A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations.

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.

Distributed cell assemblies spanning prefrontal cortex and striatum.

Highly synchronous neuronal assembly activity is deemed essential for cognitive brain function. In theory, such synchrony could coordinate multiple brain areas performing complementary processes. However, cell assemblies have been observed only in single structures, typically cortical areas, and little is known about their synchrony with downstream subcortical structures, such as the striatum. Here, we demonstrate distributed cell assemblies activated at high synchrony (∼10 ms) spanning prefrontal cortex and striatum. In addition to including neurons at different brain hierarchical levels, surprisingly, they synchronized functionally distinct limbic and associative sub-regions. These assembly activations occurred when members shifted their firing phase relative to ongoing 4 Hz and theta rhythms, in association with high gamma oscillations. This suggests that these rhythms could mediate the emergence of cross-structural assemblies. To test for the role of assemblies in behavior, we trained the rats to perform a task requiring cognitive flexibility, alternating between two different rules in a T-maze. Overall, assembly activations were correlated with task-relevant parameters, including impending choice, reward, rule, or rule order. Moreover, these behavioral correlates were more robustly expressed by assemblies than by their individual member neurons. Finally, to verify whether assemblies can be endogenously generated, we found that they were indeed spontaneously reactivated during sleep and quiet immobility. Thus, cell assemblies are a more general coding mechanism than previously envisioned, linking distributed neocortical and subcortical areas at high synchrony.

Hippocampal ripples as a mode of communication with cortical and subcortical areas.

Hippocampal sharp wave-ripple complexes are transient events of highly synchronous neuronal activity that typically occur during "offline" brain states. This endogenous surge of activity consists of behaviorally relevant spiking patterns, describing spatial trajectories. They have been shown to play a critical role in memory consolidation during sleep and in navigational planning during wakefulness. Beyond their local impact on the hippocampal formation, ripples also exert direct and indirect effects on target cortical and subcortical areas, which are thought to play a key role in information processing and semantic network reconfiguration. We review research into the function of hippocampal sharp waves-ripples, with a special focus on information flow between the hippocampus and its cortical and subcortical targets. First, we briefly review seminal work establishing a causal role of ripple-related activity in cognitive processes. We then review evidence for a functional interplay between hippocampal ripples and specific patterns of cortical and subcortical activity. Finally, we discuss the critical role of the functional coupling between ripples and other sleep rhythms, including the cortical slow oscillation and thalamocortical sleep spindles.

Isolated cortical computations during delta waves support memory consolidation.

Delta waves have been described as periods of generalized silence across the cortex, and their alternation with periods of endogenous activity results in the slow oscillation of slow-wave sleep. Despite evidence that delta waves are instrumental for memory consolidation, their specific role in reshaping cortical functional circuits remains puzzling. In a rat model, we found that delta waves are not periods of complete silence and that the residual activity is not mere neuronal noise. Instead, cortical cells involved in learning a spatial memory task subsequently formed cell assemblies during delta waves in response to transient reactivation of hippocampal ensembles during ripples. This process occurred selectively during endogenous or induced memory consolidation. Thus, delta waves represent isolated cortical computations tightly related to ongoing information processing underlying memory consolidation.

Hippocampal Sequences During Exploration: Mechanisms and Functions.

Although the hippocampus plays a critical role in spatial and episodic memories, the mechanisms underlying memory formation, stabilization, and recall for adaptive behavior remain relatively unknown. During exploration, within single cycles of the ongoing theta rhythm that dominates hippocampal local field potentials, place cells form precisely ordered sequences of activity. These neural sequences result from the integration of both external inputs conveying sensory-motor information, and intrinsic network dynamics possibly related to memory processes. Their endogenous replay during subsequent sleep is critical for memory consolidation. The present review discusses possible mechanisms and functions of hippocampal theta sequences during exploration. We present several lines of evidence suggesting that these neural sequences play a key role in information processing and support the formation of initial memory traces, and discuss potential functional distinctions between neural sequences emerging during theta vs. awake sharp-wave ripples.

Nested sequences of hippocampal assemblies during behavior support subsequent sleep replay.

Consolidation of spatial and episodic memories is thought to rely on replay of neuronal activity sequences during sleep. However, the network dynamics underlying the initial storage of memories during wakefulness have never been tested. Although slow, behavioral time scale sequences have been claimed to sustain sequential memory formation, fast ("theta") time scale sequences, nested within slow sequences, could be instrumental. We found that in rats traveling passively on a model train, place cells formed behavioral time scale sequences but theta sequences were degraded, resulting in impaired subsequent sleep replay. In contrast, when the rats actively ran on a treadmill while being transported on the train, place cells generated clear theta sequences and accurate trajectory replay during sleep. Our results support the view that nested sequences underlie the initial formation of memory traces subsequently consolidated during sleep.

Hippocampo-cortical coupling mediates memory consolidation during sleep.

Memory consolidation is thought to involve a hippocampo-cortical dialog during sleep to stabilize labile memory traces for long-term storage. However, direct evidence supporting this hypothesis is lacking. We dynamically manipulated the temporal coordination between the two structures during sleep following training on a spatial memory task specifically designed to trigger encoding, but not memory consolidation. Reinforcing the endogenous coordination between hippocampal sharp wave-ripples, cortical delta waves and spindles by timed electrical stimulation resulted in a reorganization of prefrontal cortical networks, along with subsequent increased prefrontal responsivity to the task and high recall performance on the next day, contrary to control rats, which performed at chance levels. Our results provide, to the best of our knowledge, the first direct evidence for a causal role of a hippocampo-cortical dialog during sleep in memory consolidation, and indicate that the underlying mechanism involves a fine-tuned coordination between sharp wave-ripples, delta waves and spindles.

Retrospectively and prospectively modulated hippocampal place responses are differentially distributed along a common path in a continuous T-maze.

Hippocampal place responses can be prospectively or retrospectively modulated by the animal's future or prior trajectory. Two main hypotheses explain this. The "multiple-map hypothesis" switches between different maps for different trajectories (rate remapping). In contrast, in the "buffer hypothesis," the hippocampus encodes an ongoing representation that includes the recent past and/or the impending future choice. This study examines the distribution of prospective and retrospective responses distributed along a common path in a continuous T-maze (providing all four combinations of provenance and destination) during a visual discrimination task. The multiple-map hypothesis predicts either uniform distributions or concerted shifts about a task-decision relevant point, whereas the buffer hypothesis predicts a time-limited overexpression around choice points (with retrospective responses after the central arm entry point and prospective responses nearer its exit). Here bilateral recordings in the dorsal CA1 region of the rat hippocampus show that retrospective responses were twice as prevalent as prospective responses. Furthermore, retrospective and prospective modulations have distinct spatial distributions, with retrospective primarily in the first two-thirds of the central arm and prospective restricted to the last third. To test for possible trial-by-trial remapping in relation to the two-thirds transition point, data from the first and second halves of the sessions were compared. Backward drift of path-modulated activity was significant only for retrospective, but not prospective, fields. Thus, these data are more consistent with the buffer hypothesis. Retrospective and prospective modulation would then participate in a single hippocampal representation of spatial and behavioral context.

Learning-induced plasticity regulates hippocampal sharp wave-ripple drive.

Hippocampal sharp wave-ripples (SPW-Rs) and associated place-cell reactivations are crucial for spatial memory consolidation during sleep and rest. However, it remains unclear how learning and consolidation requirements influence and regulate subsequent SPW-R activity. Indeed, SPW-R activity has been observed not only following complex behavioral tasks, but also after random foraging in familiar environments, despite markedly different learning requirements. Because transient increases in SPW-R rates have been reported following training on memory tasks, we hypothesized that SPW-R activity following learning (but not routine behavior) could involve specific regulatory processes related to ongoing consolidation. Interfering with ripples would then result in a dynamic compensatory response only when initial memory traces required consolidation. Here we trained rats on a spatial memory task, and showed that subsequent sleep periods where ripple activity was perturbed by timed electrical stimulation were indeed characterized by increased SPW-R occurrence rates compared with control sleep periods where stimulations were slightly delayed in time and did not interfere with ripples. Importantly, this did not occur following random foraging in a familiar environment. We next showed that this dynamic response was abolished following injection of an NMDA receptor blocker (MK-801) before, but not after training. Our results indicate that NMDA receptor-dependent processes occurring during learning, such as network "tagging" and plastic changes, regulate subsequent ripple-mediated consolidation of spatial memory during sleep.

Reversed theta sequences of hippocampal cell assemblies during backward travel.

Hippocampal cell assemblies coding for past, present and future events form theta-timescale (~100 ms) sequences that represent spatio-temporal episodes. However, the underlying mechanisms remain largely unknown. We recorded hippocampal and entorhinal cortical activity as rats experienced backward travel on a model train. Although the firing fields of place cells remained stable, the order in which they were activated in the theta sequence was reversed during backward travel. Thus, hippocampal cell assemblies coordinated their relative timing to correctly predict the sequential traversal of place fields in reverse order. At the single-cell level, theta phase represented distance traveled through the field, even though the head of the rat was oriented opposite to travel direction and entorhinal head-direction cells maintained their preferred firing direction. Our results challenge most theoretical models of theta sequence generation in the hippocampus.

Optic flow stimuli update anterodorsal thalamus head direction neuronal activity in rats.

Head direction (HD) neurons fire selectively according to head orientation in the yaw plane relative to environmental landmark cues. Head movements provoke optic field flow signals that enter the vestibular nuclei, indicating head velocity, and hence angular displacements. To test whether optic field flow alone affects the directional firing of HD neurons, rats walked about on a circular platform as a spot array was projected onto the surrounding floor-to-ceiling cylindrical black curtain. Directional responses in the anterodorsal thalamus of four rats remained stable as they moved about with the point field but in the absence of landmark cues. Then, the spherical projector was rotated about its yaw axis at 4.5°/s for ∼90 s. In 27 sessions the mean drift speed of the preferred directions (PDs) was 1.48°/s (SD=0.78°/s; range: 0.15 to 2.88°/s). Thus, optic flow stimulation entrained PDs, albeit at drift speeds slower than the field rotation. This could be due to conflicts with vestibular, motor command, and efferent copy signals. After field rotation ended, 20/27 PDs drifted back to within 45° of the initial values over several minutes, generally following the shortest path to return to the initial value. Poststimulation drifts could change speed and/or direction, with mean speeds of 0.68±0.64°/s (range 0 to 1.36°/s). Since the HD cell pathway (containing anterodorsal thalamus) is the only known projection of head direction information to entorhinal grid cells and hippocampal place cells, yaw plane optic flow signals likely influence representations in this spatial reference coordinate system for orientation and navigation.

Dynamics of decision-related activity in hippocampus.

Place-selective activity in hippocampal neurons can be modulated by the trajectory that will be taken in the immediate future ("prospective coding"), information that could be useful in neural processes elaborating choices in route planning. To determine if and how hippocampal prospective neurons participate in decision making, we measured the time course of the evolution of prospective activity by recording place responses in rats performing a T-maze alternation task. After five or seven alternation trials, the routine was unpredictably interrupted by a photodetector-triggered visual cue as the rat crossed the middle of central arm, signaling it to suddenly change its intended choice. Comparison of the delays between light cue presentation and the onset of prospective activity for neurons with firing fields at various locations after the trigger point revealed a 420 ms processing delay. This surprisingly long delay indicates that prospective activity in the hippocampus appears much too late to generate planning or decision signals. This provides yet another example of a prominent brain activity that is unlikely to play a functional role in the cognitive function that it appears to represent (planning future trajectories). Nonetheless, the hippocampus may provide other contextual information to areas active at the earliest stages of selecting future paths, which would then return signals that help establish hippocampal prospective activity.

Hippocampal ripples and memory consolidation.

During slow wave sleep and quiet wakefulness, the hippocampus generates high frequency field oscillations (ripples) during which pyramidal neurons replay previous waking activity in a temporally compressed manner. As a result, reactivated firing patterns occur within shorter time windows propitious for synaptic plasticity within the hippocampal network and in downstream neocortical structures. This is consistent with the long-held view that ripples participate in strengthening and reorganizing memory traces, possibly by mediating information transfer to neocortical areas. Recent studies have confirmed that ripples and associated neuronal reactivations play a causal role in memory consolidation during sleep and rest. However, further research will be necessary to better understand the neurophysiological mechanisms of memory consolidation, in particular the selection of reactivated assemblies, and the functional specificity of awake ripples.

Selective suppression of hippocampal ripples impairs spatial memory.

Sharp wave-ripple (SPW-R) complexes in the hippocampus-entorhinal cortex are believed to be important for transferring labile memories from the hippocampus to the neocortex for long-term storage. We found that selective elimination of SPW-Rs during post-training consolidation periods resulted in performance impairment in rats trained on a hippocampus-dependent spatial memory task. Our results provide evidence for a prominent role of hippocampal SPW-Rs in memory consolidation.

Entrainment of neocortical neurons and gamma oscillations by the hippocampal theta rhythm.

Although it has been tacitly assumed that the hippocampus exerts an influence on neocortical networks, the mechanisms of this process are not well understood. We examined whether and how hippocampal theta oscillations affect neocortical assembly patterns by recording populations of single cells and transient gamma oscillations in multiple cortical regions, including the somatosensory area and prefrontal cortex in behaving rats and mice. Laminar analysis of neocortical gamma bursts revealed multiple gamma oscillators of varying frequency and location, which were spatially confined and synchronized local groups of neurons. A significant fraction of putative pyramidal cells and interneurons as well as localized gamma oscillations in all recorded neocortical areas were phase biased by the hippocampal theta rhythm. We hypothesize that temporal coordination of neocortical gamma oscillators by hippocampal theta is a mechanism by which information contained in spatially widespread neocortical assemblies can be synchronously transferred to the associative networks of the hippocampus.

Hippocampal place cell assemblies are speed-controlled oscillators.

The phase of spikes of hippocampal pyramidal cells relative to the local field theta oscillation shifts forward ("phase precession") over a full theta cycle as the animal crosses the cell's receptive field ("place field"). The linear relationship between the phase of the spikes and the travel distance within the place field is independent of the animal's running speed. This invariance of the phase-distance relationship is likely to be important for coordinated activity of hippocampal cells and space coding, yet the mechanism responsible for it is not known. Here we show that at faster running speeds place cells are active for fewer theta cycles but oscillate at a higher frequency and emit more spikes per cycle. As a result, the phase shift of spikes from cycle to cycle (i.e., temporal precession slope) is faster, yet spatial-phase precession stays unchanged. Interneurons can also show transient-phase precession and contribute to the formation of coherently precessing assemblies. We hypothesize that the speed-correlated acceleration of place cell assembly oscillation is responsible for the phase-distance invariance of hippocampal place cells.

Klusters, NeuroScope, NDManager: a free software suite for neurophysiological data processing and visualization.

Recent technological advances now allow for simultaneous recording of large populations of anatomically distributed neurons in behaving animals. The free software package described here was designed to help neurophysiologists process and view recorded data in an efficient and user-friendly manner. This package consists of several well-integrated applications, including NeuroScope (http://neuroscope.sourceforce.net), an advanced viewer for electrophysiological and behavioral data with limited editing capabilities, Klusters (http://klusters.sourceforge.net), a graphical cluster cutting application for manual and semi-automatic spike sorting, NDManager (GPL,see http://www.gnu.org/licenses/gpl.html), an experimental parameter and data processing manager. All of these programs are distributed under the GNU General Public License (GPL, see ), which gives its users legal permission to copy, distribute and/or modify the software. Also included are extensive user manuals and sample data, as well as source code and documentation.

Passive movements of the head do not abolish anticipatory firing properties of head direction cells.

Neurons in the anterior dorsal thalamic nucleus (ADN) of the rat selectively discharge in relation to the animal's head direction (HD) in the horizontal plane. Temporal analyses of cell firing properties reveal that their discharge is optimally correlated with the animal's future directional heading by approximately 24 ms. Among the hypotheses proposed to explain this property is that ADN HD cells are informed of future head movement via motor efference copy signals. One prediction of this hypothesis is that when the rat's head is moved passively, the anticipatory time interval (ATI) will be attenuated because the motor efference signal reflects only the active contribution to the movement. The present study tested this hypothesis by loosely restraining the animal and passively rotating it through the cell's preferred direction. Contrary to our prediction, we found that ATI values did not decrease during passive movement but in fact increased significantly. HD cells in the postsubiculum did not show the same effect, suggesting independence between the two sites with respect to anticipatory firing. We conclude that it is unlikely that a motor efference copy signal alone is responsible for generating anticipatory firing in ADN HD cells.

Spike phase precession persists after transient intrahippocampal perturbation.

Oscillatory spike timing in the hippocampus is regarded as a temporal coding mechanism for space, but the underlying mechanisms are poorly understood. To contrast the predictions of the different models of phase precession, we transiently turned off neuronal discharges for up to 250 ms and reset the phase of theta oscillations by stimulating the commissural pathway in rats. After recovery from silence, phase precession continued. The phase of spikes for the first theta cycle after the perturbation was more advanced than the phase of spikes for the last theta cycle just before the perturbation. These findings indicate that phase advancement that emerges within hippocampal circuitry may be updated at the beginning of each theta cycle by extrahippocampal inputs.