Low rate hippocampal delay period activity encodes behavioral experience.

Remembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.

Directional Tuning of Phase Precession Properties in the Hippocampus.

Running direction in the hippocampus is encoded by rate modulations of place field activity but also by spike timing correlations known as theta sequences. Whether directional rate codes and the directionality of place field correlations are related, however, has so far not been explored, and therefore the nature of how directional information is encoded in the cornu ammonis remains unresolved. Here, using a previously published dataset that contains the spike activity of rat hippocampal place cells in the CA1, CA2, and CA3 subregions during free foraging of male Long-Evans rats in a 2D environment, we found that rate and spike timing codes are related. Opposite to a preferred firing rate direction of a place field, spikes are more likely to undergo theta phase precession and, hence, more strongly affect paired correlations. Furthermore, we identified a subset of field pairs whose theta correlations are intrinsic in that they maintain the same firing order when the running direction is reversed. Both effects are associated with differences in theta phase distributions and are more prominent in CA3 than in CA1. We thus hypothesize that intrinsic spiking is most prominent when the directionally modulated sensory-motor drive of hippocampal firing rates is minimal, suggesting that extrinsic and intrinsic sequences contribute to phase precession as two distinct mechanisms.SIGNIFICANCE STATEMENT Hippocampal theta sequences, on the one hand, are thought to reflect the running trajectory of an animal, connecting past and future locations. On the other hand, sequences have been proposed to reflect the rich, recursive hippocampal connectivity, related to memories of previous trajectories or even to experience-independent prestructure. Such intrinsic sequences are inherently one dimensional and cannot be easily reconciled with running trajectories in two dimensions as place fields can be approached on multiple one-dimensional paths. In this article, we dissect phase precession along different directions in all hippocampal subareas and find that CA3 in particular shows a high level of direction-independent correlations that are inconsistent with the notion of representing running trajectories. These intrinsic correlations are associated with later spike phases.

Stability of medial entorhinal cortex representations over time.

Distinct functional cell types in the medial entorhinal cortex (mEC) have been shown to represent different aspects of experiences. To further characterize mEC cell populations, we examined whether spatial representations of neurons in mEC superficial layers depended on the scale of the environment and changed over extended time periods. Accordingly, mEC cells were recorded while rats repeatedly foraged in a small or a large environment in sessions that were separated by time intervals from minutes to hours. Comparing between large and small environments, we found that the overall precision of grid and non-grid cell spatial maps was higher in smaller environments. When examining the stability of spatial firing patterns over time, differences and similarities were observed across cell types. Within-session stability was higher for grid cells than for non-grid cell populations. Despite differences in baseline stability between cell types, stability levels remained consistent over time between sessions, up to 1 hr. Even for sessions separated by 6 hrs, activity patterns of grid cells and of most non-grid cells lacked any systematic decrease in spatial similarity over time. However, a subset of ~15% of mEC non-grid cells recorded preferentially from layer III exhibited dramatic, time dependent changes in firing patterns across 6 hrs, reminiscent of previous characterizations of the hippocampal CA2 subregion. Collectively, our data suggest that mEC grid cell input to hippocampus in conjunction with many time invariant non-grid cells may aid in stabilizing hippocampal spatial maps, while a subset of time varying non-grid cells could provide complementary temporal information.

Temporal coding and rate remapping: Representation of nonspatial information in the hippocampus.

Hippocampal place cells represent nonspatial information through a process called rate remapping, which involves a change in the firing rate of a place cell without changes in its spatial specificity. However, many hippocampal phenomena occur on very short time scales over which long-term average firing rates are not an appropriate description of activity. To understand how rate remapping relates to fine-scale temporal firing phenomena, we asked how rate remapping affected burst firing and trial-to-trial spike count variability. In addition, we looked at how rate remapping relates to the theta-frequency oscillations of the hippocampus, which are thought to temporally organize firing on time scales faster than 100 ms. We found that theta phase coding was preserved through changes in firing rate due to rate remapping. Interestingly, rate remapping in CA1 in response to task demands preferentially occurred during the first half of the theta cycle. The other half of the theta cycle contained preferential expression of phase precession, a phenomenon associated with place cell sequences, in agreement with previous results. This difference of place cell coding during different halves of the theta cycle supports recent theoretical suggestions that different processes occur during the two halves of the theta cycle. The differentiation between the halves of the theta cycle was not clear in recordings from CA3 during rate remapping induced by task-irrelevant sensory changes. These findings provide new insight into the way that temporal coding is utilized in the hippocampus and how rate remapping is expressed through that temporal code.

The hippocampal code for space in Mongolian gerbils.

Large parts of our knowledge about the physiology of the hippocampus in the intact brain are derived from studies in rats and mice. While many of those findings fit well to the limited data available from humans and primates, there are also marked differences, for example, in hippocampal oscillation frequencies and in the persistence of theta oscillations. To test whether the distinct sensory specializations of the visual and auditory system of primates play a key role in explaining these differences, we recorded basic hippocampal physiological properties in Mongolian gerbils, a rodent species with high visual acuity, and good low-frequency hearing, similar to humans. We found that gerbils show only minor differences to rats regarding hippocampal place field activity, theta properties (frequency, persistence, phase precession, theta compression), and sharp wave ripple events. The only major difference between rats and gerbils was a considerably higher degree of head direction selectivity of gerbil place fields, which may be explained by their visual system being able to better resolve distant cues. Thus, differences in sensory specializations between rodent species only affect hippocampal circuit dynamics to a minor extent, which implies that differences to other mammalian lineages, such as bats and primates, cannot be solely explained by specialization in the auditory or visual system.

Brain State Is a Major Factor in Preseizure Hippocampal Network Activity and Influences Success of Seizure Intervention.

Neural dynamics preceding seizures are of interest because they may shed light on mechanisms of seizure generation and could be predictive. In healthy animals, hippocampal network activity is shaped by behavioral brain state and, in epilepsy, seizures selectively emerge during specific brain states. To determine the degree to which changes in network dynamics before seizure are pathological or reflect ongoing fluctuations in brain state, dorsal hippocampal neurons were recorded during spontaneous seizures in a rat model of temporal lobe epilepsy. Seizures emerged from all brain states, but with a greater likelihood after REM sleep, potentially due to an observed increase in baseline excitability during periods of REM compared with other brains states also characterized by sustained theta oscillations. When comparing the firing patterns of the same neurons across brain states associated with and without seizures, activity dynamics before seizures followed patterns typical of the ongoing brain state, or brain state transitions, and did not differ until the onset of the electrographic seizure. Next, we tested whether disparate activity patterns during distinct brain states would influence the effectiveness of optogenetic curtailment of hippocampal seizures in a mouse model of temporal lobe epilepsy. Optogenetic curtailment was significantly more effective for seizures preceded by non-theta states compared with seizures that emerged from theta states. Our results indicate that consideration of behavioral brain state preceding a seizure is important for the appropriate interpretation of network dynamics leading up to a seizure and for designing effective seizure intervention. SIGNIFICANCE STATEMENT: Hippocampal single-unit activity is strongly shaped by behavioral brain state, yet this relationship has been largely ignored when studying activity dynamics before spontaneous seizures in medial temporal lobe epilepsy. In light of the increased attention on using single-unit activity for the prediction of seizure onset and closed-loop seizure intervention, we show a need for monitoring brain state to interpret correctly whether changes in neural activity before seizure onset is pathological or normal. Moreover, we also find that the brain state preceding a seizure determines the success of therapeutic interventions to curtail seizure duration. Together, these findings suggest that seizure prediction and intervention will be more successful if tailored for the specific brain states from which seizures emerge.

Neuronal code for extended time in the hippocampus.

The time when an event occurs can become part of autobiographical memories. In brain structures that support such memories, a neural code should exist that represents when or how long ago events occurred. Here we describe a neuronal coding mechanism in hippocampus that can be used to represent the recency of an experience over intervals of hours to days. When the same event is repeated after such time periods, the activity patterns of hippocampal CA1 cell populations progressively differ with increasing temporal distances. Coding for space and context is nonetheless preserved. Compared with CA1, the firing patterns of hippocampal CA3 cell populations are highly reproducible, irrespective of the time interval, and thus provide a stable memory code over time. Therefore, the neuronal activity patterns in CA1 but not CA3 include a code that can be used to distinguish between time intervals on an extended scale, consistent with behavioral studies showing that the CA1 area is selectively required for temporal coding over such periods.

Localized APP expression results in progressive network dysfunction by disorganizing spike timing.

Progressive cognitive decline in Alzheimer's disease could either be caused by a spreading molecular pathology or by an initially focal pathology that causes aberrant neuronal activity in a larger network. To distinguish between these possibilities, we generated a mouse model with expression of mutant human amyloid precursor protein (APP) in only hippocampal CA3 cells. We found that performance in a hippocampus-dependent memory task was impaired in young adult and aged mutant mice. In both age groups, we then recorded from the CA1 region, which receives inputs from APP-expressing CA3 cells. We observed that theta oscillation frequency in CA1 was reduced along with disrupted relative timing of principal cells. Highly localized pathology limited to the presynaptic CA3 cells is thus sufficient to cause aberrant firing patterns in postsynaptic neuronal networks, which indicates that disease progression is not only from spreading pathology but also mediated by progressively advancing physiological dysfunction.

Hippocampal activation during the recall of remote spatial memories in radial maze tasks.

Temporally graded retrograde amnesia is observed in human patients with medial temporal lobe lesions as well as in animal models of medial temporal lobe lesions. A time-limited role for these structures in memory recall has also been suggested by the observation that the rodent hippocampus and entorhinal cortex are activated during the retrieval of recent but not of remote memories. One notable exception is the recall of remote memories for platform locations in the water maze, which requires an intact hippocampus and results in hippocampal activation irrespective of the age of the memory. These findings raise the question whether the hippocampus is always involved in the recall of spatial memories or, alternatively, whether it might be required for procedural computations in the water maze task, such as for calculating a path to a hidden platform. We performed spatial memory testing in radial maze tasks to distinguish between these possibilities. Radial maze tasks require a choice between spatial locations on a center platform and thus have a lesser requirement for navigation than the water maze. However, we used a behavioral design in the radial maze that retained other aspects of the standard water maze task, such as the use of multiple start locations and retention testing in a single trial. Using the immediate early gene c-fos as a marker for neuronal activation, we found that all hippocampal subregions were more activated during the recall of remote compared to recent spatial memories. In areas CA3 and CA1, activation during remote memory testing was higher than in rats that were merely reexposed to the testing environment after the same time interval. Conversely, Fos levels in the dentate gyrus were increased after retention testing to the extent that was also observed in the corresponding exposure control group. This pattern of hippocampal activation was also obtained in a second version of the task that only used a single start arm instead of multiple start arms. The CA3 and CA1 activation during remote memory recall is consistent with the interpretation that an older memory might require increased pattern completion and/or relearning after longer time intervals. Irrespective of whether the hippocampus is required for remote memory recall, the hippocampus might engage in computations that either support recall of remote memories or that update remote memories.

Low Rate Hippocampal Delay Period Activity Encodes Behavioral Experience.

Remembering what just happened is a crucial prerequisite to form long-term memories but also for establishing and maintaining working memory. So far there is no general agreement about cortical mechanisms that support short-term memory. Using a classifier-based decoding approach, we report that hippocampal activity during few sparsely distributed brief time intervals contains information about the previous sensory motor experience of rodents. These intervals are characterized by only a small increase of firing rate of only a few neurons. These low-rate predictive patterns are present in both working memory and non-working memory tasks, in two rodent species, rats and Mongolian gerbils, are strongly reduced for rats with medial entorhinal cortex lesions, and depend on the familiarity of the sensory-motor context.

Enigmas of the dentate gyrus.

We are rapidly approaching a better understanding of the mechanisms that allow our brains to form distinct representations for similar events or episodes. McHugh et al. have brought that goal one step closer by showing that NMDA receptor-dependent synaptic plasticity in the dentate gyrus is necessary for immediate differentiation between environments with similar features.

Precisely timed theta oscillations are selectively required during the encoding phase of memory.

Brain oscillations have been hypothesized to support cognitive function by coordinating spike timing within and across brain regions, yet it is often not known when timing is either critical for neural computations or an epiphenomenon. The entorhinal cortex and hippocampus are necessary for learning and memory and exhibit prominent theta oscillations (6-9 Hz), which are controlled by pacemaker cells in the medial septal area. Here we show that entorhinal and hippocampal neuronal activity patterns were strongly entrained by rhythmic optical stimulation of parvalbumin-positive medial septal area neurons in mice. Despite strong entrainment, memory impairments in a spatial working memory task were not observed with pacing frequencies at or below the endogenous theta frequency and only emerged at frequencies ≥10 Hz, and specifically when pacing was targeted to maze segments where encoding occurs. Neural computations during the encoding phase were therefore selectively disrupted by perturbations of the timing of neuronal firing patterns.

Attractor-map versus autoassociation based attractor dynamics in the hippocampal network.

The autoassociative memory model of hippocampal field CA3 postulates that Hebbian associations among external input features produce attractor states embedded in a recurrent synaptic matrix. In contrast, the attractor-map model postulates that a two-dimensional continuum of attractor states is preconfigured in the network during development and that transitions among these states are governed primarily by self-motion information ("path-integration"), giving rise to the strong spatial characteristic of hippocampal activity. In this model, learned associations between "coordinates" on the attractor map and external cues can result in abrupt jumps between states, in the case of mismatches between the current input and previous associations between internal coordinates and external landmarks. Both models predict attractor dynamics, but for fundamentally different reasons; however, the two models are not a priori mutually exclusive. We contrasted these two models by comparing the dynamics of state transitions when two previously learned environmental shapes were morphed between their endpoints, in animals that had first experienced the environments either at the same location, or at two different locations, connected by a passageway through which they walked. As predicted from attractor-map theory, the latter animals expressed abrupt transitions between representations at the midpoint of the morph series. Contrary to the predictions of autoassociation theory, the former group expressed no evidence of attractor dynamics during the morph series; there was only a gradual transition between endpoints. The results of this critical test thus cast the autoassociator theory for CA3 into doubt and indicate the need for a new theory for this structure.

Progressive transformation of hippocampal neuronal representations in "morphed" environments.

Hippocampal neural codes for different, familiar environments are thought to reflect distinct attractor states, possibly implemented in the recurrent CA3 network. A defining property of an attractor network is its ability to undergo sharp and coherent transitions between pre-established (learned) representations when the inputs to the network are changed. To determine whether hippocampal neuronal ensembles exhibit such discontinuities, we recorded in CA3 and CA1 when a familiar square recording enclosure was morphed in quantifiable steps into a familiar circular enclosure while leaving other inputs constant. We observed a gradual noncoherent progression from the initial to the final network state. In CA3, the transformation was accompanied by significant hysteresis, resulting in more similar end states than when only square and circle were presented. These observations suggest that hippocampal cell assemblies are capable of incremental plastic deformation, with incongruous information being incorporated into pre-existing representations.

Hippocampal CA1 replay becomes less prominent but more rigid without inputs from medial entorhinal cortex.

The hippocampus is an essential brain area for learning and memory. However, the network mechanisms underlying memory storage, consolidation and retrieval remain incompletely understood. Place cell sequences during theta oscillations are thought to be replayed during non-theta states to support consolidation and route planning. In animals with medial entorhinal cortex (MEC) lesions, the temporal organization of theta-related hippocampal activity is disrupted, which allows us to test whether replay is also compromised. Two different analyses-comparison of co-activation patterns between running and rest epochs and analysis of the recurrence of place cell sequences-reveal that the enhancement of replay by behavior is reduced in MEC-lesioned versus control rats. In contrast, the degree of intrinsic network structure prior and subsequent to behavior remains unaffected by MEC lesions. The MEC-dependent temporal coordination during theta states therefore appears to facilitate behavior-related plasticity, but does not disrupt pre-existing functional connectivity.

The impact of pathological high-frequency oscillations on hippocampal network activity in rats with chronic epilepsy.

In epilepsy, brain networks generate pathological high-frequency oscillations (pHFOs) during interictal periods. To understand how pHFOs differ from normal oscillations in overlapping frequency bands and potentially perturb hippocampal processing, we performed high-density single unit and local field potential recordings from hippocampi of behaving rats with and without chronic epilepsy. In epileptic animals, we observed two types of co-occurring fast oscillations, which by comparison to control animals we could classify as 'ripple-like' or 'pHFO'. We compared their spectral characteristics, brain state dependence, and cellular participants. Strikingly, pHFO occurred irrespective of brain state, were associated with interictal spikes, engaged distinct subnetworks of principal neurons compared to ripple-like events, increased the sparsity of network activity, and initiated both general and immediate disruptions in spatial information coding. Taken together, our findings suggest that events that result in pHFOs have an immediate impact on memory processes, corroborating the need for proper classification of pHFOs to facilitate therapeutic interventions that selectively target pathological activity.

Time Cells in the Hippocampus Are Neither Dependent on Medial Entorhinal Cortex Inputs nor Necessary for Spatial Working Memory.

A key function of the hippocampus and entorhinal cortex is to bridge events that are discontinuous in time, and it has been proposed that medial entorhinal cortex (mEC) supports memory retention by sustaining the sequential activity of hippocampal time cells. Therefore, we recorded hippocampal neuronal activity during spatial working memory and asked whether time cells depend on mEC inputs. Working memory was impaired in rats with mEC lesions, but the occurrence of time cells and of trajectory-coding cells in the stem did not differ from controls. Rather, the main effect of mEC lesions was an extensive spatial coding deficit of CA1 cells, which included inconsistency over time and reduced firing differences between positions on the maze. Therefore, mEC is critical for providing stable and distinct spatial information to hippocampus, while working memory (WM) maintenance is likely supported either by local synaptic plasticity in hippocampus or by activity patterns elsewhere in the brain.

Pattern separation, pattern completion, and new neuronal codes within a continuous CA3 map.

The hippocampal CA3 subregion is critical for rapidly encoding new memories, which suggests that neuronal computations are implemented in its circuitry that cannot be performed elsewhere in the hippocampus or in the neocortex. Recording studies show that CA3 cells are bound to a large degree to a spatial coordinate system, while CA1 cells can become more independent of a map-based mechanism and allow for a larger degree of arbitrary associations, also in the temporal domain. The mapping of CA3 onto a spatial coordinate system intuitively points to its role in spatial navigation but does not directly suggest how such a mechanism may support memory processing. Although bound to spatial coordinates, the CA3 network can rapidly alter its firing rate in response to novel sensory inputs and is thus not as strictly tied to spatial mapping as grid cells in the medial entorhinal cortex. Such rate coding within an otherwise stable spatial map can immediately incorporate new sensory inputs into the two-dimensional matrix of CA3, where they can be integrated with already stored information about each place. CA3 cell ensembles may thus support the fast acquisition of detailed memories by providing a locally continuous, but globally orthogonal representation, which can rapidly provide a new neuronal index when information is encountered for the first time. This information can be interpreted in CA1 and other downstream cortical areas in the context of less spatially restricted information.

Recurrent circuits within medial entorhinal cortex superficial layers support grid cell firing.

Specialized cells in the medial entorhinal cortex (mEC), such as speed cells, head direction (HD) cells, and grid cells, are thought to support spatial navigation. To determine whether these computations are dependent on local circuits, we record neuronal activity in mEC layers II and III and optogenetically perturb locally projecting layer II pyramidal cells. We find that sharply tuned HD cells are only weakly responsive while speed, broadly tuned HD cells, and grid cells show pronounced transient excitatory and inhibitory responses. During the brief period of feedback inhibition, there is a reduction in specifically grid accuracy, which is corrected as firing rates return to baseline. These results suggest that sharp HD cells are embedded in a separate mEC sub-network from broad HD cells, speed cells, and grid cells. Furthermore, grid tuning is not only dependent on local processing but also rapidly updated by HD, speed, or other afferent inputs to mEC.

Hippocampal Global Remapping Can Occur without Input from the Medial Entorhinal Cortex.

The high storage capacity of the episodic memory system relies on distinct representations for events that are separated in time and space. The spatial component of these computations includes the formation of independent maps by hippocampal place cells across environments, referred to as global remapping. Such remapping is thought to emerge by the switching of input patterns from specialized spatially selective cells in medial entorhinal cortex (mEC), such as grid and border cells. Although it has been shown that acute manipulations of mEC firing patterns are sufficient for inducing hippocampal remapping, it remains unknown whether specialized spatial mEC inputs are necessary for the reorganization of hippocampal spatial representations. Here, we examined remapping in rats without mEC input to the hippocampus and found that highly distinct spatial maps emerged rapidly in every individual rat. Our data suggest that hippocampal spatial computations do not depend on inputs from specialized cell types in mEC.