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.

Merging information in the entorhinal cortex: what can we learn from robotics experiments and modeling?

Place recognition is a complex process involving idiothetic and allothetic information. In mammals, evidence suggests that visual information stemming from the temporal and parietal cortical areas ('what' and 'where' information) is merged at the level of the entorhinal cortex (EC) to build a compact code of a place. Local views extracted from specific feature points can provide information important for view cells (in primates) and place cells (in rodents) even when the environment changes dramatically. Robotics experiments using conjunctive cells merging 'what' and 'where' information related to different local views show their important role for obtaining place cells with strong generalization capabilities. This convergence of information may also explain the formation of grid cells in the medial EC if we suppose that: (1) path integration information is computed outside the EC, (2) this information is compressed at the level of the EC owing to projection (which follows a modulo principle) of cortical activities associated with discretized vector fields representing angles and/or path integration, and (3) conjunctive cells merge the projections of different modalities to build grid cell activities. Applying modulo projection to visual information allows an interesting compression of information and could explain more recent results on grid cells related to visual exploration. In conclusion, the EC could be dedicated to the build-up of a robust yet compact code of cortical activity whereas the hippocampus proper recognizes these complex codes and learns to predict the transition from one state to another.

Distant Space Processing is Controlled by tPA-dependent NMDA Receptor Signaling in the Entorhinal Cortex.

In humans, spatial cognition and navigation impairments are a frequent situation during physiological and pathological aging, leading to a dramatic deterioration in the quality of life. Despite the discovery of neurons with location-specific activity in rodents, that is, place cells in the hippocampus and later on grid cells in the entorhinal cortex (EC), the molecular mechanisms underlying spatial cognition are still poorly known. Our present data bring together in an unusual combination 2 molecules of primary biological importance: a major neuronal excitatory receptor, N-methyl-D-aspartate receptor (NMDAR), and an extracellular protease, tissue plasminogen activator (tPA), in the control of spatial navigation. By using tPA-deficient mice and a structure-selective pharmacological approach, we demonstrate that the tPA-dependent NMDAR signaling potentiation in the EC plays a key and selective role in the encoding and the subsequent use of distant landmarks during spatial learning. We also demonstrate that this novel function of tPA in the EC is reduced during aging. Overall, these results argue for the concept that encoding of proximal versus distal landmarks is mediated not only by different anatomical pathways but also by different molecular mechanisms, with the tPA-dependent potentiation of NMDAR signaling in the EC that plays an important role.

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.

Distinct roles of medial and lateral entorhinal cortex in spatial cognition.

It is known that the entorhinal cortex plays a crucial role in spatial cognition in rodents. Neuroanatomical and electrophysiological data suggest that there is a functional distinction between 2 subregions within the entorhinal cortex, the medial entorhinal cortex (MEC), and the lateral entorhinal cortex (LEC). Rats with MEC or LEC lesions were trained in 2 navigation tasks requiring allothetic (water maze task) or idiothetic (path integration) information processing and 2-object exploration tasks allowing testing of spatial and nonspatial processing of intramaze objects. MEC lesions mildly affected place navigation in the water maze and produced a path integration deficit. They also altered the processing of spatial information in both exploration tasks while sparing the processing of nonspatial information. LEC lesions did not affect navigation abilities in both the water maze and the path integration tasks. They altered spatial and nonspatial processing in the object exploration task but not in the one-trial recognition task. Overall, these results indicate that the MEC is important for spatial processing and path integration. The LEC has some influence on both spatial and nonspatial processes, suggesting that the 2 kinds of information interact at the level of the EC.

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.

Effects of combined ferrous sulphate administration and exposure to static magnetic field on spatial learning and motor abilities in rats.

PRIMARY OBJECTIVE: Occupational exposure to static magnetic fields (SMF) increases, in particular due to the widespread use of Magnetic Resonance Imaging (MRI) for medical diagnosis, thus raising health concerns. This study investigated the behavioural effects of 128 mT SMF in rats and examined the hypothesis that iron supplementation (3 mg kg(-1) for 5 days) potentiate the effects of SMF. METHODS: Spatial learning abilities in the water maze, motor co-ordination in the rotarod and motor skills in the stationary beam and suspending string tests were assessed in iron-treated, SMF-exposed and co-exposed SMF-iron rats. RESULTS: Acquisition of the water maze navigation task was unaffected in all groups. SMF-exposed and iron-treated rats showed a deficit in the 7-day retention test. No deficit was found in the rotarod and suspended string tests in all groups. Only iron-treated rats were impaired in the stationary beam test. A combination of iron and SMF treatments did not produce additional degradation of performance in all tests. CONCLUSION: SMF exposure had no massive effect but affected long-term spatial memory. Iron supplementation and 128 mT SMF had no synergistic effects.

Impaired long-term stability of CA1 place cell representation in mice lacking the transcription factor zif268/egr1.

Zif268 is a transcriptional regulator that plays a crucial role in maintenance of the late phases of hippocampal long-term potentiation (LTP) and consolidation of spatial memories. Because the hippocampal place cell system is essential for long-term spatial memory, we tested the hypothesis that zif268 is required for long-term stability of hippocampal place cell representations by recording CA1 place cells in mice lacking zif268. We found that zif268 gene deletion destabilized the representation of a familiar environment after exposure to a novel environment and impaired the long-term (24 h), but not short-term (1 h), stability of newly formed representations. These impairments could be rescued by repeated exposure to the novel environment, however. These results indicate that zif268 contributes to the long-term stability of spatial representations in CA1 and support the notion that the long-term stability of place cell representations requires transcription-dependent mechanisms similar to those observed in LTP.

Local remapping of place cell firing in the Tolman detour task.

The existence of place cells, whose discharge is strongly related to a rat's location in its environment, has led to the proposal that they form part of an integrated neural system dedicated to spatial navigation. It has been suggested that this system could represent space as a cognitive map, which is flexibly used by animals to plan new shortcuts or efficient detours. To further understand the relationships between hippocampal place cell firing and cognitive maps, we examined the discharge of place cells as rats were exposed to a Tolman-type detour problem. In specific sessions, a transparent barrier was placed onto the maze so as to block the shortest central path between the two rewarded end locations of a familiar three-way maze. We found that rats rapidly and consistently chose the shortest alternative detour. Furthermore, both CA1 and CA3 place cells that had a field in the vicinity of the barrier displayed local remapping. In contrast, neither CA1 nor CA3 cells that had a field away from the barrier were affected. This finding, at odds with our previous report of altered CA3 discharge for distant fields in a shortcut task, suggests that the availability of a novel path and the blocking of a familiar path are not equivalent and could lead to different responses of the CA3 place cell population. Together, the two studies point to a specific role of CA3 in the representation of spatial connectivity and sequences.

Navigation using global or local reference frames in rats with medial and lateral entorhinal cortex lesions.

The medial (MEC) and the lateral (LEC) regions of the entorhinal cortex send a major input to the hippocampus and have been proposed to play a foremost role in combining spatial and non-spatial attributes of episodic memory. In addition, it has been recently suggested that the MEC is involved in the processing of information in a global reference frame and the LEC in the processing of information in a local reference frame. Whether these putative functions could be generalized to navigation contexts has not been established yet. To address this hypothesis, rats with MEC or LEC NMDA-induced lesions were trained in two versions of a navigation task in the water maze, a global cue condition in which they had to use distal room cues and a local cue condition in which they had to use 3 objects placed in the pool. In the global cue condition, MEC-lesioned rats exhibited slower acquisition and were not able to precisely locate the submerged platform during the probe trial. In contrast LEC-lesioned rats exhibited control-like performance. In the local cue condition, navigational abilities were spared in both lesion groups. In addition when the 3 different objects were replaced by 3 identical objects, all groups maintained their navigation accuracy suggesting that the identity of objects is not crucial for place navigation. Overall, the results indicate that the MEC is necessary for place navigation using a global reference frame. In contrast, navigation using a local reference frame does not require the LEC nor the MEC.

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).

Medial entorhinal cortex lesions induce degradation of CA1 place cell firing stability when self-motion information is used.

The entorhinal-hippocampus network plays a central role in navigation and episodic memory formation. To investigate these interactions, we examined the effect of medial entorhinal cortex lesions on hippocampal place cell activity. Since the medial entorhinal cortex is suggested to play a role in the processing of self-motion information, we hypothesised that such processing would be necessary for maintaining stable place fields in the absence of environmental cues. Place cells were recorded as medial entorhinal cortex-lesioned rats explored a circular arena during five 16-min sessions comprising a baseline session with all sensory inputs available followed by four sessions during which environmental (i.e. visual, olfactory, tactile) cues were progressively reduced to the point that animals could rely exclusively on self-motion cues to maintain stable place fields. We found that place field stability and a number of place cell firing properties were affected by medial entorhinal cortex lesions in the baseline session. When rats were forced to rely exclusively on self-motion cues, within-session place field stability was dramatically decreased in medial entorhinal cortex rats relative to SHAM rats. These results support a major role of the medial entorhinal cortex in processing self-motion cues, with this information being conveyed to the hippocampus to help anchor and maintain a stable spatial representation during movement.

Effects of PACAP-38 and an analog, acetyl-[Ala15, Ala20] PACAP-38-propylamide, on memory consolidation in the detection of spatial novelty task in rats.

PACAP-38 (P38) is a pleiotropic peptide that exerts multiple peripheral and central actions, including neurotrophic, neuroprotective and anti-inflammatory actions. Previous studies have suggested an improvement of memory in rats that have received a single systemic injection of P38. In a therapeutic perspective, we used an analog, acetyl-[Ala15, Ala20]PACAP-38-propylamide (ALG), to improve both stability and affinity for PAC1 receptors vs. endogen PACAP. We investigated the effect of P38 and ALG on memory consolidation using a spatial novelty detection (SND) task in which rats had to memorize a configuration of objects to identify that, during a test session, a familiar object has been moved to a new location. Rats received an intravenous injection of P38 or ALG after the last training session. In Experiment 1, P38 (30 µg/kg) improved spatial memory consolidation allowing detection of novelty vs. saline injection. In Experiment 2, we confirmed this effect and showed that P38 restored the performance similar to what was found using non-injected rats. This suggests that, contrary to ALG, P38 exerted a promesiant rather than an anxiety-related effect whereas ALG did not show similar action. We also examined whether P38 effect involved an interaction with NR2B-containing NMDA receptors (NMDARs) by administrating ifenprodil (IFE; a selective NR2B-containing NMDAR antagonist) alone or in combination with P38 or ALG. The results suggested that P38 action on memory involved NR2B-containing NMDARs. Lastly, brain-derived neutrophic factor (BDNF) modulation appeared to be not related to the behavioral performance in the SND task. Overall, the results indicate that P38 exerted a beneficial effect on memory consolidation in a non-associative task, whereas ALG did not have this action.

Different CA1 and CA3 representations of novel routes in a shortcut situation.

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. To further understand the relationships between place cell firing and spatial problem solving, we examined the discharge of CA1 and CA3 place cells as rats were exposed to a shortcut in a runway maze. On specific sessions, a wall section of the maze was removed so as to open a shorter novel route within the otherwise familiar maze. We found that the discharge of both CA1 and CA3 cells was strongly affected in the vicinity of the shortcut region but was much less affected farther away. In addition, CA3 fields away from the shortcut were more altered than CA1 fields. Thus, place cell firing appears to reflect more than just the animal's spatial location and may provide additional information about possible motions, or routes, within the environment. This kinematic representation appears to be spatially more extended in CA3 than in CA1, suggesting interesting computational differences between the two subregions.

Role of the parietal cortex in long-term representation of spatial information in the rat.

The processing of spatial information in the brain requires a network of structures within which the hippocampus plays a prominent role by elaborating an allocentric representation of space. The parietal cortex has long been suggested to have a complementary function. An overview of lesion and unit recording data in the rat indicates that the parietal cortex is involved in different aspects of spatial information processing including allocentric and egocentric processing. More specifically, the data suggest that the parietal cortex plays a fundamental role in combining visual and motion information, a process that would be important for an egocentric-to-allocentric transformation process. Furthermore, the parietal cortex may also have a role in the long-term storage of representation although this possibility needs further evidence. The data overall show that the parietal cortex occupies a unique position in the brain at the interface of perception and representation.

Effects of prolonged iron overload and low frequency electromagnetic exposure on spatial learning and memory in the young rat.

Low-frequency electromagnetic fields (EMF) have been suggested to affect the brain via alterations of blood-brain barrier permeability to iron. Because of an immature blood-brain barrier, the young brain may be particularly vulnerable to EMF exposure. It is therefore possible that behavioral and neurotoxic effects resulting from EMF-induced iron excess in the brain would be greater in young adults. The objective of the present study was to investigate the interaction between low-frequency EMF and iron overload in young rats. In Experiment 1, we tested the effects of iron overload on spatial learning and memory. Iron treatment did not affect performance in a reference (Morris water maze) and a working memory task (8-arm radial maze). In contrast, detection of a spatial change in an object exploration task was impaired. These effects correlated with modifications of the serotoninergic metabolism. In Experiment 2, the combination of EMF exposure and iron overload was tested. As in Experiment 1, rats were not impaired in reference and working memory tasks but were mildly impaired in the detection of the spatial change. Overall, the results showed an effect of iron overload on spontaneous spatial memory processes. However, low-frequency EMF exposure did not potentiate the effects of iron overload in young rats.

Path integration maintains spatial periodicity of grid cell firing in a 1D circular track.

Entorhinal grid cells are thought to provide a 2D spatial metric of the environment. In this study we demonstrate that in a familiar 1D circular track (i.e., a continuous space) grid cells display a novel 1D equidistant firing pattern based on integrated distance rather than travelled distance or time. In addition, field spacing is increased compared to a 2D open field, probably due to a reduced access to the visual cue in the track. This metrical modification is accompanied by a change in LFP theta oscillations, but no change in intrinsic grid cell rhythmicity, or firing activity of entorhinal speed and head-direction cells. These results suggest that in a 1D circular space grid cell spatial selectivity is shaped by path integration processes, while grid scale relies on external information.

Comparison of the effects of PACAP-38 and its analog, acetyl-[Ala15, Ala20] PACAP-38-propylamide, on spatial memory, post-learning BDNF expression and oxidative stress in rat.

We compared the effects of single intraveinous injection of pituitary adenylate cyclase-activating polypeptide-38 (P38) to those of its analog, acetyl-[Ala15, Ala20]PACAP-38-propylamide (P38-alg) on spatial memory in the Morris water maze (MWM) using a weak massed-learning procedure, post-training brain derived neurotrophic factor (BDNF) and post-training oxidative stress biomarker assays in male Wistar rats. Acquisition of the MWM task following P38 (30 µg/kg) and P38-alg (30 µg/kg) treatments was similar to control group (Saline: 0.9% NaCl) and there was no interaction between treatments and performance. However, in the probe test, P38-treated group showed a specific interest for the target quadrant whereas the two other groups exhibited less focused place searching behavior. Moreover, P38 had an anxiogenic effect as measured by the distribution of swimming at the periphery of the pool. The swimming test resulted in a decrease in BDNF contents in the hippocampus. P38 but not P38-alg treatment restored BDNF expression. In terms of oxidative stress, both P38 and P38-alg treatments had antioxidative effects. The activity of antioxidative enzymes in the neocortex was increased. However only P38 reduced the levels of carbonylated proteins (CP). These data show that P38 and P38-alg have different behavioral and neurobiological effects. Thus, P38-alg and other analogs with specific functional profiles, inducing beneficial central effects (e.g. neuroprotection) while minimizing undesired peripheral effects may be useful for potential therapeutical use.

Plasminogen Activator Inhibitor-1 (PAI-1) deficiency predisposes to depression and resistance to treatments.

Major depressive disorder (MDD) is one of the most frequent psychiatric illnesses, leading to reduced quality of life, ability to work and sociability, thus ranking among the major causes of disability and morbidity worldwide. To date, genetic and environmental determinants of MDD remain mostly unknown. Here, we investigated whether and how the Plasminogen Activator Inhibitor-1 (PAI-1) may contribute to MDD. We first examined the phenotype of PAI-1 knockout (PAI-1-/-) and wild-type (PAI-1+/+) male mice with a range of behavioral tests assessing depressive-like behaviors (n = 276). We next investigated the mechanisms relating PAI-1 to MDD using molecular, biochemical and pharmacological analyzes. We demonstrate here that PAI-1 plays a key role in depression by a mechanism independent of the tissue-type Plasminogen Activator (tPA) - Brain-Derived Neurotrophic Factor (BDNF) axis, but associated with impaired metabolisms of serotonin and dopamine. Our data also reveal that PAI-1 interferes with therapeutic responses to selective serotonin reuptake inhibitors (escitalopram, fluoxetine). We thus highlight a new genetic preclinical model of depression, with the lack of PAI-1 as a factor of predisposition to MDD. Altogether, these original data reveal that PAI-1 should be now considered as a key player of MDD and as a potential target for the development of new drugs to cure depressive patients resistant to current treatments.

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.