crossref Scopus (35) Google Scholar). In the current dataset, we found an association between the fast ripple index of offline events and the mean inter-layer coherence of theta oscillations recorded in the exploratory phases of the task (R = −0.87; p = 0.004; Laurent et al., 2015Laurent F. Brotons-Mas J.R. Cid E. Lopez-Pigozzi D. Valero M. Gal B. de la Prida L.M. Proximodistal structure of theta coordination in the dorsal hippocampus of epileptic rats.J. Neurosci. 2015; 35: 4760-4775Crossref PubMed Scopus (27) Google Scholar). To dissect the contribution of different physiological indices, we used a generalized linear model (GLM). This analysis models the discrimination index as a combination of independent effects of (1) ripple spectral indices (Ibarz et al., 2010Ibarz J.M. Foffani G. Cid E. Inostroza M. Menendez de la Prida L. Emergent dynamics of fast ripples in the epileptic hippocampus.J. Neurosci. 2010; 30: 16249-16261Crossref PubMed Scopus (132) Google Scholar), (2) theta power at the stratum lacunosum-moleculare (Inostroza et al., 2013Inostroza M. Brotons-Mas J.R. Laurent F. Cid E. de la Prida L.M. Specific impairment of “what-where-when” episodic-like memory in experimental models of temporal lobe epilepsy.J. Neurosci. 2013; 33: 17749-17762Crossref PubMed Scopus (78) Google Scholar), (3) coherence with molecular layers (Laurent et al., 2015Laurent F. Brotons-Mas J.R. Cid E. Lopez-Pigozzi D. Valero M. Gal B. de la Prida L.M. Proximodistal structure of theta coordination in the dorsal hippocampus of epileptic rats.J. Neurosci. 2015; 35: 4760-4775Crossref PubMed Scopus (27) Google Scholar), and (4) interaction between theta and gamma (30–60 Hz) at the stratum radiatum (Lopez-Pigozzi et al., 2016Lopez-Pigozzi D. Laurent F. Brotons-Mas J.R. Valderrama M. Valero M. Fernandez-Lamo I. Cid E. Gomez-Dominguez D. Gal B. Menendez de la Prida L. Altered oscillatory dynamics of CA1 parvalbumin basket cells during theta-gamma rhythmopathies of temporal lobe epilepsy.eNeuro. 2016; 3: 3Crossref Scopus (35) Google Scholar). We found that the fast ripple index explained most of the variance of discrimination for both objects A1 and B2 at a significance level of p < 0.05 (Figure 1H). Thus, excluding covariation, ripple spectral dynamics is directly correlated with discrimination ability, suggesting some direct effect on consolidation processes. To test this point further, we evaluated ripple effects by using one-trial object recognition tasks at 50 min and 100 min intervals (OR task) in an independent cohort of animals (n = 7 control, n = 9 epileptic, Figure 1A). Differences of exploration between objects would suggest interferences between novelty and familiarity that when tested allocentrically and with long delays depend on the hippocampus (Barker and Warburton, 2011Barker G.R.I. Warburton E.C. When is the hippocampus involved in recognition memory?.J. Neurosci. 2011; 31: 10721-10731Crossref PubMed Scopus (571) Google Scholar). We found that epileptic rats performed similar to controls at 50 min but less well at 100 min inter-trial interval (Figure 1I; F(1,12) = 4.32, p = 0.047 for groups; no effect for interval; interaction p = 0.068; two-way ANOVA). The temporal trend for control rats was compatible with successful recall after sleep typical of 100 min interval (p = 0.021; Binder et al., 2012Binder S. Baier P.C. Mölle M. Inostroza M. Born J. Marshall L. Sleep enhances memory consolidation in the hippocampus-dependent object-place recognition task in rats.Neurobiol. Learn. Mem. 2012; 97: 213-219Crossref PubMed Scopus (57) Google Scholar). Epileptic rats failed to show such a trend (Figure 1I) and differences between groups became more pronounced at longer intervals (p = 0.011). These data suggest similar abilities between groups for encoding and retrieval for short retention intervals and a failure of epileptic rats in memory consolidation at long intervals of 100 min. Spectral indices of sharp-wave ripples were similar for events recorded in sleep and during immobility (Figure S1E). We asked whether sleep pattern could contribute but found no difference between epileptic and control animals of either the sleep stages or the duration of REM episodes (control: 22–164 s; epileptic: 43–147 s). Instead, only the discrimination index in the 100 min interval OR task correlated with the fast ripple index (Figure 1J). These data therefore suggest that spectrally disorganized sharp-wave ripples during immobility and sleep may impair memory function. Do differences in ripple spectra reflect some specific cellular process of memory consolidation? We looked for cellular determinants of ripple spectral features in juxtacellular recordings of CA1 pyramidal cells from freely moving rats (Figure 2A). Sharp-wave ripple events recorded with glass pipettes exhibited similar spectral features to those obtained with silicon probes (Figures S2A and S2B). Pyramidal cells from normal rats generally fired 1–3 spikes at the trough of spontaneous ripples recorded with the glass pipette and were identified by their characteristic autocorrelogram (Figure 2B; n = 14 cells; n = 8 histologically confirmed). In contrast, cells recorded from epileptic rats were more typically active (3–6 spikes; Figure 2C; n = 7 cells, 4 histologically confirmed) and their firing was less coherent with LFP than in control cells (Figure S2C; Foffani et al., 2007Foffani G. Uzcategui Y.G. Gal B. Menendez de la Prida L. Reduced spike-timing reliability correlates with the emergence of fast ripples in the rat epileptic hippocampus.Neuron. 2007; 55: 930-941Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). Un-identified putative pyramidal cells exhibited similar action potential features and autocorrelation than histologically validated cells. Previously, we described a bias of CA1 neuronal firing and participation during physiological sharp-wave ripples along the deep-superficial sub-layers (Valero et al., 2015Valero M. Cid E. Averkin R.G. Aguilar J. Sanchez-Aguilera A. Viney T.J. Gomez-Dominguez D. Bellistri E. de la Prida L.M. Determinants of different deep and superficial CA1 pyramidal cell dynamics during sharp-wave ripples.Nat. Neurosci. 2015; 18: 1281-1290Crossref PubMed Scopus (134) Google Scholar). We considered histological information to predict the position of un-identified cells with respect to the border with the stratum radiatum (Figures S2D–S2G; STAR Methods). Firing from control cells exhibited the bias that we described before, with superficial cells firing more and more consistently during sharp-wave ripples (Figure 2D, left). In contrast, in epileptic rats the deep-superficial trend was impaired (Figure 2D, right; Figure S2H). Overall, the group effect dominated differences of single-cell firing rate (F(1,17) = 29.99, p < 0.0001) and participation during sharp-wave ripples (F(1,17) = 10.19, p = 0.005; Figure S2I) (no deep-superficial effect nor interaction, two-way ANOVA). Next, we looked for the cellular correlates of ripple features by comparing single-cell firing and the spectral indices of nearby field events. We found a steep correlation between the fast ripple index and the firing rate of single cells (Figure 2E; Figures S3A and S3B). This single-cell/ripple correlation was also evident in n = 3 cells recorded together with an additional tungsten wire at a distance of 150–400 μm (Figures S3C and S3D; see STAR Methods), suggesting that it reflected collective behavior of neighboring neurons. Single-cell participation was higher for sharp-wave ripples with faster spectral components, especially in epileptic rats (Figure 2F). In information theory, the probability of participation P is related to the information content as –log(P). Thus, higher participation resulted in less information content of single cells during sharp-wave ripples in epileptic rats (Figure 2F, right). Altogether, these results suggest that extracellular ripple features are good proxy for microcircuit firing dynamics. When sharp-wave ripple frequency spectrum is most disorganized, single-cell firing is least selective. Cells that participate indiscriminately in more events have the least information content. In normal animals, this may occur exceptionally while in epileptic rats is rather the norm (see events indicated in Figure 1D for instance). These data provide further evidence that cognitive behavior and sharp-wave ripple spectral content are linked, possibly through common cellular or synaptic processes involved in memory consolidation. How can single cells fire selectively during some events? A major role of sharp-wave ripples is reactivation of single cells with specific neuronal ensembles. Presumably, different ensembles consist of unique groups of neurons, which may generate specific LFP events (Bazelot et al., 2016Bazelot M. Teleńczuk M.T. Miles R. Single CA3 pyramidal cells trigger sharp waves in vitro by exciting interneurones.J. Physiol. 2016; 594: 2565-2577Crossref PubMed Scopus (25) Google Scholar). In order to capture this specificity, we made an unsupervised classification of different sharp-wave ripple fields to test firing selectivity of pyramidal cells recorded juxtacellularly. All ripple events recorded in a given session were grouped into self-organizing maps (SOMs) according to their topological similarities in a multi-dimensional parameter space (Kohonen, 2001Kohonen T. Self-Organizing Maps. Springer Berlin Heidelberg, 2001Crossref Google Scholar, Reichinnek et al., 2010Reichinnek S. Künsting T. Draguhn A. Both M. Field potential signature of distinct multicellula" @default.
• W2651397524 created "2017-06-30" @default.
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• W2651397524 date "2017-06-01" @default.
• W2651397524 modified "2023-10-12" @default.
• W2651397524 title "Mechanisms for Selective Single-Cell Reactivation during Offline Sharp-Wave Ripples and Their Distortion by Fast Ripples" @default.
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• W2651397524 doi "https://doi.org/10.1016/j.neuron.2017.05.032" @default.
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• W2651397524 hasPublicationYear "2017" @default.

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