Olfactory traces and spatial learning in rats.

We conducted an experiment to assess the use of olfactory traces for spatial orientation in an open environment in rats, Rattus norvegicus. We trained rats to locate a food source at a fixed location from different starting points, in the presence or absence of visual information. A single food source was hidden in an array of 19 petri dishes regularly arranged in an open-field arena. Rats were trained to locate the food source either in white light (with full access to distant visuospatial information) or in darkness (without any visual information). In both cases, the goal was in a fixed location relative to the spatial frame of reference. The results of this experiment revealed that the presence of noncontrolled olfactory traces coherent with the spatial frame of reference enables rats to locate a unique position as accurately in darkness as with full access to visuospatial information. We hypothesize that the olfactory traces complement the use of other orientation mechanisms, such as path integration or the reliance on visuospatial information. This experiment demonstrates that rats can rely on olfactory traces for accurate orientation, and raises questions about the establishment of such traces in the absence of any other orientation mechanism. Copyright 1998 The Association for the Study of Animal Behaviour.

Spatial learning by rats across visually disconnected environments

Experiments were designed to examine some properties of spatial representations in rats. Adult subjects were trained to escape through a hole at a fixed position in a large circular arena (see Schenk 1989). The experiments were conducted in the dark, with a limited number of controlled visual light cues in order to assess the minimal cue requirement for place learning. Three identical light cues (shape, height and distance from the table) were used. Depending on the condition, they were either permanently on, or alternatively on or off, depending on the position of the rat in the field. Two questions were asked: a) how many identical visual cues were necessary for spatial discrimination in the dark, and b) could rats integrate the relative positions of separate cues, under conditions in which the rat was never allowed to perceive all three cues simultaneously. The results suggest that rats are able to achieve a place discrimination task even if the three cues necessary for efficient orientation can never be seen simultaneously. A dissociation between the discrimination of the spatial position of the goal and the capacity to reach it by a direct path suggests that a reduced number of cues might require prolonged locomotion to allow an accurate orientation in the environment.

Spatial learning by rats across visually disconnected environments

Two spatial tasks were designed to test specific properties of spatial representation in rats. In the first task, rats were trained to locate an escape hole at a fixed position in a visually homogeneous arena. This arena was connected with a periphery where a full view of the room environment existed. Therefore, rats were dependent on their memory trace of the previous position in the periphery to discriminate a position within the central region. Under these experimental conditions, the test animals showed a significant discrimination of the training position without a specific local view. In the second task, rats were trained in a radial maze consisting of tunnels that were transparent at their distal ends only. Because the central part of the maze was non-transparent, rats had to plan and execute appropriate trajectories without specific visual feedback from the environment. This situation was intended to encourage the reliance on prospective memory of the non-visited arms in selecting the following move. Our results show that acquisition performance was only slightly decreased compared to that shown in a completely transparent maze and considerably higher than in a translucent maze or in darkness. These two series of experiments indicate (1) that rats can learn about the relative position of different places with no common visual panorama, and (2) that they are able to plan and execute a sequence of visits to several places without direct visual feed-back about their relative position.

Metabolic activation pattern of distinct hippocampal subregions during spatial learning and memory retrieval.

Activation dynamics of hippocampal subregions during spatial learning and their interplay with neocortical regions is an important dimension in the understanding of hippocampal function. Using the (14C)-2-deoxyglucose autoradiographic method, we have characterized the metabolic changes occurring in hippocampal subregions in mice while learning an eight-arm radial maze task. Autoradiogram densitometry revealed a heterogeneous and evolving pattern of enhanced metabolic activity throughout the hippocampus during the training period and on recall. In the early stages of training, activity was enhanced in the CA1 area from the intermediate portion to the posterior end as well as in the CA3 area within the intermediate portion of the hippocampus. At later stages, CA1 and CA3 activations spread over the entire longitudinal axis, while dentate gyrus (DG) activation occurred from the anterior to the intermediate zone. Activation of the retrosplenial cortex but not the amygdala was also observed during the learning process. On recall, only DG activation was observed in the same anterior part of the hippocampus. These results suggest the existence of a functional segmentation of the hippocampus, each subregion being dynamically but also differentially recruited along the acquisition, consolidation, and retrieval process in parallel with some neocortical sites.

Ibotenate Lesions of Hippocampus and/or Subiculum: Dissociating Components of Allocentric Spatial Learning

This study examined the effects of ibotenic acid-induced lesions of the hippocampus, subiculum and hippocampus +/- subiculum upon the capacity of rats to learn and perform a series of allocentric spatial learning tasks in an open-field water maze. The lesions were made by infusing small volumes of the neurotoxin at a total of 26 (hippocampus) or 20 (subiculum) sites intended to achieve complete target cell loss but minimal extratarget damage. The regional extent and axon-sparing nature of these lesions was evaluated using both cresyl violet and Fink - Heimer stained sections. The behavioural findings indicated that both the hippocampus and subiculum lesions caused impairment to the initial postoperative acquisition of place navigation but did not prevent eventual learning to levels of performance almost as effective as those of controls. However, overtraining of the hippocampus + subiculum lesioned rats did not result in significant place learning. Qualitative observations of the paths taken to find a hidden escape platform indicated that different strategies were deployed by hippocampal and subiculum lesioned groups. Subsequent training on a delayed matching to place task revealed a deficit in all lesioned groups across a range of sample choice intervals, but the subiculum lesioned group was less impaired than the group with the hippocampal lesion. Finally, unoperated control rats given both the initial training and overtraining were later given either a hippocampal lesion or sham surgery. The hippocampal lesioned rats were impaired during a subsequent retention/relearning phase. Together, these findings suggest that total hippocampal cell loss may cause a dual deficit: a slower rate of place learning and a separate navigational impairment. The prospect of unravelling dissociable components of allocentric spatial learning is discussed.

Indirect effects of peri-and postnatal choline treatment on place-learning abilities in rat.

This work was aimed at analyzing the effects of perinatal choline supplementation on the development of spatial abilities and upon adult performance. Choline supplementation (3.5 g/L in 0.02 M saccharin solution in tap water) was maintained for two weeks before birth and for up to four weeks postnatally. Additional supplementation was maintained from the fifth to the tenth week postnatally. Spatial-learning capacities were studied at the ages of 26, 65, or 80 days in a circular swimming pool (Morris place-navigation task) and at the age of 7 months in a homing arena. Treatment effects were found in both juvenile and adult rats, and thus persisted for several months after the cessation of the supplementation. The choline supplementation improved the performance in the water maze in a very selective manner. The most consistent effect was a reduction in the latency to reach a cued platform at a fixed position in space, whereas the improvement was limited when the platform was invisible and had to be located relative to distant cues only. However, after removal of the goal cue, the treated rats showed a better retention of the training position than did the control rats. A similar effect was observed in a dry-land task conducted in the homing arena. The choline supplementation thus induced a significant improvement of spatial memory. But since this effect was only evident following training with a salient cue, it might be regarded as an indirect effect promoted by an optimal combination of cue guidance with a place strategy.

Glucose-dependent insulinotropic polypeptide receptor knockout mice are impaired in learning, synaptic plasticity, and neurogenesis.

Glucose-dependent insulinotropic polypeptide (GIP) is a key incretin hormone, released from intestine after a meal, producing a glucose-dependent insulin secretion. The GIP receptor (GIPR) is expressed on pyramidal neurons in the cortex and hippocampus, and GIP is synthesized in a subset of neurons in the brain. However, the role of the GIPR in neuronal signaling is not clear. In this study, we used a mouse strain with GIPR gene deletion (GIPR KO) to elucidate the role of the GIPR in neuronal communication and brain function. Compared with C57BL/6 control mice, GIPR KO mice displayed higher locomotor activity in an open-field task. Impairment of recognition and spatial learning and memory of GIPR KO mice were found in the object recognition task and a spatial water maze task, respectively. In an object location task, no impairment was found. GIPR KO mice also showed impaired synaptic plasticity in paired-pulse facilitation and a block of long-term potentiation in area CA1 of the hippocampus. Moreover, a large decrease in the number of neuronal progenitor cells was found in the dentate gyrus of transgenic mice, although the numbers of young neurons was not changed. Together the results suggest that GIP receptors play an important role in cognition, neurotransmission, and cell proliferation.

Postnatal intracerebroventricular administrations of NGF alter spatial memory in adulthood

The present work assessed the effects of intracerebroventricular injections (2x5 mg/2.5 ml) of recombined human nerve growth factor (rhNGF) at postnatal days 2 and 3 upon the development of spatial learning capacities in rats. The treated rats were trained at the age of 22 days to escape onto an invisible platform at a fixed position in space in a Morris navigation task. For half of the subjects, the training position was also cued, a procedure aimed at facilitating escape and reducing attention to the distant spatial cues. At the age of 2 months all the rats were retrained in the same task. Treatment effects were found in both immature and adult rats. The injection of NGF induced a slight alteration of the immature rats' performance. In contrast, a marked impairment of spatial abilities was shown in the 2-month-old rats. The most consistent effects were a significant increase in the escape latency and a decrease bias towards the training platform area during probe trials. The reduction of spatial memory was particularly marked if the subjects had been trained in a cued condition. Taken together, these experiments reveal that an acute pharmacological treatment that leads to transient modifications during early development might induce a behavioural change long after treatment. Thus, the development and the maintenance of an accurate spatial representation are tightly related to the development of brain structures that could be altered by precocious NGF administrations.

Spatial radial maze procedures and setups to dissociate local and distal relational spatial frameworks in humans.

BACKGROUND: Radial maze tasks have been used to assess optimal foraging and spatial abilities in rodents. The spatial performance was based on a capacity to rely on a configuration of local and distant cues. We adapted maze procedures assessing the relative weight of local cues and distant landmarks for arm choice in humans. NEW METHOD: The procedure allowed testing memory of places in four experimental setups: a fingertip texture-groove maze, a tactile screen maze, a virtual radial maze and a walking size maze. During training, the four reinforced positions remained fixed relative to local and distal cues. During subsequent conflict trials, these frameworks were made conflictive in the prediction of reward locations. RESULTS: Three experiments showed that the relative weight of local and distal relational cues is affected by different factors such as cues' nature, visual access to the environment, real vs. virtual environment, and gender. A fourth experiment illustrated how a walking maze can be used with people suffering intellectual disability. COMPARISON WITH EXISTING METHODS: In our procedure, long-term (reference) and short-term (working) memory can be assessed. It is the first radial task adapted to human that enables dissociating local and distal cues, to provides an indication as to their relative salience. Our mazes are moveable and easily used in limited spaces. Tasks are performed with realistic and spontaneous though controlled exploratory movements. CONCLUSION: Our tasks enabled highlighting the use of different strategies. In a clinical perspective, considering the use of compensatory strategies should orient towards adapted behavioural rehabilitation.

Mise en oeuvre de protocoles spatiaux pour analyser la modulation de processus cognitifs en fonction de la dimension émotionnelle chez le rongeur

Résumé : Emotion et cognition sont deux termes généralement employés pour désigner des processus psychiques de nature opposée. C'est ainsi que les sciences cognitives se sont longtemps efforcées d'écarter la composante «chaude »des processus «froids »qu'elles visaient, si ce n'est pour montrer l'effet dévastateur de la première sur les seconds. Pourtant, les processus cognitifs (de collecte, maintien et utilisation d'information) et émotioAnels (d'activation subjective, physiologique et comportementale face à ce qui est attractif ou aversif) sont indissociables. Par l'approche neuro-éthologique, à l'interface entre le substrat biologique et les manifestations comportementales, nous nous sommes intéressés à une fonction cognitive essentielle, la fonction mnésique, classiquement exprimée chez le rongeur par l'orientation spatiale. Au niveau du substrat, McDonald et White (1993) ont montré la dissociation de trois systèmes de mémoire, avec les rôles de l'hippocampe, du néostriatum et de l'amygdale dans l'encodage des informations respectivement épisodiques, procédurales et émotionnelles. Nous nous sommes penchés sur l'interaction entre ces systèmes en fonction de la dimension émotionnelle par l'éclairage du comportement. L'état émotionnel de l'animal dépend de plusieurs facteurs, que nous avons tenté de contrôler indirectement en comparant leurs effets sur l'acquisition, dans diverses conditions, de la tâche de Morris (qui nécessite la localisation dans un bassin de la position d'une plate-forme submergée), ainsi que sur le style d'exploration de diverses arènes, ouvertes ou fermées, plus ou moins structurées par la présence de tunnels en plexiglas transparent. Nous avons d'abord exploré le rôle d'un composant du système adrénergique dans le rapport à la difficulté et au stress, à l'aide de souris knock-out pour le récepteur à la noradrénaline a-1 B dans un protocole avec 1 ou 4 points de départ dans un bassin partitionné. Ensuite, nous nous sommes penchés, chez le rat, sur les effets de renforcement intermittent dans différentes conditions expérimentales. Dans ces conditions, nous avons également tenté d'analyser en quoi la situation du but dans un paysage donné pouvait interférer avec les effets de certaines formes de stress. Finalement, nous avons interrogé les conséquences de perturbations passées, y compris le renforcement partiel, sur l'organisation des déplacements sur sol sec. Nos résultats montrent la nécessité, pour les souris cont~ô/es dont l'orientation repose sur l'hippocampe, de pouvoir varier les trajectoires, ce qui favoriserait la constitution d'une carte cognitive. Les souris a->B KO s'avèrent plus sensibles au stress et capables de bénéficier de la condition de route qui permet des réponses simples et automatisées, sous-tendues par l'activité du striatum. Chez les rats en bassin 100% renforcé, l'orientation apparaît basée sur l'hippocampe, relayée par le striatum pour le développement d'approches systématiques et rapides, avec réorientation efficace en nouvelle position par réactivation dépendant de l'hippocampe. A 50% de renforcement, on observe un effet du type de déroulement des sessions, transitoirement atténué par la motivation Lorsque les essais s'enchaînent sans pause intrasession, les latences diminuent régulièrement, ce qui suggère une prise en charge possible par des routines S-R dépendant du striatum. L'organisation des mouvements exploratoires apparaît dépendante du niveau d'insécurité, avec différents profils intermédiaires entre la différentiation maximale et la thigmotaxie, qui peuvent être mis en relation avec différents niveaux d'efficacité de l'hippocampe. Ainsi, notre travail encourage à la prise en compte de la dimension émotionnelle comme modulatrice du traitement d'information, tant en phase d'exploration de l'environnement que d'exploitation des connaissances spatiales. Abstract : Emotion and cognition are terms widely used to refer to opposite mental processes. Hence, cognitive science research has for a long time pushed "hot" components away from "cool" targeted processes, except for assessing devastating effects of the former upon the latter. However, cognitive processes (of information collection, preservation, and utilization) and emotional processes (of subjective, physiological, and behavioral activation roue to attraction or aversion) are inseparable. At the crossing between biological substrate and behavioral expression, we studied a chief cognitive function, memory, classically shown in animals through spatial orientation. At the substrate level, McDonald et White (1993) have shown a dissociation between three memory systems, with the hippocampus, neostriatum, and amygdala, encoding respectively episodic, habit, and emotional information. Through the behavior of laboratory rodents, we targeted the interaction between those systems and the emotional axis. The emotional state of an animal depends on different factors, that we tried to check in a roundabout way by the comparison of their effects on acquisition, in a variety of conditions, of the Morris task (in which the location of a hidden platform in a pool is required), as well as on the exploration profile in different apparatus, open-field and closed mazes, more or less organized by clear Plexiglas tunnels. We first tracked the role, under more or less difficult and stressful conditions, of an adrenergic component, with knock-out mice for the a-1 B receptor in a partitioned water maze with 1 or 4 start positions. With rats, we looked for the consequences of partial reinforcement in the water maze in different experimental conditions. In those conditions, we further analyzed how the situation of the goal in the landscape could interfere with the effect of a given stress. At last, we conducted experiments on solid ground, in an open-field and in radial mazes, in order to analyze the organization of spatial behavior following an aversive life event, such as partial reinforcement training in the water maze. Our results emphasize the reliance of normal mice to be able to vary approach trajectories. One of our leading hypotheses is that such strategies are hippocampus-dependent and are best developed for of a "cognitive map like" representation. Alpha-1 B KO mice appear more sensitive to stress and able to take advantage of the route condition allowing simple and automated responses, most likely striatum based. With rats in 100% reinforced water maze, the orientation strategy is predominantly hippocampus dependent (as illustrated by the impairment induced by lesions of this structure) and becomes progressively striatum dependent for the development of systematic and fast successful approaches. Training towards a new platform position requires a hippocampus based strategy. With a 50% reinforcement rate, we found a clear impairment related to intersession disruption, an effect transitorily minimized by motivation enhancement (cold water). When trials are given without intrasession interruption, latencies consistently diminish, suggesting a possibility for striatum dependent stimulus-response routine to occur. The organization of exploratory movements is shown to depend on the level of subjective security, with different intermediary profiles between maximum differentiation and thigmotaxy, which can be considered in parallel with different efficiency levels of the hippocampus dependent strategies. Thus, our work fosters the consideration of emotion as a cognitive treatment modulator, during spatial exploration as well as spatial learning. It leads to a model in which the predominance of hippocampus based exploration is challenged by training conditions of various nature.

Unpacking the cognitive map: the parallel map theory of hippocampal function

In the parallel map theory, the hippocampus encodes space with 2 mapping systems. The bearing map is constructed primarily in the dentate gyrus from directional cues such as stimulus gradients. The sketch map is constructed within the hippocampus proper from positional cues. The integrated map emerges when data from the bearing and sketch maps are combined. Because the component maps work in parallel, the impairment of one can reveal residual learning by the other. Such parallel function may explain paradoxes of spatial learning, such as learning after partial hippocampal lesions, taxonomic and sex differences in spatial learning, and the function of hippocampal neurogenesis. By integrating evidence from physiology to phylogeny, the parallel map theory offers a unified explanation for hippocampal function.

Étude de l'influence de l'activité inflammatoire liée au TNFα sur les altérations cognitives et comportementales et le dépôt de plaques β amyloïdes chez la souris

Résumé Les mutations du gène APP (amyloïde de la protéine de précurseur) sur le chromosome 21 mènent à une surproduction de protéines β amyloïdes dans la maladie d'Alzheimer (MA). Il existe donc un consensus impliquant la cascade amyloïde dans la genèse et le développement de la MA. C'est pourquoi, afin d'évaluer l'hypothèse de la cascade inflammatoire de la MA, on combine des manipulations génétiques chez des modèles de souris transgéniques avec des traitements anti-inflammatoires. Les animaux porteurs d'une mutation génétique induite permettent d'évaluer le rôle de certains gènes dans le développement de la maladie. Pour ce faire j'ai étudié les performances de différentes cohortes de souris soumises à un ensemble de trois épreuves comportementales complémentaires ; la première étudiant les conduites exploratoires, la deuxième évaluant la capacité de l'animal à effectuer un apprentissage de lieu et la troisième explorant l'efficacité des animaux dans une tâche dite d'élimination. Enfin, une évaluation complémentaire a été fondée sur le répertoire des troubles du comportement des animaux. Chez les animaux APP homozygotes, l'organisation de la mémoire se dégrade et se modifie avec l'âge. Chez ces animaux, le déficit des mémoires de références et de travail se manifeste déjà chez les souris jeunes (dès l'âge de 50 jours).De plus, il est apparu un certain nombre de troubles comportementaux. Enfin les APP homozygotes sont ceux qui ont le plus de dépôt de plaques amyloïdes localisé dans l'hippocampe. Chez les animaux APP hétérozygotes, tant la mémoire de référence, utilisée au cours d'un apprentissage de lieu, que la mémoire de travail permettant d'éviter des bras déjà visités, ne sont affectées que chez les sujets de 15 mois. De plus, tous les troubles du comportement sont présents à 15 mois, mais de manière moins intense que chez les animaux APP homozygotes. Un traitement anti-TNF administré aux APP hétérozygotes n'a pas permis d'améliorer leur performance mais a un effet bénéfique sur les troubles du comportement. Enfin, le pourcentage des dépôts de plaques a été estimé à trois fois moins élevé chez ces animaux hétérozygotes de 16 mois que chez les APP homozygotes de 8 mois. Chez les animaux APP hétérozygotes dont le gène TNFα est bloqué, les mémoires de travail et de référence sont altérées déjà à l'âge de 6 mois, en dépit du blocage de l'expression de TNF. Ces jeunes animaux ont même une capacité cognitive inférieure à celle des animaux hétérozygotes APP, en gardant toutefois leur activité et performance exploratoires intactes. Ainsi, il semble que le blocage de l'expression du gène TNFα chez des souris APP n'influence pas leurs capacités cognitives mais permet, d'une part, d'éviter l'apparition des troubles du comportement et d'autre part, ralentit le processus du déclin cognitif. Enfin, le pourcentage de plaques amyloïdes a été évalué à deux fois plus élevés pour les KO TNF-α APP hétérozygotes de 15 mois par rapport à des APP hétérozygotes sans traitement du même âge. Chez les animaux APP hétérozygotes surexprimant le TNFα, cette association génétique péjore la performance cognitive comparée à celle des APP homozygotes. Ces animaux ont une altération des mémoires de travail et de référence équivalente à celle retrouvée chez des APP homozygotes. Un traitement anti-inflammatoire administré à ces souris n'améliore pas la capacité cognitive mais permet d'une part, d'éviter l'apparition des troubles comportementaux, et d'autre part, d'entraîner la presque disparition des plaques amyloïdes. Abstract Mutations on the amyloid precursor protein (APP) gene on chromosome 21 lead to an overproduction of β amyloid in both human early onset familial Alzheimer's Disease (AD) and transgenic (TG) mice. On the other hand, inflammatory responses in the brain seem to contribute to the genesis and evolution of neurodegenerative damage. To study the influence of inflammatory factors - especially TNFα - on brain amyloid and behavioural components, TG mice expressing mutant amyloid precursor protein were treated with anti-TNFα antibody and compared with controls injected with PBS buffer or human globulins, as well as with APP mice knockout for the TNFα gene. The APP/V717 mutation leads to a brain deposit of amyloid and to significant behavioural deficits in both homozygous at different ages and heterozygous only at 15 months. The percentage of amyloid is almost triple in APP+/+ than in APP+/- animals, indicating a gene dosage effect. There is no significant effect of an anti-TNF treatment on the deposit of brain amyloid nor spatial learning capabilities. Transgenic mice show also stereotyped behaviour but the anti-TNF treatment decreases the production of stereotypies. The blockade of gene TNFα seems several cognitive alterations and increases the production of amyloid in APP mice at 15 months; but this combination allows to avoid the appearance of stereotyped behavior and in addition, the process of the cognitive decline slows down. Tg6074 mice (overexpressing TNF) increase deleterious effects on behavioural adaptive resources. Treatment with anti-TNF doesn't show changes in cognitive performances but seems to increase the production of amyloid and the stereotyped behaviour.

JULIDE: a software tool for 3D reconstruction and statistical analysis of autoradiographic mouse brain sections.

In this article we introduce JULIDE, a software toolkit developed to perform the 3D reconstruction, intensity normalization, volume standardization by 3D image registration and voxel-wise statistical analysis of autoradiographs of mouse brain sections. This software tool has been developed in the open-source ITK software framework and is freely available under a GPL license. The article presents the complete image processing chain from raw data acquisition to 3D statistical group analysis. Results of the group comparison in the context of a study on spatial learning are shown as an illustration of the data that can be obtained with this tool.