Breaking a dogma: acute anti-inflammatory treatment alters both post-lesional functional recovery and endogenous adaptive plasticity mechanisms in a rodent model of acute peripheral vestibulopathy.

BACKGROUND: Due to their anti-inflammatory action, corticosteroids are the reference treatment for brain injuries and many inflammatory diseases. However, the benefits of acute corticotherapy are now being questioned, particularly in the case of acute peripheral vestibulopathies (APV), characterized by a vestibular syndrome composed of sustained spinning vertigo, spontaneous ocular nystagmus and oscillopsia, perceptual-cognitive, posturo-locomotor, and vegetative disorders. We assessed the effectiveness of acute corticotherapy, and the functional role of acute inflammation observed after sudden unilateral vestibular loss. METHODS: We used the rodent model of unilateral vestibular neurectomy, mimicking the syndrome observed in patients with APV. We treated the animals during the acute phase of the vestibular syndrome, either with placebo or methylprednisolone, an anti-inflammatory corticosteroid. At the cellular level, impacts of methylprednisolone on endogenous plasticity mechanisms were assessed through analysis of cell proliferation and survival, glial reactions, neuron's membrane excitability, and stress marker. At the behavioral level, vestibular and posturo-locomotor functions' recovery were assessed with appropriate qualitative and quantitative evaluations. RESULTS: We observed that acute treatment with methylprednisolone significantly decreases glial reactions, cell proliferation and survival. In addition, stress and excitability markers were significantly impacted by the treatment. Besides, vestibular syndrome's intensity was enhanced, and vestibular compensation delayed under acute methylprednisolone treatment. CONCLUSIONS: We show here, for the first time, that acute anti-inflammatory treatment alters the expression of the adaptive plasticity mechanisms in the deafferented vestibular nuclei and generates enhanced and prolonged vestibular and postural deficits. These results strongly suggest a beneficial role for acute endogenous neuroinflammation in vestibular compensation. They open the way to a change in dogma for the treatment and therapeutic management of vestibular patients.

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.

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.

Ventral striatal plasticity and spatial memory.

Spatial memory formation is a dynamic process requiring a series of cellular and molecular steps, such as gene expression and protein translation, leading to morphological changes that have been envisaged as the structural bases for the engram. Despite the role suggested for medial temporal lobe plasticity in spatial memory, recent behavioral observations implicate specific components of the striatal complex in spatial information processing. However, the potential occurrence of neural plasticity within this structure after spatial learning has never been investigated. In this study we demonstrate that blockade of cAMP response element binding protein-induced transcription or inhibition of protein synthesis or extracellular proteolytic activity in the ventral striatum impairs long-term spatial memory. These findings demonstrate that, in the ventral striatum, similarly to what happens in the hippocampus, several key molecular events crucial for the expression of neural plasticity are required in the early stages of spatial memory formation.

Strategy inference during learning via cognitive activity-based credit assignment models.

We develop a method for selecting meaningful learning strategies based solely on the behavioral data of a single individual in a learning experiment. We use simple Activity-Credit Assignment algorithms to model the different strategies and couple them with a novel hold-out statistical selection method. Application on rat behavioral data in a continuous T-maze task reveals a particular learning strategy that consists in chunking the paths used by the animal. Neuronal data collected in the dorsomedial striatum confirm this strategy.

Long-lasting spatial memory deficits and impaired hippocampal plasticity following unilateral vestibular loss.

Unilateral vestibular loss (UVL) induces a characteristic vestibular syndrome composed of various posturo-locomotor, oculomotor, vegetative and perceptivo-cognitive symptoms. Functional deficits are progressively recovered over time during vestibular compensation, that is supported by the expression of multiscale plasticity mechanisms. While the dynamic of post-UVL posturo-locomotor and oculomotor deficits is well characterized, the expression over time of the cognitive deficits, and in particular spatial memory deficits, is still debated. In this study we aimed at investigating spatial memory deficits and their recovery in a rat model of unilateral vestibular neurectomy (UVN), using a wide spectrum of behavioral tasks. In parallel, we analyzed markers of hippocampal plasticity involved in learning and memory. Our results indicate the UVN affects all domains of spatial memory, from working memory to reference memory and object-in-place recognition. These deficits are associated with long-lasting impaired plasticity in the ipsilesional hippocampus. These results highlight the crucial role of symmetrical vestibular information in spatial memory and contribute to a better understanding of the cognitive disorders observed in vestibular patients.

Rats build and update topological representations through exploration.

Although rats are able to build complex spatial representations of their surroundings during exploration, the nature of the encoded information is still a matter for debate. In particular, it is not well established if rats can process the topological structure of the environment in such a way that they are aware of the connections existing between remote places. Here, rats were first exposed for four 5-min trials to a complex environment divided into several sectors that were separated by doors allowing either unrestricted or restricted access to other sectors. In the fifth test trial, we measured the behavior of the animals while they explored the same environment in which, however, they faced changes that either altered or did not alter the topological structure of the environment. In experiment 1, closing previously opened doors prevented the rat from having direct access between corresponding sectors. In experiment 2, opening previously closed doors allowed direct access between sectors that had not been directly accessible. In each experiment, control doors allowed us to discard the mere influence of door manipulation. We compared the rats' exploratory behavior in response to door manipulations that either strongly altered or did not alter the ability to commute between sectors and found evidence that the animals displayed differential reactions to the two types of door manipulations. This implies that during exploration rats build a precise map of the connectivity of space that can be flexibly updated and used for efficient navigation.

Contributions of dorsal striatal subregions to spatial alternation behavior.

Considerable evidence has shown a clear dissociation between the dorsomedial (DMS) and the dorsolateral (DLS) striatum in instrumental conditioning. In particular, DMS activity is necessary to form action-outcome associations, whereas the DLS is required for developing habitual behavior. However, few studies have investigated whether a similar dissociation exists in more complex goal-directed learning processes. The present study examined the role of the two structures in such complex learning by analyzing the effects of excitotoxic DMS and DLS lesions during the acquisition and extinction of spatial alternation behavior, in a continuous alternation T-maze task. We demonstrate that DMS and DLS lesions have opposite effects, the former impairing and the latter improving animal performance during learning and extinction. DMS lesions may impair the acquisition of spatial alternation behavior by disrupting the signal necessary to link a goal with a specific spatial sequence. In contrast, DLS lesions may accelerate goal-driven strategies by minimizing the influence of external stimuli on the response, thus increasing the impact of action-reward contingencies. Taken together, these results suggest that DMS- and DLS-mediated learning strategies develop in parallel and compete for the control of the behavioral response early in learning.

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.

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.

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.

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.

Effects of intra-accumbens NMDA and AMPA receptor antagonists on short-term spatial learning in the Morris water maze task.

Glutamatergic transmission within the nucleus accumbens (Nac) is considered to subserve the transfer of different types of information from the cortical and limbic regions. In particular, it has been suggested that glutamatergic afferences from the hippocampus and the prefrontal cortex provide the main source of contextual information to the Nac. Accordingly, several authors have demonstrated that the blockade of glutamate receptors within the Nac impairs various spatial tasks. However, the exact role of the different classes of glutamate receptors within the Nac in short-term spatial memory is still not clear. In this study we investigated the involvement of two major classes of glutamate receptors, NMDA and AMPA receptors, within the Nac in the acquisition of spatial information, using the Morris water maze task. Focal injections of the NMDA antagonist, AP-5 (0.1 and 0.15 microg/side), and the AMPA antagonist, DNQX (0.005, 0.01 microg/side), were performed before a massed training phase, and mice were tested for retention immediately after. NMDA and AMPA receptor blockade induced no effect during training. On the contrary, injection of the two glutamatergic antagonists impaired spatial localization during the probe test. These data demonstrate an involvement of the Nac in short-term spatial learning. Moreover, they prove that within this structure the short-term processing of spatial information needs the activation of both NMDA and AMPA receptors.

Disentangling the Role of the MEC and LEC in the Processing of Spatial and Non-Spatial Information: Contribution of Lesion Studies.

It is now widely accepted that the entorhinal cortex (EC) plays a pivotal role in the processing of spatial information and episodic memory. The EC is segregated into two sub-regions, the medial EC (MEC) and the lateral EC (LEC) but a comprehensive understanding of their roles across multiple behavioral contexts remains unclear. Considering that it is still useful to investigate the impact of lesions of EC on behavior, we review the contribution of lesion approach to our knowledge of EC functions. We show that the MEC and LEC play different roles in the processing of spatial and non-spatial information. The MEC is necessary to the use of distal but not proximal landmarks during navigation and is crucial for path integration, in particular integration of linear movements. Consistent with predominant hypothesis, the LEC is important for combining the spatial and non-spatial aspects of the environment. However, object exploration studies suggest that the functional segregation between the MEC and the LEC is not as clearly delineated and is dependent on environmental and behavioral factors. Manipulation of environmental complexity and therefore of cognitive demand shows that the MEC and the LEC are not strictly necessary to the processing of spatial and non-spatial information. In addition we suggest that the involvement of these sub-regions can depend on the kind of behavior, i.e., navigation or exploration, exhibited by the animals. Thus, the MEC and the LEC work in a flexible manner to integrate the "what" and "where" information in episodic memory upstream the hippocampus.

Processing of spatial and non-spatial information in rats with lesions of the medial and lateral entorhinal cortex: Environmental complexity matters.

The entorhinal-hippocampal circuitry has been suggested to play an important role in episodic memory but the contribution of the entorhinal cortex remains elusive. Predominant theories propose that the medial entorhinal cortex (MEC) processes spatial information whereas the lateral entorhinal cortex (LEC) processes non spatial information. A recent study using an object exploration task has suggested that the involvement of the MEC and LEC spatial and non-spatial information processing could be modulated by the amount of information to be processed, i.e. environmental complexity. To address this hypothesis we used an object exploration task in which rats with excitotoxic lesions of the MEC and LEC had to detect spatial and non-spatial novelty among a set of objects and we varied environmental complexity by decreasing the number of objects or amount of object diversity. Reducing diversity resulted in restored ability to process spatial and non-spatial information in MEC and LEC groups, respectively. Reducing the number of objects yielded restored ability to process non-spatial information in the LEC group but not the ability to process spatial information in the MEC group. The findings indicate that the MEC and LEC are not strictly necessary for spatial and non-spatial processing but that their involvement depends on the complexity of the information to be processed.

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.

Effects of intra-accumbens focal administrations of glutamate antagonists on object recognition memory in mice.

Generally recognition memory is distinguished into spatial and object memories that have been suggested to relay at a cortical level on different neural substrates. Recent studies point to a possible involvement of the nucleus accumbens (Nac) in spatial memory, demonstrating that blockade of glutamate antagonists within this structure impairs acquisition and consolidation of spatial information, while not many data are available on the potential role of this structure in object recognition. Thus in this study we wanted to investigate the effects of intra-accumbens focal administrations of NMDA antagonist, AP-5 (0.05, 0.1, 0.15 or 0.2 microg per side), and AMPA antagonist, DNQX (0.0005 or 0.001 microg per side), in object recognition memory. The spontaneous preference displayed by mice for novel objects was taken as an index for measuring object recognition. Pre-training focal administrations of both antagonists impaired the ability of mice to selectively explore the novel object in test session. However, the AMPA antagonist induced also a decrease in exploration and locomotion. In order to assess whether glutamate receptors located within the Nac were also involved in subsequent steps of object information processing, we performed additional experiments injecting AP-5 and DNQX immediately after training and testing the animals 24-h later. In this case, AP-5 but not the AMPA antagonist impaired exploration of the novel object. These results demonstrate that the Nac is involved in object recognition, and confirm that the different glutamate receptors mediate different component of information processing within the accumbens.