Disruption of ripple‐associated hippocampal activity during rest impairs spatial learning in the rat

The hippocampus plays a key role in the acquisition of new memories for places and events. Evidence suggests that the consolidation of these memories is enhanced during sleep. At the neuronal level, reactivation of awake experience in the hippocampus during sharp‐wave ripple events, characteristic of slow‐wave sleep, has been proposed as a neural mechanism for sleep‐dependent memory consolidation. However, a causal relation between sleep reactivation and memory consolidation has not been established. Here we show that disrupting neuronal activity during ripple events impairs spatial learning. We trained rats daily in two identical spatial navigation tasks followed each by a 1‐hour rest period. After one of the tasks, stimulation of hippocampal afferents selectively disrupted neuronal activity associated with ripple events without changing the sleep‐wake structure. Rats learned the control task significantly faster than the task followed by rest stimulation, indicating that interfering with hippocampal processing during sleep led to decreased learning. © 2009 Wiley‐Liss, Inc.     

The effects of sleep on the neural correlates of pattern separation

Effective memory representations must be specific to prevent interference between episodes that may overlap in terms of place, time, or items present. Pattern separation, a computational process performed by the hippocampus, overcomes this interference by establishing nonoverlapping memory representations. Although it is widely accepted that declarative memories are consolidated during sleep, the effects of sleep on pattern separation have yet to be elucidated. We used whole‐brain, high‐resolution functional neuroimaging to investigate the effects of sleep on a task that places high demands on pattern separation. Sleep had a selective effect on memory specificity and not general recognition memory. Activity in brain regions related to memory retrieval and cognitive control demonstrated an interaction between sleep and delay. Surprisingly, there was no effect of sleep on hippocampal activity using a group‐level analysis. To further understand the role of the hippocampus on our task, we performed a representational similarity analysis, which showed that hippocampal activation was biased toward pattern separation relative to cortical activation and that this bias increased following a delay (regardless of sleep). Cortical activation, conversely, was biased toward pattern completion and this bias was preferentially enhanced by sleep.     

Involvement of hippocampal extracellular signal-regulated kinase 1/2 in spatial working memory in rats

The role of the phosphorylation of hippocampal extracellular signal-regulated kinase 1/2 in spatial working memory in rats was assessed with a delayed spatial win-shift task in a radial arm maze. The task consisted of two phases, a training phase and a test phase, separated by a delay. Phosphorylated extracellular signal-regulated kinase 1/2 levels were significantly and transiently increased in the hippocampus by 60 min, and then returned to the control levels 120 min after the training phase. Bilateral microinjections of the PD98059, an inhibitor of the extracellular signal-regulated kinase 1/2 kinase MEK, into the hippocampus impaired performance in the test phase of the delayed spatial win-shift task at 5-min delay. These results suggest that extracellular signal-regulated kinase 1/2 activation in the hippocampus plays a crucial role in spatial working memory.     

Functional connectivity of hippocampal and prefrontal networks during episodic and spatial memory based on real‐world environments

Several recent studies have compared episodic and spatial memory in neuroimaging paradigms in order to understand better the contribution of the hippocampus to each of these tasks. In the present study, we build on previous findings showing common neural activation in default network areas during episodic and spatial memory tasks based on familiar, real‐world environments (Hirshhorn et al. (2012) Neuropsychologia 50:3094–3106). Following previous demonstrations of the presence of functionally connected sub‐networks within the default network, we performed seed‐based functional connectivity analyses to determine how, depending on the task, the hippocampus and prefrontal cortex differentially couple with one another and with distinct whole‐brain networks. We found evidence for a medial prefrontal‐parietal network and a medial temporal lobe network, which were functionally connected to the prefrontal and hippocampal seeds, respectively, regardless of the nature of the memory task. However, these two networks were functionally connected with one another during the episodic memory task, but not during spatial memory tasks. Replicating previous reports of fractionation of the default network into stable sub‐networks, this study also shows how these sub‐networks may flexibly couple and uncouple with one another based on task demands. These findings support the hypothesis that episodic memory and spatial memory share a common medial temporal lobe‐based neural substrate, with episodic memory recruiting additional prefrontal sub‐networks. © 2014 Wiley Periodicals, Inc.     

Evaluating the temporal context of episodic memory: the role of CA3 and CA1

It has been suggested that the hippocampus mediates episodic memory processing involving snapshot memory and temporal sequence learning. To test this theory, rats learned trial-unique sequences of spatial locations along a runway box and were tested on recall by removing one of the locations in the sequence and making the rat choose the correct location to be rewarded. Once animals were able to reliably perform this episodic memory task, they received lesions to either CA3 or CA1. Animals with lesions to either CA3 or CA1 had difficulty with episodic memory processing, although CA1 lesioned animals had a much greater deficit. However, when animals were trained on a non-episodic version of the same task, hippocampal lesions had no effect. These results suggest that CA3 and CA1 both contribute to episodic memory processing since lesions to CA3 or CA1 result in an inability to process spatial information episodically, whereas they have no effect on non-episodic information processing.     

Visual presentation of novel objects and new spatial arrangements of objects differentially activates the medial temporal lobe subareas in humans

A number of studies in rodents and monkeys report a distinction between the contributions of the hippocampus and perirhinal cortex to memory, such that the hippocampus is crucial for spatial memory whereas the perirhinal cortex has a pivotal role in perception and memory for visual objects. To determine if there is such a distinction in humans, we conducted a functional magnetic resonance imaging study to compare the medial temporal lobe responses to changes in object identity and spatial configurations of objects. We found evidence for the predicted distinction between hippocampal and perirhinal cortical activations, although part of the hippocampus was also activated by identification of novel objects. Additionally, an anterior-posterior activation gradient emerged inside the hippocampus and parahippocampal cortex. The anterior hippocampus, perirhinal cortex and anterior parahippocampal cortex are involved in perception of contextually novel objects, whereas the posterior hippocampus and posterior parahippocampal cortex are involved in processing of novel arrangements of familiar objects. These results demonstrate that there is a functional dissociation between processing of novel object identities and new spatial locations of objects among the subregions of medial temporal lobe structures in humans also.     

Ventral hippocampal involvement in temporal order, but not recognition, memory for spatial information

The hippocampus is critical for spatial memory. Recently, subregional differences in the function of hippocampus have been described in a number of behavioral tasks. The present experiments assessed the effects of reversibly lesioning either the dorsal (dHip) or ventral hippocampus (vHip) on spontaneous tests of spatial recognition and temporal order memory. We report that although the dHip is necessary for spatial recognition memory (RM) (distinguishing a novel from a familiar spatial location), the vHip is involved in temporal order memory (the capacity to distinguish between two spatial locations visited at different points in time), but not RM. These findings and others are consistent with the hypothesis that temporal order memory is supported by an integrated circuit of limbic areas including the vHip and the medial prefrontal cortex.     

Processing idiothetic cues to remember visited locations: hippocampal and vestibular contributions to radial-arm maze performance

This research examined whether rats can use idiothetic cues to form spatial memories in the radial-arm maze (RM) and whether the hippocampus is involved in such ability. A possible contribution of the vestibular system to RM performance was also investigated. Rats with excitotoxic hippocampal lesions and sham-operated controls were trained on two versions of the RM task. In the Light condition, a unique visual insert was apposed on each arm floor and rats could choose which arm to enter next by relying on visual and/or idiothetic stimuli. In the Dark condition, the task was administered in darkness and success required processing of idiothetic cues to remember visited locations on the maze. In experiment 1, the performance of lesioned rats was impaired in the Light condition, but both control and lesioned rats learned to avoid already visited arms. In the Dark condition, the performance of controls improved over time whereas a severe deficit was observed in rats with hippocampal lesions. Thus, control rats, but not hippocampal lesioned rats, can form spatial memories by processing idiothetic inputs. Experiment 2 showed that vestibular lesions disrupt performance in both the Light and the Dark conditions and confirmed that rats use idiothetic information, especially vestibular cues, while navigating in the RM. Therefore, cues generated during locomotion play an important role in hippocampal-dependent spatial memory.     

Impaired hippocampal function during the detection of novel words in schizophrenia.

BACKGROUND: Patients with schizophrenia have smaller hippocampal volumes and perform abnormally on most declarative memory tasks. Although these findings are likely related, the impact of hippocampal pathology on cognitive performance in schizophrenia remains unclear. This study examined this relationship by measuring the volume of the hippocampus and its activation during memory task performance. METHODS: Participants included 15 patients with schizophrenia and 16 age-matched control subjects. Hippocampal volume was determined via three-dimensional volumetric analysis of high-resolution magnetic resonance images. Hippocampal activity was assessed by measuring changes in blood oxygen level-dependent signal during a recognition memory task. RESULTS: Patients with schizophrenia had smaller hippocampal volumes bilaterally and demonstrated poorer performance on the recognition memory task, largely because of a heightened rate of false alarms to novel stimuli. Both groups showed robust hippocampal activity to old and new items when compared with a low-level baseline task; however, direct comparison of hippocampal activity during recognition task performance revealed that healthy control, but not the schizophrenia, subjects showed significant right anterior hippocampal activation during the evaluation of novel items. CONCLUSIONS: The impaired ability to classify new items as previously not experienced is associated with decreased recruitment and smaller volume of the hippocampus in schizophrenia.     

Spatial Learning Drives Rapid Goal Representation in Hippocampal Ripples without Place Field Accumulation or Goal-Oriented Theta Sequences

The hippocampus is critical for rapid acquisition of many forms of memory, although the circuit-level mechanisms through which the hippocampus rapidly consolidates novel information are unknown. Here, the activity of large ensembles of hippocampal neurons in adult male Long-Evans rats was monitored across a period of rapid spatial learning to assess how the network changes during the initial phases of memory formation and retrieval. In contrast to several reports, the hippocampal network did not display enhanced representation of the goal location via accumulation of place fields or elevated firing rates at the goal. Rather, population activity rates increased globally as a function of experience. These alterations in activity were mirrored in the power of the theta oscillation and in the quality of theta sequences, without preferential encoding of paths to the learned goal location. In contrast, during brief “offline” pauses in movement, representation of a novel goal location emerged rapidly in ripples, preceding other changes in network activity. These data demonstrate that the hippocampal network can facilitate active navigation without enhanced goal representation during periods of active movement, and further indicate that goal representation in hippocampal ripples before movement onset supports subsequent navigation, possibly through activation of downstream cortical networks.SIGNIFICANCE STATEMENT Understanding the mechanisms through which the networks of the brain rapidly assimilate information and use previously learned knowledge are fundamental areas of focus in neuroscience. In particular, the hippocampal circuit is a critical region for rapid formation and use of spatial memory. In this study, several circuit-level features of hippocampal function were quantified while rats performed a spatial navigation task requiring rapid memory formation and use. During periods of active navigation, a general increase in overall network activity is observed during memory acquisition, which plateaus during memory retrieval periods, without specific enhanced representation of the goal location. During pauses in navigation, rapid representation of the distant goal well emerges before either behavioral improvement or changes in online activity.     

Effects of hippocampal lesions on patterned motor learning in the rat

Motor skill learning in rats has been linked to cerebellar function as well as to cortical and striatal influences. The present study evaluated the contribution of the hippocampus to motor learning. Adult male rats received electrolytic lesions designed to selectively destroy the hippocampus; a sham-lesioned group of animals served as a control. The animals with hippocampal lesions acquired a patterned motor learning task as well as sham controls. In contrast, rats with hippocampal lesions were impaired in spatial, but not cued, learning in the Morris water maze. In addition, lesioned rats showed profound impairment in the novel object recognition memory task, when a 1-h delay was used between training and testing. Taken together, these results suggest that the hippocampus is not necessary during acquisition of the motor learning task.     

Double dissociation between the contributions of the septal and temporal hippocampus to spatial learning: The role of prior experience

The mammalian hippocampus is anatomically heterogeneous along its longitudinal axis, and there is evidence that distinct functions are executed by different septotemporal subregions. The best documented example is the dependency of spatial learning on the septal, but not the temporal, hippocampus. Here, we carried out a watermaze memory task in rats with partial lesions of the septal or temporal hippocampus made either before or after training. We then studied memory retention, reversal, and new spatial learning in a novel environment. This resulted in the surprising finding that spatial learning in a new environment is dependent on the temporal hippocampus in rats with preoperative experience of a different pool. Rats with septal hippocampal lesions made after learning not only retained the focused search strategy that was acquired during preoperative training, but were also capable of rapid spatial learning in a second pool. This demonstrates that once spatial information has been acquired in one context, related new learning in a different context can be mediated by the temporal hippocampus, a result that challenges the widely held view that spatial memory is an exclusive function of the septal hippocampus. © 2014 Wiley Periodicals, Inc.     

Retrograde amnesia: neither partial nor complete hippocampal lesions in rats result in preferential sparing of remote spatial memory, even after reminding

Many lesion experiments have provided evidence that the hippocampus plays a time-limited role in memory, consistent with the operation of a systems-level memory consolidation process during which lasting neocortical memory traces become established [see Squire, L. R., Clark, R. E., & Knowlton, B. J. (2001). Retrograde amnesia. Hippocampus 11, 50]. However, large lesions of the hippocampus at different time intervals after acquisition of a watermaze spatial reference memory task have consistently resulted in temporally ungraded retrograde amnesia [Bolhuis, J. J., Stewart, C. A., Forrest, E. M. (1994). Retrograde amnesia and memory reactivation in rats with ibotenate lesions to the hippocampus or subiculum. Quarterly Journal of Experimental Psychology 47B, 129; Mumby, D. G., Astur, R. S., Weisend, M. P., Sutherland, R. J. (1999). Retrograde amnesia and selective damage to the hippocampal formation: memory for places and object discriminations. Behavioural Brain Research 106, 97; Sutherland, R. J., Weisend, M. P., Mumby, D., Astur, R. S., Hanlon, F. M., et al. (2001). Retrograde amnesia after hippocampal damage: recent vs. remote memories in two tasks. Hippocampus 11, 27]. It is possible that spatial memories acquired during such a task remain permanently dependent on the hippocampus, that chance performance may reflect a failure to access memory traces that are initially unexpressed but still present, or that graded retrograde amnesia for spatial information might only be observed following partial hippocampal lesions. This study examined the retrograde memory impairments of rats that received either partial or complete lesions of the hippocampus either 1-2 days, or 6 weeks after training in a watermaze reference memory task. Memory retention was assessed using a novel 'reminding' procedure consisting of a series of rewarded probe trials, allowing the measurement of both free recall and memory reactivation. Rats with complete hippocampal lesions exhibited stable, temporally ungraded retrograde amnesia, and could not be reminded of the correct location. Partially lesioned rats could be reminded of a recently learned platform location, but no recovery of remote memory was observed. These results offer no support for hippocampus-dependent consolidation of allocentric spatial information, and suggest that the hippocampus can play a long-lasting role in spatial memory. The nature of this role--in the storage, retrieval, or expression of memory--is discussed.     

A double dissociation of dorsal and ventral hippocampal function on a learning and memory task mediated by the dorso-lateral striatum

The objectives of this research were to further delineate the neural circuits subserving proposed memory-based behavioural subsystems in the hippocampal formation. These studies were guided by anatomical evidence showing a topographical organization of the hippocampal formation. Briefly, perpendicular to the medial/lateral entorhinal cortex division there is a second system of parallel circuits that separates the dorsal and ventral hippocampus. Recent work from this laboratory has provided evidence that the hippocampus incidentally encodes a context-specific inhibitory association during acquisition of a visual discrimination task. One question that emerges from this dataset is whether the dorsal or ventral hippocampus makes a unique contribution to this newly described function. Rats with neurotoxic lesions of the dorsal or ventral hippocampus were assessed on the acquisition of the visual discrimination task. Following asymptotic performance they were given reversal training in either the same or a different context from the original training. The results showed that the context-specific inhibition effect is mediated by a circuit that includes the ventral but not the dorsal hippocampus. Results from a control procedure showed that rats with either dorso-lateral striatum damage or dorsal hippocampal lesions were impaired on a tactile/spatial discrimination. Taken together, the results represent a double dissociation of learning and memory function between the ventral and dorsal hippocampus. The formation of an incidental inhibitory association was dependent on ventral but not dorsal hippocampal circuitry, and the opposite dependence was found for the spatial component of a tactile/spatial discrimination.     

Unilateral hippocampal blockade reveals that one hippocampus is sufficient for learning a passive avoidance task

Understanding hippocampal participation in memory processes is one of the goals in neuroscience research. By blocking the hippocampus unilaterally in Wistar rats, we assessed the contribution of this brain structure to memory in a passive avoidance task. Subjects were distributed into four groups. Group 1 received tetrodotoxin (TTX) in the right hippocampus during acquisition and retrieval phases. Group 2 had the same procedure as group 1, except that the contralateral hippocampus was blocked during retrieval. Subjects from group 3 acquired the task with saline (both hippocampi intact) and retrieved with the right hippocampus inactivated. Finally, group 4 received TTX unilaterally 2 min after acquisition to determine the hippocampal role in consolidation. Results showed that group 2 was impaired, compared with the other groups, during retrieval. These findings reveal that the hippocampal contribution to this task differs from that in other tasks considered to be hippocampus dependent.     

Impaired spatial and non-spatial configural learning in patients with hippocampal pathology

The hippocampus has been proposed to play a critical role in memory through its unique ability to bind together the disparate elements of an experience. This hypothesis has been widely examined in rodents using a class of tasks known as "configural" or "non-linear", where outcomes are determined by specific combinations of elements, rather than any single element alone. On the basis of equivocal evidence that hippocampal lesions impair performance on non-spatial configural tasks, it has been proposed that the hippocampus may only be critical for spatial configural learning. Surprisingly few studies in humans have examined the role of the hippocampus in solving configural problems. In particular, no previous study has directly assessed the human hippocampal contribution to non-spatial and spatial configural learning, the focus of the current study. Our results show that patients with primary damage to the hippocampus bilaterally were similarly impaired at configural learning within both spatial and non-spatial domains. Our data also provide evidence that residual configural learning can occur in the presence of significant hippocampal dysfunction. Moreover, evidence obtained from a post-experimental debriefing session suggested that patients acquired declarative knowledge of the underlying task contingencies that corresponded to the best-fit strategy identified by our strategy analysis. In summary, our findings support the notion that the hippocampus plays an important role in both spatial and non-spatial configural learning, and provide insights into the role of the medial temporal lobe (MTL) more generally in incremental reinforcement-driven learning.     

Rest boosts the long‐term retention of spatial associative and temporal order information

People retain more new verbal episodic information for at least 7 days if they rest for a few minutes after learning than if they attend to new information. It is hypothesized that rest allows for superior consolidation of new memories. In rodents, rest periods promote hippocampal replay of a recently travelled route, and this replay is thought to be critical for memory consolidation and subsequent spatial navigation. If rest boosts human memory by promoting hippocampal replay/consolidation, then the beneficial effect of rest should extend to complex (hippocampal) memory tasks, for example, tasks probing associations and sequences. We investigated this question via a virtual reality route memory task. Healthy young participants learned two routes to a 100% criterion. One route was followed by a 10‐min rest and the other by a 10‐min spot the difference game. For each learned route, participants performed four delayed spatial memory tests probing: (i) associative (landmark‐direction) memory, (ii) cognitive map formation, (iii) temporal (landmark) order memory, and (iv) route memory. Tests were repeated after 7 days to determine any long‐term effects. No effect of rest was detected in the route memory or cognitive map tests, most likely due to ceiling and floor effects, respectively. Rest did, however, boost retention in the associative memory and temporal order memory tests, and this boost remained for at least 7 days. We therefore demonstrate that the benefit of rest extends to (spatial) associative and temporal order memory in humans. We hypothesise that rest allows superior consolidation/hippocampal replay of novel information pertaining to a recently learned route, thus boosting new memories over the long term. © 2015 Wiley Periodicals, Inc.     

Object and spatial alternation tasks with minimal delays activate the right anterior hippocampus proper in humans

Substantial evidence indicates that the hippocampus plays a critical role in long-term declarative memory. In contrast, the role of the human hippocampus in working memory, particularly when information needs to be maintained only for a few seconds, remains controversial. Using PET, we show robust activation of the right anterior hippocampus proper during the performance of both object and spatial alternation tasks. Hippocampal activation emerged even though subjects only had to remember a single, simple stimulus over a minimum delay of 1 s. No hippocampal activation occurred when the delay was increased to 5 s. This suggests that the role of the hippocampus in working memory is not to maintain information across a delay interval. Instead, its activity reflects a more transient function during encoding and/or retrieval. These data are among the first observations to demonstrate human hippocampal involvement in working memory.     

Human Hippocampal Neurons Track Moments in a Sequence of Events

An indispensable feature of episodic memory is our ability to temporally piece together different elements of an experience into a coherent memory. Hippocampal time cells—neurons that represent temporal information—may play a critical role in this process. Although these cells have been repeatedly found in rodents, it is still unclear to what extent similar temporal selectivity exists in the human hippocampus. Here, we show that temporal context modulates the firing activity of human hippocampal neurons during structured temporal experiences. We recorded neuronal activity in the human brain while patients of either sex learned predictable sequences of pictures. We report that human time cells fire at successive moments in this task. Furthermore, time cells also signaled inherently changing temporal contexts during empty 10 s gap periods between trials while participants waited for the task to resume. Finally, population activity allowed for decoding temporal epoch identity, both during sequence learning and during the gap periods. These findings suggest that human hippocampal neurons could play an essential role in temporally organizing distinct moments of an experience in episodic memory.SIGNIFICANCE STATEMENT Episodic memory refers to our ability to remember the what, where, and when of a past experience. Representing time is an important component of this form of memory. Here, we show that neurons in the human hippocampus represent temporal information. This temporal signature was observed both when participants were actively engaged in a memory task, as well as during 10-s-long gaps when they were asked to wait before performing the task. Furthermore, the activity of the population of hippocampal cells allowed for decoding one temporal epoch from another. These results suggest a robust representation of time in the human hippocampus.     

Genetic deletion of melanin‐concentrating hormone neurons impairs hippocampal short‐term synaptic plasticity and hippocampal‐dependent forms of short‐term memory

The cognitive role of melanin‐concentrating hormone (MCH) neurons, a neuronal population located in the mammalian postero‐lateral hypothalamus sending projections to all cortical areas, remains poorly understood. Mainly activated during paradoxical sleep (PS), MCH neurons have been implicated in sleep regulation. The genetic deletion of the only known MCH receptor in rodent leads to an impairment of hippocampal dependent forms of memory and to an alteration of hippocampal long‐term synaptic plasticity. By using MCH/ataxin3 mice, a genetic model characterized by a selective deletion of MCH neurons in the adult, we investigated the role of MCH neurons in hippocampal synaptic plasticity and hippocampal‐dependent forms of memory. MCH/ataxin3 mice exhibited a deficit in the early part of both long‐term potentiation and depression in the CA1 area of the hippocampus. Post‐tetanic potentiation (PTP) was diminished while synaptic depression induced by repetitive stimulation was enhanced suggesting an alteration of pre‐synaptic forms of short‐term plasticity in these mice. Behaviorally, MCH/ataxin3 mice spent more time and showed a higher level of hesitation as compared to their controls in performing a short‐term memory T‐maze task, displayed retardation in acquiring a reference memory task in a Morris water maze, and showed a habituation deficit in an open field task. Deletion of MCH neurons could thus alter spatial short‐term memory by impairing short‐term plasticity in the hippocampus. Altogether, these findings could provide a cellular mechanism by which PS may facilitate memory encoding. Via MCH neuron activation, PS could prepare the day's learning by increasing and modulating short‐term synaptic plasticity in the hippocampus. © 2015 Wiley Periodicals, Inc.