Michaël B. Zugaro

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.

Hippocampal place cell assemblies are speed-controlled oscillators

The phase of spikes of hippocampal pyramidal cells relative to the local field θ oscillation shifts forward (“phase precession”) over a full θ cycle as the animal crosses the cells 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 animals 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 θ 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.

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.

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.

Multisensory processing in the elaboration of place and head direction responses by limbic system neurons.

This review explores the roles of several sensory modalities in the establishment and maintenance of discharges correlated with head position and orientation in neurons of the hippocampus and associated structures in the Papez circuit. Focus is placed on the integration of signals related to environmental cues and to displacement movements, both of external and internal origin. While the visual, vestibular and motor systems each exert influences, position and head direction signals are nevertheless maintained in the absence of any one of these respective inputs. Context-related changes in hippocampal discharge correlates are also highlighted. These characteristics provide these signals with robustness and flexibility, properties particularly suited for cognitive processes such as contextual processing, memory and planning.

Lesions of the medial shell of the nucleus accumbens impair rats in finding larger rewards, but spare reward-seeking behavior.

The goal of this study was to help better understand the importance of the nucleus accumbens (Nacc) in the processing of position and reward value information for goal-directed orientation behaviors. Sixteen male Long-Evans rats, under partial water deprivation, were trained in a plus-maze to find water rewards in the respective arms which were lit in pseudo-random sequence (training trials). Each day one reward arm was selected to deliver six drops of water (at 1 s intervals) the others provided only one drop per visit. After 32 visits, probe trials were intermittently presented among training trials. Here, all four arms were lit and offered the previously assigned reward. The rats rapidly learned to go to the highly rewarded arm. Six trained rats were given bilateral electrolytic lesions in the Nacc shell, two others had unilateral lesions and eight had sham operations (with approved protocols). Field potentials evoked by fornix stimulation were recorded in lesion electrodes to guide placements. Only the lesioned rats showed significant impairments (P<0.05) in selecting the greater reward on probe trials. However on training trials, lesioned (and sham-operated) rats made only rare errors. While the motivation to drink and the capacity for cue-guided goal-directed orientation behavior was spared, lesioned rats were impaired in learning the location of the larger reward. The accumbens lesions apparently impaired integration of position and reward value information, consistent with anatomical and electrophysiological data showing the convergence of hippocampal, amygdalar, ventral tegmental area (VTA) and prefrontal cortical inputs there.

Rat anterodorsal thalamic head direction neurons depend upon dynamic visual signals to select anchoring landmark cues.

Head direction cells, which are functionally coupled to ‘place’ cells of the hippocampus, a structure critically involved in spatial cognition, are likely neural substrates for the sense of direction. Here we studied the mechanism by which head direction cells are principally anchored to background visual cues [M.B. Zugaro et al. (2001) J. Neurosci., 21, RC154,1–5]. Anterodorsal thalamic head direction cells were recorded while the rat foraged on a small elevated platform in a 3‐m diameter cylindrical enclosure. A large card was placed in the background, near the curtain, and a smaller card was placed in the foreground, near the platform. The cards were identically marked, proportionally dimensioned, subtended the same visual angles from the central vantage point and separated by 90°. The rat was then disoriented in darkness, the cards were rotated by 90° in opposite directions about the center and the rat was returned. Preferred directions followed either the background card, foreground card or midpoint between the two cards. In continuous lighting, preferred directions shifted to follow the background cue in most cases (30 of the 53 experiments, Batschelet V‐test, P < 0.01). Stroboscopic illumination, which perturbs dynamic visual signals (e.g. motion parallax), blocked this selectivity. Head direction cells remained equally anchored to the background card, foreground card or configuration of the two cards (Watson test, P > 0.1). This shows that dynamic visual signals are critical in distinguishing typically more stable background cues which govern spatial neuronal responses and orientation behaviors.

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.

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.

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 animals 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.