Awake replay of remote experiences in the hippocampus

“We know that the neocortex and the hippocampus can both show oscillatory, synchronized patterns of activity during sleep and sleep-like states15, 34, 35.”

“Reactivation is hypothesized to depend on hippocampal sharp wave – ripple (SWR) events5–8 because SWRs propagate from the hippocampus to adjacent cortical regions9, 10 and include firing patterns associated with previous 6, 11–16 as well as current experiences17–19.”

“This process is thought to involve rapid encoding in highly plastic hippocampal circuits followed by a consolidation process in which hippocampal representations are 'reactivated', allowing these patterns to be engrained in less-plastic hippocampal-neocortical circuit”

“Complementary studies have shown that entire sequences can be replayed at high speeds14–16, 19.”

“because SWRs propagate from the hippocampus to adjacent cortical region”

“During these periods hippocampal place cells that fire together during exploration tend to fire together afterwards Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/autho…”

“We computed cross-correlation histograms of spike trains from all pair-wise combinations of simultaneously recorded place cells and plotted the normalized histograms as a function of the linear distance between the place field peak”

“Our findings complement recent reports of memory-related activity in the huma”

“After the animals alternated reliably for liquid reward (sweetened condensed milk), they were implanted with a microdrive array containing 30 independently movable tetrodes targeting CA3 and CA120, 27 according to UCSF and NIH guidelines.”

“Putative interneurons were identified based on spike width and average firing rate36, 37, and were excluded from all analyses.”

“This process is thought to involve rapid encoding in highly plastic hippocampal circuits followed by a consolidation process where hippocampal representations are “reactivated”, allowing these patterns to be engrained in less plastic hippocampal – neocortical circuits3, 4.”

“We and others have found that novel experiences generate a long lasting increase in neuronal excitability and neuronal coordination for the cells active during those experiences13, 17, 20, 30.”

“1)20.”

“Complementary studies have shown that entire sequences can be replayed at high speeds14–16, 19.”

“In addition to current learning experience, more remote learning experiences are also reactivated, indicating that wake reactivations do not depend on the actual perceptual input (621).”

“…know that reactivations occur outside of sleep, i.e., in quiet wakefulness (Davidson et al., 2009; Diba and Buzsáki, 2007; Foster and Wilson, 2006; Karlsson and Frank, 2009; Kudrimoti et al., 1999), during initial learning (Singer et al., 2013), and during many states of cortical activation…”

“Consistent with this expectation, hippocampal neural ensembles have been shown to replay place cell firing sequences during sleep and quiet waking periods following learning in rodents [20], and blocking this replay prevents subsequent memory retrieval [21].”

“…experimental studies on both humans (Gelbard-Sagiv et al., 2008; Paz et al., 2010) and animals (Louie and Wilson, 2001; Foster and Wilson, 2006; Karlsson and Frank, 2009; Davidson et al., 2009) have shown that hippocampal neuronal ensembles ''replay'' specific event representations following…”

“In contrast, as we argue below, awake replay is consistent with the patterns of activity necessary to support a hippocampal retrieval mechanism, indicating that hippocampal replay during the awake state could be a common neural mechanism for both consolidation and retrieva”

“Whereas previous studies (Wil- son and McNaughton, 1994; Jackson et al., 2006; O’Neill et al., 2006; Karlsson and Frank, 2009) have found increasing replay with experience, these studies did not compare tasks with different behavioral requirements in which parts of the environment were experienced…”

“Quiet Wakefulness Although spike sequence replay was initially discovered during sleep, recent studies have shown that it also occurs during wakefulness, especially during quiet immobility or consummatory behaviors (Diba and Buzsá ki, 2007; Foster and Wilson, 2006; Karlsson and Frank, 2009).”

“Such replay is observed time locked either to an immediate experience (Foster & Wilson 2006, Csicsvari et al. 2007, Diba & Buzsaki 2007) or to a spatially and temporally remote one (Davidson et al. 2009, Karlsson & Frank 2009).”

“Supporting this latter notion, reactivation of experience-dependent patterns of activity has recently been described in the rodent hippocampus and primate cortex during the awake state when animals are resting (Diba and Buzsáki, 2007; Foster and Wilson, 2006; Hoffman and McNaughton, 2002; Karlsson and Frank, 2009).”

“The rest period was intended to be analogous to the awake resting periods in rodent studies in which hippocampal replay has been observed in spatial tasks (Davidson et al., 2009; Foster and Wilson, 2006; Karlsson and Frank, 2009).”

“In animals, sharp-wave ripples can activate cells along both past and future trajectories (Karlsson and Frank 2009; Gupta et al. 2010; Pfeiffer and Foster 2013).”

“Existing rodent (Ji and Wilson, 2007; Karlsson and Frank, 2009) and human (Kuhl et al., 2010) research has primarily linked memory reactivation with hippocampal responses.”

“The challenge remains to establish a clear link between these observations and memory consolidation and to determine how the replay that occurs during sleep relates to the replay that can occur during wakefulness (Karlsson and Frank, 2009).”

“The neuronal sequence is often similar to place cell sequences observed during exploration (Foster and Wilson, 2006; Diba and Buzsáki, 2007; Karlsson and Frank, 2009).”

“In particular, reactivation during pauses in waking behavior frequently results in the sequential activity of place cells active on paths to or from the animal’s current location (Foster and Wilson, 2006; Diba and Buzsáki, 2007; Karlsson and Frank, 2009; Davidson et al., 2009).”

“Awake replay, although on a similar temporally compressed timescale as in sleep, was often in the reverse order to the order in which the fields were arranged along the track (Csicsvari et al. 2007, Diba & Buzsaki 2007, Foster & Wilson 2006, Gupta et al. 2010, Karlsson & Frank 2009).”

“(B) On exposure to an unfamiliar enclosure place cells ‘remap’, rapidly generating a novel representation; individual cells change their firing rate and field locations relative to each other and the environment [32,64,158].”

“Further, reductions in brain 5- HT concentrations after acute or chronic tryptophan depletion has been demonstrated to impair contextual fear memory in mice (Uchida et al., 2007), object memory in rats (Jenkins et al., 2009), and declarative memory in humans (Schmitt et al., 2006).”

“Neuronal sequences corresponding to remote trajectories [86] as well as routes never experienced before (‘shortcuts’, [88 ]) have also been reported.”

“Subsequently, reverse replay was replicated, but additionally, it was found that forward replay also occurred during awake immobility (Csicsvari et al., 2007; Davidson et al., 2009; Diba and Buzsáki, 2007; Gupta et al., 2010; Karlsson and Frank, 2009).”

“If so, then this inhibitory modulation might compromise the consolidation of the suppressedmemory by, for example, disrupting the replay of its hippocampal representation (Karlsson and Frank, 2009; Carr et al., 2011).”

“…demonstrations that nonlocal activity sequences are spontaneously emitted independent of immediate cues arising from the environment (Csicsvari et al. 2007, Davidson et al. 2009, Diba & Buzsáki 2007, Foster & Wilson 2006, Johnson & Redish 2007, Karlsson & Frank 2009, Pastalkova et al. 2008).”

“…and Hubel, 1981) and attentional states (Briggs et al., 2013; Desimone and Duncan, 1995), while others have established mechanisms by which offline limbic processing of memories is enhanced during sleep and quiet wakefulness (Buzsaki, 2010; Ji and Wilson, 2007; Karlsson and Frank, 2009).”

“Because replay events are thought tomainly reflect short sequences of states (3), if the activity we measured in the hippocampus at rest indeed reflects sequential replay, we can therefore expect that consecutively decoded states would be nearby in the task’s state space (that is, separated by few intervening states i…”

“…(Buzsáki, 1989; Wilson and McNaughton, 1994; Skaggs and McNaughton, 1996; Kudrimoti et al., 1999; Nadasdy et al., 1999; Lee and Wilson 2002; Foster and Wilson, 2006; O’Neill et al., 2006, 2008; Diba and Buzsáki, 2007; Karlsson and Frank, 2008, 2009; Singer and Frank, 2009; Dupret et al., 2010).”

“For instance, electrophysiological studies in rodents have shown hippocampally mediated replay of prior event sequences in new spatial contexts (Karlsson and Frank, 2009) and sequential activation of hippocampal place cells for never-experienced spatial trajectories that represent a shortcut…”

“Identifying replay events generally requires that each SWR contains spikes from at least five different place cells (Karlsson and Frank, 2009) and, as a result, many events that happen to activate a smaller number of recorded place cells cannot be examined.”

“First, studies in rodents have provided conclusive evidence that action potential sequences of spatially selective hippocampal place cells reoccur spontaneously during subsequent sleep (Skaggs and McNaughton, 1996; Ji and Wilson, 2007), but also during awake resting periods (Foster and Wilson, 2006; Karlsson and Frank…”

“As previously reported (Karlsson and Frank, 2009), we found lower correlations between place field location and relative spike timing during quiescent SWRs than observed during waking SWRs (Figure 8E; permutation test; Spearman r awake > quiescent p < 0.001).”

“…leading theory for how this hippocampal replay works involves the phenomenon of sharp waves during sleep or quiet waking (Euston & McNaughton, 2006; Karlsson & Frank, 2009; Lee & Wilson, 2002; Nadasdy, Hirase, Czurko, Csicsvari, & Buzsaki, 1999), where sequences of events that might have stretched…”

“Proc Natl Acad Sci USA 107(16):7550–7555.”

“…1999; Skaggs and McNaughton, 1996; Wilson and McNaughton, 1994; Lee and Wilson, 2002; Foster and Wilson, 2006; Diba and Buzsá ki, 2007; O'Neill et al., 2006, 2008; Ponomarenko et al., 2008; Dupret et al., 2010; Foster and Wilson, 2006; Diba and Buzsá ki, 2007; Karlsson and Frank, 2008, 2009; Fig.”

“…activity during awake SWRs has revealed that these events can contain sequential spiking that recapitulates patterns seen during both recent (Foster and Wilson, 2006; Diba and Buzsá ki, 2007; Davidson et al., 2009) and more remote past experiences (Karlsson and Frank, 2009; Gupta et al., 2010).”

“Although such reactivation has most typically been observed in the form of spontaneous firing patterns during sleep, recent evidence indicates that reactivation also occurs during awake behavio”

“…memory retrieval, the MTL spontaneously reactivates both task relevant and task irrelevant information (e.g., Kuhl et al., 2013), and both the MTL and PCC/RSC are involved in the spontaneous replay of recent experiences during waking rest and sleep (Karlsson & Frank, 2009; Rasch & Born, 2007).”

“The assessment of replay events for significance was implemented as previously described (Karlsson and Frank, 2009).”

“However, there is also evidence that the “replay” of neural circuits can also occur in wake, not just in sleep (Karlsson and Frank 2009), and “preplay” can also occur during wake before learning (Dragoi and Tonegawa 2011).”

“…event, we determined whether it was a replay using a Bayesian approach: first decoding the spatial positions encoded by the firing pattern within the candidate event based on the template 35 , and then statistically quantifying whether the decoded positions matched a trajectory on the track 17,18 .”

“This is perhaps not surprising since in the sleeping animal activity of subcortical neuromodulators is considerably more strongly attenuated than in the waking but still animal (Csicsvari et al., 2007; Karlsson and Frank, 2009; O’Neill et al., 2006).”

“Together, these results indicate distinct contributions of VTA reinforcement activity associated with hippocampal spatial replay to the processing of wake and SWS-associated spatial memory.”

“, 2011), but also involves wakefulness (Carr et al., 2011; Foster and Wilson, 2006; Karlsson and Frank, 2009).”

“Karlsson and Frank (2009) argued that wake replay in rats provided a higher-fidelity recapitulation of past experiences than replay during sleep.”

“200 Neuron 91, 194–204, July 6, 2016 rent location of the animal (Diba and Buzsáki, 2007; Foster and Wilson, 2006) but also encode trajectories that do not include the current location of the animal (Davidson et al., 2009; Gupta et al., 2010; Karlsson and Frank, 2009).”

“It is now well established that hippocampal place cells engage in extended spiking sequences across neuronal ensembles that match sequences from previous behavioral episodes, often in a temporally condensed form during 100 –200 ms sharp-wave–ripple (SWR) events in the hippocampal local field potential (LFP; Louie and…”

“…has been suggested to be an important mechanism for memory retrieval and consolidation in both hippocampus and connected extra-hippocampal structures (EgoStengel & Wilson, 2010; Girardeau, Benchenane, Wiener, Buzsaki, & Zugaro, 2009; Jadhav, Kemere, German, & Frank, 2012; Karlsson & Frank, 2009).”

“More structured hippocampal reactivation in awake compared with rest periods has been observed (Karlsson and Frank, 2009; Grosmark and Buzsáki, 2016), but activity outside the hippocampus and changes over learning have not been studied.”

“…an environment are known or have at least been sampled, the hippocampus is capable of generating place-cell sequences in an order that has never been experienced 2,4,5,24,41 , and sequences that depict as yet never experienced trajectories 6,41 , in particular, novel paths to a remembered goal 6 .”

“Comparable results were observed during offline periods of sleep but with lower fidelity (Figures S1B, S7D, and S7E), as reported for replay of spatial firing patterns during awake rest versus sleep (Karlsson and Frank, 2009).”

“A prominent physiological pattern involved in memory consolidation is the sharp wave–ripple complex, which occurs mainly during non-rapid eye movement sleep, immobility, and consummatory behaviors (Buzsàki, 1983; Wilson and McNaughton, 1994; Karlsson and Frank, 2009).”

“…to encode paths starting from the animal’s current location and crossing the immediate environment (Csicsvari et al., 2007; Davidson et al., 2009; Karlsson & Frank, 2009; O’Neill et al., 2006; Pfeiffer & Foster, 2013; Wu & Foster, 2014), Karlsson & Frank reported that during brief pauses in…”

“…1994; Skaggs and McNaughton, 1996; Kudrimoti et al., 1999; Nádasdy et al., 1999; Lee and Wilson 2002; Foster and Wilson, 2006; O’Neill et al., 2006, 2008; Diba and Buzsáki, 2007; Karlsson and Frank, 2008, 2009; Singer and Frank, 2009; Dupret et al., 2010; but see Dragoi and Tonegawa, 2011, 2013).”

“…M anuscript voltage gated Ca2+ channels to allow in a little calcium, and that small amount of intracellular Ca2+ is not augmented by simultaneous pre and postsynaptic depolarization in the ~ 50% of slow waves that do not include ordered replay (Karlsson and Frank, 2009; Foster and Wilson, 2006).”

“Neuronal reinstatement relating to consolidation has been described in rodents (Davidson et al., 2009; Karlsson and Frank, 2009; Foster and Wilson, 2006) and Received May 7, 2015; revised Aug. 20, 2015; accepted Aug. 31, 2015.”

“Following practice, replay rates receded to pre-training levels rather rapidly contrary to the slow decrease reported in rodents (Karlsson and Frank, 2009), a difference that could be attributed to the explicit awareness of training termination in humans (likely to be absent in rodents) or to the presence of reward co…”

“These sequences reflect previous sensory experience (Buzsáki et al., 1992; Karlsson and Frank, 2009).”

“This ‘awake replay’ (Carr, Jadhav, & Frank, 2011; Karlsson & Frank, 2009) presents features very similar to sleep replay.”

“1G,H), consistent with reports of remote replay of recent behavioural sequences (Karlsson and Frank, 2009) which is proposed to be important for the consolidation of memory.”

“When animals stop running, theta oscillation gives way to irregular local field potential (LFP) activity, interspersed with intermittent sharp wave-ripples (SWRs) that are transient synchronous network events linked to replaying memory traces off-line (Buzsáki, 2015; Karlsson and Frank, 2009).”