Memory trace replay: the shaping of memory consolidation by neuromodulation
Authors: Laura A. Atherton, David Dupret, Jack R. Mellor
Journal: Trends in Neurosciences (2015)

•Memory trace replay results from lingering excitability and synaptic plasticity.•The balance of replay mechanisms may be determined by neuromodulation.•Acetylcholine release can shape the direction of replay in sharp wave ripples.•Dopamine release can dictate which cell assemblies are replayed. The consolidation of memories for places and events is thought to rely, at the network level, on the replay of spatially tuned neuronal firing patterns representing discrete places and spatial trajectories. This occurs in the hippocampal-entorhinal circuit during sharp wave ripple events (SWRs) that occur during sleep or rest. Here, we review theoretical models of lingering place cell excitability and behaviorally induced synaptic plasticity within cell assemblies to explain which sequences or places are replayed. We further provide new insights into how fluctuations in cholinergic tone during different behavioral states might shape the direction of replay and how dopaminergic release in response to novelty or reward can modulate which cell assemblies are replayed. The consolidation of memories for places and events is thought to rely, at the network level, on the replay of spatially tuned neuronal firing patterns representing discrete places and spatial trajectories. This occurs in the hippocampal-entorhinal circuit during sharp wave ripple events (SWRs) that occur during sleep or rest. Here, we review theoretical models of lingering place cell excitability and behaviorally induced synaptic plasticity within cell assemblies to explain which sequences or places are replayed. We further provide new insights into how fluctuations in cholinergic tone during different behavioral states might shape the direction of replay and how dopaminergic release in response to novelty or reward can modulate which cell assemblies are replayed. What determines which memories are retained and which are lost is an absorbing topic for scientists and nonscientists alike, yet the mechanisms underlying the persistence of some pieces of information and the forgetting of others remain to be identified. Well-established theories propose that memories are encoded during wake behavior, with information being represented in the coordinated activity of subsets of neurons forming cell assemblies [1Buzsaki G. Two-stage model of memory trace formation: a role for "noisy" brain states.Neuroscience. 1989; 31: 551-570Crossref PubMed Scopus (773) Google Scholar, 2McGaugh J.L. Neuroscience – memory – a century of consolidation.Science. 2000; 287: 248-251Crossref PubMed Google Scholar, 3Hebb D.O. The Organisation of Behavior. Wiley, 1949Google Scholar, 4Harris K.D. et al.Organization of cell assemblies in the hippocampus.Nature. 2003; 424: 552-556Crossref PubMed Scopus (350) Google Scholar]. However newly encoded memories are typically fragile and, because they may decay, require additional maintenance processes. At the network level, one such process is the off-line reactivation of assembly firing patterns observed during active behavior. This process is best illustrated by the location-specific firing of principal cells [5O'Keefe J. Dostrovsky J. The hippocampus as a spatial map. Preliminary evidence from unit activity in the freely-moving rat.Brain Res. 1971; 34: 171-175Crossref PubMed Scopus (1957) Google Scholar, 6Leutgeb S. et al.Independent codes for spatial and episodic memory in hippocampal neuronal ensembles.Science. 2005; 309: 619-623Crossref PubMed Scopus (292) Google Scholar, 7Muller R.U. et al.Spatial firing patterns of hippocampal complex-spike cells in a fixed environment.J. Neurosci. 1987; 7: 1935-1950PubMed Google Scholar, 8Wilson M.A. McNaughton B.L. Dynamics of the hippocampal ensemble code for space.Science. 1993; 261: 1055-1058Crossref PubMed Google Scholar] in the hippocampus. These place cells (see Glossary) are activated sequentially as an animal runs through an arena. Subsequently, co-active place cells representing a discrete place or sequential place cell activation representing a trajectory are reactivated or replayed during SWRs (Box 1, Box 2), which intermittently occur in slow wave sleep (SWS) (sSWRs), long periods of awake immobility (iSWRs), or brief pauses in exploration (eSWRs) (reviewed in [9O'Neill J. et al.Play it again: reactivation of waking experience and memory.Trends Neurosci. 2010; 33: 220-229Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, 10Carr M.F. et al.Hippocampal replay in the awake state: a potential substrate for memory consolidation and retrieval.Nat. Neurosci. 2011; 14: 147-153Crossref PubMed Scopus (135) Google Scholar]).Box 1Sharp wave ripples in the hippocampusSharp wave ripples (Figure I) are transient hippocampal network events observed in a variety of species, including humans [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 113O'Keefe J. Nadal L. The Hippocampus as a Cognitive Map. Clarendon Press, 1978Google Scholar, 114Le Van Quyen M. et al.Cell type-specific firing during ripple oscillations in the hippocampal formation of humans.J. Neurosci. 2008; 28: 6104-6110Crossref PubMed Scopus (62) Google Scholar, 115Skaggs W.E. et al.EEG sharp waves and sparse ensemble unit activity in the Macaque hippocampus.J. Neurophysiol. 2007; 98: 898-910Crossref PubMed Scopus (53) Google Scholar]. They comprise negative potentials (sharp waves) in the CA1 stratum radiatum superimposed with short-lived, fast frequency oscillations (ripples) in the CA1 stratum pyramidale. Sharp waves have a current sink in the stratum radiatum of CA1 and CA3 and a current source in the pyramidal cell layer [55Sullivan D. et al.Relationships between hippocampal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical activity.J. Neurosci. 2011; 31: 8605-9616Crossref PubMed Scopus (65) Google Scholar, 72Buzsaki G. et al.Cellular bases of hippocampal EEG in the behaving rat.Brain Res. 1983; 287: 139-171Crossref PubMed Scopus (241) Google Scholar, 116Buzsaki G. Hippocampal sharp waves: their origin and significance.Brain Res. 1986; 398: 242-252Crossref PubMed Scopus (430) Google Scholar, 117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar], whereas ripples have sink–source pairs at the level of the stratum pyramidale [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar]. The frequency of the ripple oscillations in CA1 spans a large frequency range [118Csicsvari J. et al.Fast network oscillations in the hippocampal CA1 region of the behaving rat.J. Neurosci. 1999; 19: RC20PubMed Google Scholar] that is positively correlated to the amplitude of the sharp wave, with frequencies ranging from 140 to 250 Hz for large sharp waves down to the fast gamma range of 90–140 Hz for smaller sharp waves [55Sullivan D. et al.Relationships between hippocampal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical activity.J. Neurosci. 2011; 31: 8605-9616Crossref PubMed Scopus (65) Google Scholar, 119Patel J. et al.Local generation and propagation of ripples along the septotemporal axis of the hippocampus.J. Neurosci. 2013; 33: 17029-17041Crossref PubMed Scopus (14) Google Scholar], a frequency that is more akin to those of ripples in CA3 [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar]. Given the absence of CA3–CA1 ripple coherence [117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar], CA3 units firing in an uncorrelated manner to CA1 ripples [118Csicsvari J. et al.Fast network oscillations in the hippocampal CA1 region of the behaving rat.J. Neurosci. 1999; 19: RC20PubMed Google Scholar], incoherent interhemispheric CA1 ripples [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 120Chrobak J.J. Buzsaki G. High-frequency oscillations in the output networks of the hippocampal-entorhinal axis of the freely behaving rat.J. Neurosci. 1996; 16: 3056-3066Crossref PubMed Google Scholar], and decreasing ripple coherence with distance along the septotemporal hippocampal axis [119Patel J. et al.Local generation and propagation of ripples along the septotemporal axis of the hippocampus.J. Neurosci. 2013; 33: 17029-17041Crossref PubMed Scopus (14) Google Scholar], ripples are likely to be generated locally within CA1. Indeed, recent work suggests that SWRs occur when a build-up of excitation drives a population of parvalbumin-positive basket cells to fire. Reciprocal inhibition synchronizes this firing at ripple frequency and creates critical windows for alternate basket cell and pyramidal cell firing [121Schlingloff D. et al.Mechanisms of sharp wave initiation and ripple generation.J. Neurosci. 2014; 34: 11385-11398Crossref PubMed Scopus (2) Google Scholar, 122Stark E. et al.Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations.Neuron. 2014; 83: 467-480Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. Approximately 10–20% of hippocampal pyramidal cells fire in any given SWR, but notably usually only with a single action potential each [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar].Despite the lack of widespread ripple coherence, SWRs nevertheless occur simultaneously throughout the hippocampus, subiculum, pre- and parasubiculum cortices, and entorhinal cortex, creating temporal windows of heightened neuronal firing [120Chrobak J.J. Buzsaki G. High-frequency oscillations in the output networks of the hippocampal-entorhinal axis of the freely behaving rat.J. Neurosci. 1996; 16: 3056-3066Crossref PubMed Google Scholar, 123Chrobak J.J. Buzsaki G. Selective activation of deep layer (V-VI) retrohippocampal cortical neurons during hippocampal sharp waves in the behaving rat.J. Neurosci. 1994; 14: 6160-6170PubMed Google Scholar] and widespread changes in activity throughout the cortical network [124Logothetis N.K. et al.Hippocampal-cortical interaction during periods of subcortical silence.Nature. 2012; 491: 547-553Crossref PubMed Scopus (49) Google Scholar]. As such, they have been proposed as an ideal candidate to transfer labile hippocampal memories to more stable neocortical sites during offline states [72Buzsaki G. et al.Cellular bases of hippocampal EEG in the behaving rat.Brain Res. 1983; 287: 139-171Crossref PubMed Scopus (241) Google Scholar, 90Buzsaki G. The hippocampo-neocortical dialogue.Cereb. Cortex. 1996; 6: 81-92Crossref PubMed Scopus (437) Google Scholar] and also to downstream structures, including the ventral striatum [125Pennartz C.M.A. et al.The ventral striatum in off-line processing: ensemble reactivation during sleep and modulation by hippocampal ripples.J. Neurosci. 2004; 24: 6446-6456Crossref PubMed Scopus (122) Google Scholar, 126Lansink C.S. et al.Hippocampus leads ventral striatum in replay of place–reward information.PLoS Biol. 2009; 7: e1000173Crossref PubMed Scopus (118) Google Scholar].Box 2Replay of place cell activityAs a rodent follows a spatial trajectory, place cells are sequentially activated. In subsequent SWRs, this sequence of place cells may be reactivated in a time-compressed manner in either a forward or a backward direction. The directional bias is dependent on the behavioral state of the animal, with more backward replay in eSWRs, a similar occurrence probability of forward and backward replay in iSWRs, and more forward replay in sSWRs [11Csicsvari J. et al.Place-selective firing contributes to the reverse-order reactivation of CA1 pyramidal cells during sharp waves in open-field exploration.Eur. J. Neurosci. 2007; 26: 704-716Crossref PubMed Scopus (50) Google Scholar, 17Wikenheiser A.M. Redish A.D. The balance of forward and backward hippocampal sequences shifts across behavioral states.Hippocampus. 2013; 23: 22-29Crossref PubMed Scopus (6) Google Scholar] (Figure I).Figure IReplay of place cell activity in sharp wave ripples (SWRs).View Large Image Figure ViewerDownload (PPT) Sharp wave ripples (Figure I) are transient hippocampal network events observed in a variety of species, including humans [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 113O'Keefe J. Nadal L. The Hippocampus as a Cognitive Map. Clarendon Press, 1978Google Scholar, 114Le Van Quyen M. et al.Cell type-specific firing during ripple oscillations in the hippocampal formation of humans.J. Neurosci. 2008; 28: 6104-6110Crossref PubMed Scopus (62) Google Scholar, 115Skaggs W.E. et al.EEG sharp waves and sparse ensemble unit activity in the Macaque hippocampus.J. Neurophysiol. 2007; 98: 898-910Crossref PubMed Scopus (53) Google Scholar]. They comprise negative potentials (sharp waves) in the CA1 stratum radiatum superimposed with short-lived, fast frequency oscillations (ripples) in the CA1 stratum pyramidale. Sharp waves have a current sink in the stratum radiatum of CA1 and CA3 and a current source in the pyramidal cell layer [55Sullivan D. et al.Relationships between hippocampal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical activity.J. Neurosci. 2011; 31: 8605-9616Crossref PubMed Scopus (65) Google Scholar, 72Buzsaki G. et al.Cellular bases of hippocampal EEG in the behaving rat.Brain Res. 1983; 287: 139-171Crossref PubMed Scopus (241) Google Scholar, 116Buzsaki G. Hippocampal sharp waves: their origin and significance.Brain Res. 1986; 398: 242-252Crossref PubMed Scopus (430) Google Scholar, 117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar], whereas ripples have sink–source pairs at the level of the stratum pyramidale [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar]. The frequency of the ripple oscillations in CA1 spans a large frequency range [118Csicsvari J. et al.Fast network oscillations in the hippocampal CA1 region of the behaving rat.J. Neurosci. 1999; 19: RC20PubMed Google Scholar] that is positively correlated to the amplitude of the sharp wave, with frequencies ranging from 140 to 250 Hz for large sharp waves down to the fast gamma range of 90–140 Hz for smaller sharp waves [55Sullivan D. et al.Relationships between hippocampal sharp waves, ripples, and fast gamma oscillation: influence of dentate and entorhinal cortical activity.J. Neurosci. 2011; 31: 8605-9616Crossref PubMed Scopus (65) Google Scholar, 119Patel J. et al.Local generation and propagation of ripples along the septotemporal axis of the hippocampus.J. Neurosci. 2013; 33: 17029-17041Crossref PubMed Scopus (14) Google Scholar], a frequency that is more akin to those of ripples in CA3 [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar]. Given the absence of CA3–CA1 ripple coherence [117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar], CA3 units firing in an uncorrelated manner to CA1 ripples [118Csicsvari J. et al.Fast network oscillations in the hippocampal CA1 region of the behaving rat.J. Neurosci. 1999; 19: RC20PubMed Google Scholar], incoherent interhemispheric CA1 ripples [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 120Chrobak J.J. Buzsaki G. High-frequency oscillations in the output networks of the hippocampal-entorhinal axis of the freely behaving rat.J. Neurosci. 1996; 16: 3056-3066Crossref PubMed Google Scholar], and decreasing ripple coherence with distance along the septotemporal hippocampal axis [119Patel J. et al.Local generation and propagation of ripples along the septotemporal axis of the hippocampus.J. Neurosci. 2013; 33: 17029-17041Crossref PubMed Scopus (14) Google Scholar], ripples are likely to be generated locally within CA1. Indeed, recent work suggests that SWRs occur when a build-up of excitation drives a population of parvalbumin-positive basket cells to fire. Reciprocal inhibition synchronizes this firing at ripple frequency and creates critical windows for alternate basket cell and pyramidal cell firing [121Schlingloff D. et al.Mechanisms of sharp wave initiation and ripple generation.J. Neurosci. 2014; 34: 11385-11398Crossref PubMed Scopus (2) Google Scholar, 122Stark E. et al.Pyramidal cell-interneuron interactions underlie hippocampal ripple oscillations.Neuron. 2014; 83: 467-480Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar]. Approximately 10–20% of hippocampal pyramidal cells fire in any given SWR, but notably usually only with a single action potential each [43Buzsaki G. et al.High-frequency network oscillation in the hippocampus.Science. 1992; 256: 1025-1027Crossref PubMed Google Scholar, 117Ylinen A. et al.Sharp wave-associated high-frequency oscillation (200 Hz) in the intact hippocampus: network and intracellular mechanisms.J. Neurosci. 1995; 15: 30-46Crossref PubMed Google Scholar]. Despite the lack of widespread ripple coherence, SWRs nevertheless occur simultaneously throughout the hippocampus, subiculum, pre- and parasubiculum cortices, and entorhinal cortex, creating temporal windows of heightened neuronal firing [120Chrobak J.J. Buzsaki G. High-frequency oscillations in the output networks of the hippocampal-entorhinal axis of the freely behaving rat.J. Neurosci. 1996; 16: 3056-3066Crossref PubMed Google Scholar, 123Chrobak J.J. Buzsaki G. Selective activation of deep layer (V-VI) retrohippocampal cortical neurons during hippocampal sharp waves in the behaving rat.J. Neurosci. 1994; 14: 6160-6170PubMed Google Scholar] and widespread changes in activity throughout the cortical network [124Logothetis N.K. et al.Hippocampal-cortical interaction during periods of subcortical silence.Nature. 2012; 491: 547-553Crossref PubMed Scopus (49) Google Scholar]. As such, they have been proposed as an ideal candidate to transfer labile hippocampal memories to more stable neocortical sites during offline states [72Buzsaki G. et al.Cellular bases of hippocampal EEG in the behaving rat.Brain Res. 1983; 287: 139-171Crossref PubMed Scopus (241) Google Scholar, 90Buzsaki G. The hippocampo-neocortical dialogue.Cereb. Cortex. 1996; 6: 81-92Crossref PubMed Scopus (437) Google Scholar] and also to downstream structures, including the ventral striatum [125Pennartz C.M.A. et al.The ventral striatum in off-line processing: ensemble reactivation during sleep and modulation by hippocampal ripples.J. Neurosci. 2004; 24: 6446-6456Crossref PubMed Scopus (122) Google Scholar, 126Lansink C.S. et al.Hippocampus leads ventral striatum in replay of place–reward information.PLoS Biol. 2009; 7: e1000173Crossref PubMed Scopus (118) Google Scholar]. As a rodent follows a spatial trajectory, place cells are sequentially activated. In subsequent SWRs, this sequence of place cells may be reactivated in a time-compressed manner in either a forward or a backward direction. The directional bias is dependent on the behavioral state of the animal, with more backward replay in eSWRs, a similar occurrence probability of forward and backward replay in iSWRs, and more forward replay in sSWRs [11Csicsvari J. et al.Place-selective firing contributes to the reverse-order reactivation of CA1 pyramidal cells during sharp waves in open-field exploration.Eur. J. Neurosci. 2007; 26: 704-716Crossref PubMed Scopus (50) Google Scholar, 17Wikenheiser A.M. Redish A.D. The balance of forward and backward hippocampal sequences shifts across behavioral states.Hippocampus. 2013; 23: 22-29Crossref PubMed Scopus (6) Google Scholar] (Figure I). Sequential replay can occur in both a forward [11Csicsvari J. et al.Place-selective firing contributes to the reverse-order reactivation of CA1 pyramidal cells during sharp waves in open-field exploration.Eur. J. Neurosci. 2007; 26: 704-716Crossref PubMed Scopus (50) Google Scholar, 12Lee A.K. Wilson M.A. Memory of sequential experience in the hippocampus during slow wave sleep.Neuron. 2002; 36: 1183-1194Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar, 13Davidson T.J. et al.Hippocampal replay of extended experience.Neuron. 2009; 63: 497-507Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 14Diba K. Buzsaki G. Forward and reverse hippocampal place-cell sequences during ripples.Nat. Neurosci. 2007; 10: 1241-1242Crossref PubMed Scopus (252) Google Scholar, 15Gupta A.S. et al.Hippocampal replay is not a simple function of experience.Neuron. 2010; 65: 695-705Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar] and backward [11Csicsvari J. et al.Place-selective firing contributes to the reverse-order reactivation of CA1 pyramidal cells during sharp waves in open-field exploration.Eur. J. Neurosci. 2007; 26: 704-716Crossref PubMed Scopus (50) Google Scholar, 13Davidson T.J. et al.Hippocampal replay of extended experience.Neuron. 2009; 63: 497-507Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 14Diba K. Buzsaki G. Forward and reverse hippocampal place-cell sequences during ripples.Nat. Neurosci. 2007; 10: 1241-1242Crossref PubMed Scopus (252) Google Scholar, 15Gupta A.S. et al.Hippocampal replay is not a simple function of experience.Neuron. 2010; 65: 695-705Abstract Full Text Full Text PDF PubMed Scopus (144) Google Scholar, 16Foster 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 (484) Google Scholar] direction, with the directional balance proposed to be dependent on the ongoing behavioral state of the animal [17Wikenheiser A.M. Redish A.D. The balance of forward and backward hippocampal sequences shifts across behavioral states.Hippocampus. 2013; 23: 22-29Crossref PubMed Scopus (6) Google Scholar]. Similar to theta-phase precession [18Skaggs W.E. et al.Theta phase precession in hippocampal neuronal populations and the compression of temporal sequences.Hippocampus. 1996; 6: 149-172Crossref PubMed Scopus (705) Google Scholar], these replayed sequences are temporally compressed compared with those observed during wake behavior [12Lee A.K. Wilson M.A. Memory of sequential experience in the hippocampus during slow wave sleep.Neuron. 2002; 36: 1183-1194Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar, 13Davidson T.J. et al.Hippocampal replay of extended experience.Neuron. 2009; 63: 497-507Abstract Full Text Full Text PDF PubMed Scopus (169) Google Scholar, 19Nadasdy Z. et al.Replay and time compression of recurring spike sequences in the hippocampus.J. Neurosci. 1999; 19: 9497-9507PubMed Google Scholar, 20Ji D.Y. Wilson M.A. Coordinated memory replay in the visual cortex and hippocampus during sleep.Nat. Neurosci. 2007; 10: 100-107Crossref PubMed Scopus (513) Google Scholar]. Consequently they have been posited to provide the appropriate temporal neural activity for the Hebbian synaptic modification occurring downstream in neocortical networks during memory consolidation [1Buzsaki G. Two-stage model of memory trace formation: a role for "noisy" brain states.Neuroscience. 1989; 31: 551-570Crossref PubMed Scopus (773) Google Scholar, 12Lee A.K. Wilson M.A. Memory of sequential experience in the hippocampus during slow wave sleep.Neuron. 2002; 36: 1183-1194Abstract Full Text Full Text PDF PubMed Scopus (455) Google Scholar, 21Kruskal P.B. et al.Circuit reactivation dynamically regulates synaptic plasticity in neocortex.Nat. Commun. 2013; 4: 2574Crossref PubMed Google Scholar, 22Wilson M.A. McNaughton B.L. Reactivation of hippocampal ensemble memories during sleep.Science. 1994; 265: 676-679Crossref PubMed Google Scholar]. Although direct support for this hypothesis is currently lacking, intact NMDA receptor (NMDAR) activity during learning and intrahippocampal synaptic transmission during consolidation are at least necessary for unimpaired memory consolidation and place cell reactivation during SWRs [23Nakashiba T. et al.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 (83) Google Scholar, 24Dupret D. et al.The reorganization and reactivation of hippocampal maps predict spatial memory performance.Nat. Neurosci. 2010; 13: 995-1002Crossref PubMed Scopus (117) Google Scholar]. Moreover, evidence suggests the hippocampus and neocortex are actively engaged during SWRs and SWS. Cortical and hippocampal sequences, reflecting the same experiences, replay together during SWS [20Ji D.Y. Wilson M.A. Coordinated memory replay in the visual cortex and hippocampus during sleep.Nat. Neurosci. 2007; 10: 100-107Crossref PubMed Scopus (513) Google Scholar] and, during SWRs, prefrontal neurons consistently fire within tight temporal windows <100 ms after hippocampal pyramidal cells, which could plausibly drive plasticity at the level of single cell pairs [25Wierzynski C.M. et al.State-dependent spike-timing relationships between hippocampal and prefrontal circuits during sleep.Neuron. 2009; 61: 587-596Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar]. Concordantly, a growing body of literature has linked SWRs to learning and memory. SWR incidence during SWS is increased following training on a place-reward association task [26Ramadan W. et al.Hippocampal sharp wave/ripples during sleep for consolidation of associative memory.PLoS ONE. 2009; 4: e6697Crossref PubMed Scopus (44) Google Scholar]. Conversely, electrically interrupting SWRs during post-training sleep impaired spatial learning [27Girardeau G. et al.Selective suppression of hippocampal ripples impairs spatial memory.Nat. Neurosci. 2009; 12: 1222-1223Crossref PubMed Scopus (270) Google Scholar, 28Ego-Stengel V. Wilson M.A. Disruption of ripple-associated hippocampal activity during rest impairs spatial learning in the rat.Hippocampus. 2010; 20: 1-10PubMed Google Scholar], while interrupting SWRs during training on a spatial alternation task selectively impaired spatial working memory, but not spatial reference memory [29Jadhav S.P. et al.Awake hippocampal sharp-wave ripples support spatial memory.Science. 2012; 336: 1454-1458Crossref PubMed Scopus (123) Google Scholar]. Critically, it remains to be determined whether the ongoing hippocampal network activity during SWRs (i.e., global transient changes in interneuron and pyramidal cell activities) or specifically the reactivation or replay of place cell activity during SWRs is the more important for spatial learning and memory. Indeed, SWR activity content can be biased towards newly learnt firing patterns and predict memory performance [24Dupret D. et al.The reorganization and reactivation of hippocampal maps predict spatial memory performance.Nat. Neurosci. 2010; 13: 995-1002Crossref PubMed Scopus (117) Google Scholar]. Moreover, recent work also showed the induction of an artificial place-preference behavior following intracranial stimulation, triggered by single-place cell activity during sleep. This further suggests that replay of place cell activity serves an important role in spatial memory [30de Lavilleon G. et al.Explicit memory creation during sleep demonstrates a causal role of place cells in navigation.Nat. Neurosci. 2015; 18: 493-495Crossref PubMed Scopus (1) Google Scholar], although how this applies to the coordinated neuronal ensemble activity during SWRs remains to be investigated. By contrast, replay, particularly during awake SWRs, has also been proposed to have functional roles other than for spatial memory consolidation; for example, in temporal credit assignment to reward locations (particularly backward replay) [16Foster 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 (484) Google Scholar, 31Singer A.C. Frank L.M. Rewarded outcomes enhance reactivation of experience in the hippocampus.Neuron. 2009; 64: 910-