Time as the fourth dimension in the hippocampus.

Experiences of animal and human beings are structured by the continuity of space and time coupled with the uni-directionality of time. In addition to its pivotal position in spatial processing and navigation, the hippocampal system also plays a central, multiform role in several types of temporal processing. These include timing and sequence learning, at scales ranging from meso-scales of seconds to macro-scales of minutes, hours, days and beyond, encompassing the classical functions of short term memory, working memory, long term memory, and episodic memories (comprised of information about when, what, and where). This review article highlights the principal findings and behavioral contexts of experiments in rats showing: 1) timing: tracking time during delays by hippocampal 'time cells' and during free behavior by hippocampal-afferent lateral entorhinal cortex ramping cells; 2) 'online' sequence processing: activity coding sequences of events during active behavior; 3) 'off-line' sequence replay: during quiescence or sleep, orderly reactivation of neuronal assemblies coding awake sequences. Studies in humans show neurophysiological correlates of episodic memory comparable to awake replay. Neural mechanisms are discussed, including ion channel properties, plateau and ramping potentials, oscillations of excitation and inhibition of population activity, bursts of high amplitude discharges (sharp wave ripples), as well as short and long term synaptic modifications among and within cell assemblies. Specifically conceived neural network models will suggest processes supporting the emergence of scalar properties (Weber's law), and include different classes of feedforward and recurrent network models, with intrinsic hippocampal coding for 'transitions' (sequencing of events or places).

Insensitivity of Place Cells to the Value of Spatial Goals in a Two-Choice Flexible Navigation Task.

Hippocampal place cells show position-specific activity thought to reflect a self-localization signal. Several reports also point to some form of goal encoding by place cells. We investigated this by asking whether they also encode the value of spatial goals, which is crucial information for optimizing goal-directed navigation. We used a continuous place navigation task in which male rats navigate to one of two (freely chosen) unmarked locations and wait, triggering the release of reward, which is then located and consumed elsewhere. This allows sampling of place fields and dissociates spatial goal from reward consumption. The two goals varied in the amount of reward provided, allowing assessment of whether the rats factored goal value into their navigational choice and of possible neural correlates of this value. Rats successfully learned the task, indicating goal localization, and they preferred higher-value goals, indicating processing of goal value. Replicating previous findings, there was goal-related activity in the out-of-field firing of CA1 place cells, with a ramping-up of firing rate during the waiting period, but no general overrepresentation of goals by place fields, an observation that we extended to CA3 place cells. Importantly, place cells were not modulated by goal value. This suggests that dorsal hippocampal place cells encode space independently of its associated value despite the effect of that value on spatial behavior. Our findings are consistent with a model of place cells in which they provide a spontaneously constructed value-free spatial representation rather than encoding other navigationally relevant but nonspatial information.SIGNIFICANCE STATEMENT We investigated whether hippocampal place cells, which compute a self-localization signal, also encode the relative value of places, which is essential information for optimal navigation. When choosing between two spatial goals of different value, rats preferred the higher-value goal. We saw out-of-field goal firing in place cells, replicating previous observations that the cells are influenced by the goal, but their activity was not modulated by the value of these goals. Our results suggest that place cells do not encode all of the navigationally relevant aspects of a place, but instead form a value-free "map" that links to such aspects in other parts of the brain.

Deficits in temporal order memory induced by interferon-alpha (IFN-α) treatment are rescued by aerobic exercise.

Patients receiving cytokine immunotherapy with IFN-α frequently present with neuropsychiatric consequences and cognitive impairments, including a profound depressive-like symptomatology. While the neurobiological substrates of the dysfunction that leads to adverse events in IFN-α-treated patients remains ill-defined, dysfunctions of the hippocampus and prefrontal cortex (PFC) are strong possibilities. To date, hippocampal deficits have been well-characterised; there does however remain a lack of insight into the nature of prefrontal participation. Here, we used a PFC-supported temporal order memory paradigm to examine if IFN-α treatment induced deficits in performance; additionally, we used an object recognition task to assess the integrity of the perirhinal cortex (PRH). Finally, the utility of exercise as an ameliorative strategy to recover temporal order deficits in rats was also explored. We found that IFN-α-treatment impaired temporal order memory discriminations, whereas recognition memory remained intact, reflecting a possible dissociation between recognition and temporal order memory processing. Further characterisation of temporal order memory impairments using a longitudinal design revealed that deficits persisted for 10 weeks following cessation of IFN-α-treatment. Finally, a 6 week forced exercise regime reversed IFN-α-induced deficits in temporal order memory. These data provide further insight into the circuitry involved in cognitive impairments arising from IFN-α-treatment. Here we suggest that PFC (or the hippocampo-prefrontal pathway) may be compromised whilst the function of the PRH is preserved. Deficits may persist after cessation of IFN-α-treatment which suggests that extended patient monitoring is required. Aerobic exercise may be restorative and could prove beneficial for patients treated with IFN-α.

Influences of photic stress on postsubicular head-directional processing.

The stress response serves vital adaptive functions. However, acute stress episodes often negatively impact cognitive processing. Here, we aimed to elucidate whether stress detrimentally affects the head-direction cells of the postsubiculum, which may in turn impair downstream spatial information processing. We recorded neurons in the rats' postsubiculum during a pellet-chasing task during baseline non-stress conditions and after a 30-min acute photic stress exposure. Based on their baseline firing rate, we identified a subpopulation of head-direction cells that drastically decreased its firing rate as a response to stress while preserving their head directionality. The remaining population of head-direction cells as well as other neurons recorded in the postsubiculum were unaffected. The observed altered activity in the subpopulation might be the basis for spatial processing deficits observed following acute stress episodes.

Ventral Midline Thalamus Is Necessary for Hippocampal Place Field Stability and Cell Firing Modulation.

The reuniens (Re) and rhomboid (Rh) nuclei of the ventral midline thalamus are reciprocally connected with the hippocampus (Hip) and the medial prefrontal cortex (mPFC). Growing evidence suggests that these nuclei might play a crucial role in cognitive processes requiring Hip-mPFC interactions, including spatial navigation. Here, we tested the effect of ReRh lesions on the firing properties and spatial activity of dorsal hippocampal CA1 place cells as male rats explored a familiar or a novel environment. We found no change in the spatial characteristics of CA1 place cells in the familiar environment following ReRh lesions. Contrariwise, spatial coherence was decreased during the first session in a novel environment. We then investigated field stability of place cells recorded across 5 d both in the familiar and in a novel environment presented in a predefined sequence. While the remapping capacity of the place cells was not affected by the lesion, our results clearly demonstrated a disruption of the CA1 cellular representation of both environments in ReRh rats. More specifically, we found ReRh lesions to produce (1) a pronounced and long-lasting decrease of place field stability and (2) a strong alteration of overdispersion (i.e., firing variability). Thus, in ReRh rats, exploration of a novel environment appears to interfere with the representation of the familiar one, leading to decreased field stability in both environments. The present study shows the involvement of ReRh nuclei in the long-term spatial stability of CA1 place fields.SIGNIFICANCE STATEMENT Growing evidence suggest that the ventral midline thalamic nuclei (reuniens and rhomboid) might play a substantial role in various cognitive tasks including spatial memory. In the present article, we show that the lesions of these nuclei impair the spatial representations encoded by CA1 place cells of both familiar and novel environments. First, reduced variability of place cell firing appears to indicate an impairment of attentional processes. Second, impaired stability of place cell representations could explain the long-term memory deficits observed in previous behavioral studies.

Spatial cognition in mice and rats: similarities and differences in brain and behavior.

The increasing use of mice models in cognitive tasks that were originally designed for rats raises crucial questions about cross-species comparison in the study of spatial cognition. The present review focuses on the major neuroethological differences existing between mice and rats, with particular attention given to the neurophysiological basis of space coding. While little difference is found in the basic properties of space representation in these two species, it appears that the stability of this representation changes more drastically over time in mice than in rats. We consider several hypotheses dealing with attentional, perceptual, and genetic aspects and offer some directions for future research that might help in deciphering hippocampal function in learning and memory processes. WIREs Cogn Sci 2016, 7:406-421. doi: 10.1002/wcs.1411 For further resources related to this article, please visit the WIREs website.

Is there a pilot in the brain? Contribution of the self-positioning system to spatial navigation.

Since the discovery of place cells, the hippocampus is thought to be the neural substrate of a cognitive map. The later discovery of head direction cells, grid cells and border cells, as well as of cells with more complex spatial signals, has led to the idea that there is a brain system devoted to providing the animal with the information required to achieve efficient navigation. Current questioning is focused on how these signals are integrated in the brain. In this review, we focus on the issue of how self-localization is performed in the hippocampal place cell map. To do so, we first shortly review the sensory information used by place cells and then explain how this sensory information can lead to two coding modes, respectively based on external landmarks (allothetic information) and self-motion cues (idiothetic information). We hypothesize that these two modes can be used concomitantly with the rat shifting from one mode to the other during its spatial displacements. We then speculate that sequential reactivation of place cells could participate in the resetting of self-localization under specific circumstances and in learning a new environment. Finally, we provide some predictions aimed at testing specific aspects of the proposed ideas.

Differential role of the dorsal hippocampus, ventro-intermediate hippocampus, and medial prefrontal cortex in updating the value of a spatial goal.

Encoding of a goal with a specific value while performing a place navigation task involves the medial prefrontal cortex (mPFC) and the dorsal hippocampus (dHPC), and depends on the coordination between mPFC and the ventro-intermediate hippocampus (vHPC).The present work investigates the contribution of mPFC, dHPC, and vHPC when the rat has to update the value of a goal. Rats were trained to navigate to an uncued goal in order to release a food pellet in a continuous place navigation task. When they had reached criterion performance level in the task, they were subjected to a single "flash session" in which they were exposed to an aversive strobe light during goal visits instead of receiving a food reward. Just before the flash session, the GABA(A) agonist muscimol was injected to temporarily inactivate mPFC, dHPC, or vHPC. The ability to recall the changed value of the goal was tested on the next day. We first demonstrate the aversive effect of the strobe light by showing that rats learn to avoid the goal much more rapidly in the flash session than during a simple extinction session in which goal visits are not rewarded. Furthermore, while dHPC inactivation had no effect on learning and recalling the new goal value, vHPC muscimol injections considerably delayed goal value updating during the flash session, which resulted in a slight deficit during recall. In contrast, mPFC muscimol injections induced faster goal value updating but the rats were markedly impaired on recalling the new goal value on the next day. These results suggest that, contrary to mPFC and dHPC, vHPC is required for updating the value of a goal. In contrast, mPFC is necessary for long-term retention of this updating.

Prefrontal cortex focally modulates hippocampal place cell firing patterns.

Previous work shows that medial prefrontal cortex (mPFC) cells exhibit spatio-selective activity at a goal location when rats are trained in a goal-oriented navigation task. Damaging the ventral and intermediate hippocampal regions severely disrupts both mPFC goal firing and behavioral performance in the same task. Additionally, hippocampal place cells tend to develop a secondary place field at the goal location, suggesting that goal locations can be encoded by local changes in firing rate, within an otherwise stable spatial representation. Therefore, it has been suggested that the coordinated activity of a large fraction of hippocampal cells at the goal location may interact with the mPFC to compute accurate planning trajectories, relying on both precise location-specific firing of place cells and the coarse-coded, goal-trajectory planning function of the prefrontal cortex. To test this hypothesis, we inactivated the mPFC and recorded hippocampal place cell activity while animals were performing the navigation task. The results show that post-training inactivation of the prefrontal cortex does not affect behavioral performance, suggesting that this structure is no longer required when animals are overtrained. The goal-related activity of place cells was not affected at either single unit or local field potential level. Conversely, profound modifications of place cell firing variability (overdispersion) were observed after suppression of prefrontal input, suggesting a possible mechanism underlying behavioral flexibility.

Age-related declines in delayed non-match-to-sample performance (DNMS) are reversed by the novel 5HT6 receptor antagonist SB742457.

Alterations in synaptic plasticity and neurocognitive function with age have been well documented in the literature. These changes are accompanied by modifications of neurotransmitter systems in the central nervous system (CNS). The serotonergic system in particular plays an important role in attention, alertness and cognition. Disturbances in serotonergic function have been implicated in differing neurological and neuropsychiatric disorders including depression, psychosis aggression and dementia. The serotonin receptor subtype 5HT6 is distributed within CNS regions relevant to learning and memory, including the striatum, cortex and hippocampus. We examined here the effects of acute and chronic administration of the 5HT6 receptor antagonist SB742457 on performance in a delayed non-matching-to-sample task (DNMS), which was used to identify neurocognitive differences between middle-aged (MA, 13 months) and young adult (YG, 3 months) rats. We found that MA rats have significantly lower performance in the DNMS task compared to YG rats. Acute administration of SB742457 (3 mg/kg/po) significantly improved performance of the MA rats. Chronic administration of SB742457 (3 mg/kg) reversed the age-related deficit of the MA to match their performance to that of YG rats. Furthermore, these improvements were observed for 1 week post-SB742457 treatment cessation. The acute and chronic effects of this treatment suggest that there is both an immediate effect on neurotransmitter action and potentially a longer-term modification of synaptic plasticity. Together these data indicate a role for modulation of the serotonergic system in the development of cognition-enhancing agents.

Hippocampal dynamics predict interindividual cognitive differences in rats.

There are important and sustained interindividual differences in cognition during aging. Here, we investigated hippocampal spatial representations in a rat model of cognitive aging characterized by individual differences in a mnemonic task. Individual cognitive capabilities in old rats were assessed in a delayed non-matching-to-position task. We recorded hippocampal CA1 place cells as the rats explored a familiar environment. Unlike the usual place cells commonly described in the literature, we found that a significant fraction of pyramidal neurons recorded in our study showed a substantial delayed onset of their place field activity. We established that this firing onset delay naturally occurs under basal conditions in old rats and is positively correlated with the remapping status of the animals. The lack of firing during the first few hundred seconds after the animals were introduced into a familiar environment was also associated with an increased locomotion in the remapping rats. This delayed activity is central to understanding the individual basis of age-related cognitive impairment and to resolving numerous discrepancies in the literature on the place cell contribution to the etiology of aged-related decline. Finally, we also found a positive correlation between the degree of firing variability of place cells ("overdispersion") and performance during the long delays in the delayed non-matching-to-position task. Place cell overdispersion might provide the functional basis for interindividual differences in behavior and cognition.

Rosiglitazone enhances learning, place cell activity, and synaptic plasticity in middle-aged rats.

As an antidiabetic agent, rosiglitazone (ROSI) binds and activates peroxisome proliferator-activator receptor gamma (PPARγ), altering the expression of genes involved in glucose uptake and disposal, ultimately affecting glucose regulation. ROSI might therefore be a potential treatment to ameliorate age-related decline in cognitive function, particularly on an insulin-resistant background, where improvements in peripheral insulin sensitivity and central nervous system (CNS) glucose utilization may facilitate recovery of cognitive function. We therefore examined the amelioration potential of ROSI for neurocognitive deficits resulting from aging in an animal model. Behaviorally, acute and chronic ROSI treatments enhanced acquisition of learning in the water plus maze, a modified version of the Morris water maze task. In parallel, restoration of synaptic plasticity in the dentate gyrus of ROSI-treated middle-aged rats was evident after a single dose intake. Additionally, the spatial receptive fields of hippocampal CA1 place cells were significantly improved by chronic ROSI administration. ROSI treatment reversed basal plasma insulin abnormalities and increased hippocampal glucose transporter (GLUT)-3 expression in middle-aged rats. Taken together, these results suggest that ROSI modulates hippocampal circuitry effectively to promote an improvement in cognitive function, possibly via a glucose transporter-3 mechanism.

Dissociation of dorsal hippocampal regional activation under the influence of stress in freely behaving rats.

Stress has deleterious effects on brain, body, and behavior in humans and animals alike. The present work investigated how 30-min acute photic stress exposure impacts on spatial information processing in the main sub-regions of the dorsal hippocampal formation [CA1, CA3, and dentate gyrus (DG)], a brain structure prominently implicated in memory and spatial representation. Recordings were performed from spatially tuned hippocampal and DG cells in rats while animals foraged in a square arena for food. The stress procedure induced a decrease in firing frequencies in CA1 and CA3 place cells while sparing locational characteristics. In contrast to the CA1-CA3 network, acute stress failed to induce major changes in the DG neuronal population. These data demonstrate a clear dissociation of the effects of stress on the main hippocampal sub-regions. Our findings further support the notion of decreased hippocampal excitability arising from behavioral stress in areas CA1 and CA3, but not in DG.

A waveform independent cell identification method to study long-term variability of spike recordings.

Extracellular potential recordings are important in neuroscience; however the variability of spike waveforms has not been extensively studied to date. This study examines the variability of spike recordings within and between sessions. Place cell recordings were used in order to identify the cells across successive sessions. Place cells allow neuron spike recordings to be identified across different sessions using place fields, which are independent of the cell's spike waveform. The results show that the distribution of the residues within a session does not follow a normal distribution, a t-distribution is more suitable. The results also show that the amplitude of the spikes can vary largely between successive sessions (up to 47%), this is an important factor to be considered in long term spike recording systems.

[The hippocampus and the neural code of spatial memory]. / L'hippocampe et le code neural de la mémoire spatiale.

Recent work on the neural substrate of spatial memory strongly suggests the existence of a neuronal network dedicated to the coding of spatial information and allowing the subject to orient in space. This network includes place cells of the hippocampus, head direction cells which are found in several brain regions and particularly the post-subiculum, and grid cells in the entorhinal cortex. Several recently discovered features of place cell activity shed light on how the hippocampus contributes to memory construction. For instance, learning a novel environment relies on a dynamic population code in which place cell activity suddenly changes towards stable states built during previous experience. We briefly review these properties to show how they constrain the hippocampal memory code.

Tagging items in spatial working memory: a unit-recording study in the rat medial prefrontal cortex.

The rat medial prefrontal cortex has been suggested to be involved in executive functions and, more specifically, in working memory and response selection. Here, we looked for prefrontal neural correlates as rats performed a modified radial arm maze task that taxed such functions. Rats had to learn the position of four rewarded arms among eight, and visit each rewarded arm only once, thus avoiding repeated visits. In addition, rats were left on the maze after the four successful visits to baited arms until they had visited all the arms twice. Prefrontal neural activity was examined during choice periods, i.e. 2s before the rat entered the arms. We found that a substantial proportion of recorded medial prefrontal neurons were selectively activated before either the first or second visit to the arms irrespective of their reward status, thereby tagging already visited arms. These behavioral correlates show that, within the rodent medial prefrontal cortex, neuronal populations demonstrate behavioral correlates suggestive of its role in guiding prospective search behavior and thus executive functions.

Lesion of the ventral and intermediate hippocampus abolishes anticipatory activity in the medial prefrontal cortex of the rat.

The medial prefrontal cortex (mPFC) of the rat receives a prominent input from the ventral two thirds of the hippocampus, a structure important for spatial awareness, working memory and motivation. We recently found [Hok V, Lenck-Santini PP, Roux S, Save E, Muller RU, Poucet B. Goal-related activity in hippocampal place cells. J Neurosci 2007;27:472-82.] that neurones in the dorsal hippocampus exhibit anticipatory firing prior to the release of a food pellet on an operant task. Here we look for similar activity in the mPFC on the same task and test whether this activity is dependent on the hippocampus. Rats were trained to navigate to a goal zone, wait for the release of a food pellet and then forage for the pellet while unit activity was recorded in the prelimbic and infralimbic areas of the mPFC. Two 16 min sessions were conducted per day, one session with the goal delimited by a cue disc, the second without the cue. In controls, a large proportion of mPFC neurones exhibited activity similar to that seen in the hippocampus while the animal was stationary at the goal. Over half exhibited the same activity regardless of goal location. Anticipatory activity was largely abolished in animals with bilateral lesions of the ventral and intermediate hippocampus, both in cued and uncued sessions. Even though lesioned animals continued to perform the task, they tended to leave the goal zone prematurely. We suggest that the anticipatory activity in the mPFC is dependent on similar activity in the hippocampus and that both structures have a role in either impulse control or reward expectation.

A test of the time estimation hypothesis of place cell goal-related activity.

Place cells are hippocampal pyramidal neurons that discharge strongly in relation to the rat's location in the environment. We recently reported that many place cells recorded from rats performing place or cue navigation tasks also discharged when they were at the goal location rather than in the primary firing field. Furthermore, subtle differences in discharge timing were found in the two navigation tasks, with activity occurring later in the place task compared to the cue task. Here we tested the possibility that such delayed firing in the place task may reflect the differential involvement of time estimation, which would allow the rat to predict forthcoming reward delivery. More specifically, we reasoned that failure to obtain a reward after a fixed 2s delay in the place task reliably reflected the rat's misplacement relative to the correct location, thus making time a valuable cue to help the rat perform the task. To test this hypothesis, well-trained rats were run on a partial extinction procedure in place and cue navigation tasks so that no feed-back signal was provided about their actual accuracy during extinction periods. Although the time estimation hypothesis predicts that only in the place task will the rat make correction movements at the end of goal periods during extinction, we found that such movements occurred in all rats, indicating correct time estimation in both place and cue tasks. We briefly discuss the results in the light of current computational theories of hippocampal function.

Goal-related activity in hippocampal place cells.

Place cells are hippocampal neurons whose discharge is strongly related to a rat's location in its environment. The existence of place cells has led to the proposal that they are part of an integrated neural system dedicated to spatial navigation, an idea supported by the discovery of strong relationships between place cell activity and spatial problem solving. To further understand such relationships, we examined the discharge of place cells recorded while rats solved a place navigation task. We report that, in addition to having widely distributed firing fields, place cells also discharge selectively while the hungry rat waits in an unmarked goal location to release a food pellet. Such firing is not duplicated in other locations outside the main firing field even when the rat's behavior is constrained to be extremely similar to the behavior at the goal. We therefore propose that place cells provide both a geometric representation of the current environment and a reflection of the rat's expectancy that it is located correctly at the goal. This on-line feedback about a critical aspect of navigational performance is proposed to be signaled by the synchronous activity of the large fraction of place cells active at the goal. In combination with other (prefrontal) cells that provide coarse encoding of goal location, hippocampal place cells may therefore participate in a neural network allowing the rat to plan accurate trajectories in space.