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.

Dorsal, but not ventral, hippocampal inactivation alters deliberation in rats.

When facing a choice at a decision point in a maze, rats often display hesitations, pauses and reorientations. Such "vicarious trial and error" (VTE) behavior is thought to reflect decision making about which choice option is best, and thus a deliberation process. Although deliberation relies on a wide neural network, the dorsal hippocampus appears to play a prominent role through both its neural activity and its dynamic interplay with other brain areas. In contrast, the involvement of the ventral hippocampus in deliberation is unexplored. Here, we compared directly the effects of dorsal (dHPC) and ventral intermediate (vHPC) hippocampal inactivations induced by intracerebral muscimol injections on VTE behavior as a model of deliberation. To this aim, we analyzed VTE events as rats were required to switch strategy to a new unlearned reward rule. We used a protocol in which task performance in muscimol-injected animals was minimally altered so as to evidence specific effects on VTE behavior. Our results show subtle alterations in VTE behavior following dHPC, but not vHPC, inactivations, therefore suggesting a specific contribution of the dorsal hippocampus to deliberation through its role in prospective evaluation of future actions.

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.

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.

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.

Spared cognitive and behavioral functions prior to epilepsy onset in a rat model of subcortical band heterotopia.

Subcortical band heterotopia (SBH), also known as doublecortex syndrome, is a malformation of cortical development resulting from mutations in the doublecortin gene (DCX). It is characterized by a lack of migration of cortical neurons that accumulate in the white matter forming a heterotopic band. Patients with SBH may present mild to moderate intellectual disability as well as epilepsy. The SBH condition can be modeled in rats by in utero knockdown (KD) of Dcx. The affected cells form an SBH reminiscent of that observed in human patients and the animals develop a chronic epileptic condition in adulthood. Here, we investigated if the presence of a SBH is sufficient to induce cognitive impairment in juvenile Dcx-KD rats, before the onset of epilepsy. Using a wide range of behavioral tests, we found that the presence of SBH did not appear to affect motor control or somatosensory processing. In addition, cognitive abilities such as learning, short-term and long-term memory, were normal in pre-epileptic Dcx-KD rats. We suggest that the SBH presence is not sufficient to impair these behavioral functions.

Using MRI to predict the fate of excitotoxic lesions in rats.

Excitotoxic lesions are frequently used to assess the role of cerebral structures in cognitive processes in rodents. However, the precise site and extent of these lesions remain unknown without histological verifications. Using a 7-Teslas MRI system and a T2-weighted turbo-RARE sequence, MR images were acquired at several time points following NMDA lesions (1h, 6h, 24h, 48h, 1 week and 2 weeks). NMDA infusions into the parenchyma induced a clear and delineable hyperintense signal from 1h up to 1-week post-surgery. Hyperintensity volumes were compared with NeuN and Cresyl violet histological quantifications of the lesion magnitude. NMDA-induced hypersignal is observed as soon as 1h post-injection and is a reliable estimate of the presence (or absence) of a lesion. Compared to NeuN, Cresyl violet staining underestimates the extent of the lesion in significant proportions. The MRI hyperintensity generated by NMDA instillation into the parenchyma can be used as a powerful tool to confirm the diffusion of the drug into the cerebral tissue, to ascertain the locus of injection and predict with a high success rate the fate of NMDA lesions as soon as 1h post-surgery. This approach could be very useful in a large variety of lesion studies in rodents.

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.

Medial entorhinal cortex and medial septum contribute to self-motion-based linear distance estimation.

Path integration is a navigation strategy that requires animals to integrate self-movements during exploration to determine their position in space. The medial entorhinal cortex (MEC) has been suggested to play a pivotal role in this process. Grid cells, head-direction cells, border cells as well as speed cells within the MEC collectively provide a dynamic representation of the animal position in space based on the integration of self-movements. All these cells are strongly modulated by theta oscillations, thus suggesting that theta rhythmicity in the MEC may be essential for integrating and coordinating self-movement information during navigation. In this study, we first show that excitotoxic MEC lesions, but not dorsal hippocampal lesions, impair the ability of rats to estimate linear distances based on self-movement information. Next, we report similar deficits following medial septum inactivation, which strongly impairs theta oscillations in the entorhinal-hippocampal circuits. Taken together, these findings demonstrate a major role of the MEC and MS in estimating distances to be traveled, and point to theta oscillations within the MEC as a neural mechanism responsible for the integration of information generated by linear self-displacements.

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.

Vestibular control of entorhinal cortex activity in spatial navigation.

Navigation in rodents depends on both self-motion (idiothetic) and external (allothetic) information. Idiothetic information has a predominant role when allothetic information is absent or irrelevant. The vestibular system is a major source of idiothetic information in mammals. By integrating the signals generated by angular and linear accelerations during exploration, a rat is able to generate and update a vector pointing to its starting place and to perform accurate return. This navigation strategy, called path integration, has been shown to involve a network of brain structures. Among these structures, the entorhinal cortex (EC) may play a pivotal role as suggested by lesion and electrophysiological data. In particular, it has been recently discovered that some neurons in the medial EC display multiple firing fields producing a regular grid-like pattern across the environment. Such regular activity may arise from the integration of idiothetic information. This hypothesis would be strongly strengthened if it was shown that manipulation of vestibular information interferes with grid cell activity. In the present paper we review neuroanatomical and functional evidence indicating that the vestibular system influences the activity of the brain network involved in spatial navigation. We also provide new data on the effects of reversible inactivation of the peripheral vestibular system on the EC theta rhythm. The main result is that tetrodotoxin (TTX) administration abolishes velocity-controlled theta oscillations in the EC, indicating that vestibular information is necessary for EC activity. Since recent data demonstrate that disruption of theta rhythm in the medial EC induces a disorganization of grid cell firing, our findings indicate that the integration of idiothetic information in the EC is essential to form a spatial representation of the environment.

Variation in brain organization of coral reef fish larvae according to life history traits.

In coral reefs, one of the great mysteries of teleost fish ecology is how larvae locate the relatively rare patches of habitat to which they recruit. The recruitment of fish larvae to a reef, after a pelagic phase lasting between 10 and 120 days, depends strongly on larval ability to swim and detect predators, prey and suitable habitat via sensory cues. However, no information is available about the relationship between brain organization in fish larvae and their sensory and swimming abilities at recruitment. For the first time, we explore the structural diversity of brain organization (comparative sizes of brain subdivisions: telencephalon, mesencephalon, cerebellum, vagal lobe and inferior lobe) among larvae of 25 coral reef fish species. We then investigate links between variation in brain organization and life history traits (swimming ability, pelagic larval duration, social behavior, diel activity and cue use relying on sensory perception). After accounting for phylogeny with independent contrasts, we found that brain organization covaried with some life history traits: (1) fish larvae with good swimming ability (>20 cm/s), a long pelagic duration (>30 days), diurnal activity and strong use of cues relying on sensory perception for detection of recruitment habitat had a larger cerebellum than other species. (2) Fish larvae with a short pelagic duration (<30 days) and nocturnal activity had a larger mesencephalon and telencephalon. Lastly, (3) fish larvae exhibiting solitary behavior during their oceanic phase had larger inferior and vagal lobes. Overall, we hypothesize that a well-developed cerebellum may allow fish larvae to improve their chances of successful recruitment after a long pelagic phase in the ocean. Our study is the first one to bring together quantitative information on brain organization and the relative development of major brain subdivisions across coral reef fish larvae, and more specifically to address the way in which this variation correlates with the recruitment process.

Spatial learning, monoamines and oxidative stress in rats exposed to 900 MHz electromagnetic field in combination with iron overload.

The increasing use of mobile phone technology over the last decade raises concerns about the impact of high frequency electromagnetic fields (EMF) on health. More recently, a link between EMF, iron overload in the brain and neurodegenerative disorders including Parkinson's and Alzheimer's diseases has been suggested. Co-exposure to EMF and brain iron overload may have a greater impact on brain tissues and cognitive processes than each treatment by itself. To examine this hypothesis, Long-Evans rats submitted to 900 MHz exposure or combined 900 MHz EMF and iron overload treatments were tested in various spatial learning tasks (navigation task in the Morris water maze, working memory task in the radial-arm maze, and object exploration task involving spatial and non spatial processing). Biogenic monoamines and metabolites (dopamine, serotonin) and oxidative stress were measured. Rats exposed to EMF were impaired in the object exploration task but not in the navigation and working memory tasks. They also showed alterations of monoamine content in several brain areas but mainly in the hippocampus. Rats that received combined treatment did not show greater behavioral and neurochemical deficits than EMF-exposed rats. None of the two treatments produced global oxidative stress. These results show that there is an impact of EMF on the brain and cognitive processes but this impact is revealed only in a task exploiting spontaneous exploratory activity. In contrast, there are no synergistic effects between EMF and a high content of iron in the brain.

Independence of landmark and self-motion-guided navigation: a different role for grid cells.

Recent interest in the neural bases of spatial navigation stems from the discovery of neuronal populations with strong, specific spatial signals. The regular firing field arrays of medial entorhinal grid cells suggest that they may provide place cells with distance information extracted from the animal's self-motion, a notion we critically review by citing new contrary evidence. Next, we question the idea that grid cells provide a rigid distance metric. We also discuss evidence that normal navigation is possible using only landmarks, without self-motion signals. We then propose a model that supposes that information flow in the navigational system changes between light and dark conditions. We assume that the true map-like representation is hippocampal and argue that grid cells have a crucial navigational role only in the dark. In this view, their activity in the light is predominantly shaped by landmarks rather than self-motion information, and so follows place cell activity; in the dark, their activity is determined by self-motion cues and controls place cell activity. A corollary is that place cell activity in the light depends on non-grid cells in ventral medial entorhinal cortex. We conclude that analysing navigational system changes between landmark and no-landmark conditions will reveal key functional properties.

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.