Nonspatial Changes Research Articles

Involvement of CA1 GABAA Receptors in Ketamine-Induced Impairment of Spatial and Non-Spatial Novelty Detection in Mice

Inhibitory GABAergic and excitatory glutamatergic neurons from multiple brain areas, send fibers to the hippocampal CA1 region. NMDA receptors have been identified as important compoents of the brain system underlying memory formation, which that through an increase in glutamate-mediated neurotransmission. Ketamine and other NMDA receptor antagonists produce deficits in cognitive tasks, including both spatial and non-spatial memory. In the current study, we tested whether the activation or inhibition of GABAA receptors in CA1 hippocampal of mice has an impact on ketamine (NMDA antagonist) induced spatial and non-spatial novelty detection deficits. Adult male mice weighing between 25–30 g were used. The open-field method was used to evaluate spatial and non-spatial memory information. Data obtained from the present study revealed that an intra-CA1 injection with a sub-threshold dose the GABAA receptor antagonist bicuculline (0.0625 µg mouse) disrupted spatial memory but restored non-spatial memory induced by lower and higher doses of ketamine (0.05 and 0.01 mg/kg) respectively. Meanwhile, the co-administration of the intra-CA1 injection with a sub-threshold dose of muscimol (GABAA receptor agonist at 0.25 µg/mouse) and a lower dose of ketamine could only impair the ability of non-spatial change detection but could not alter spatial novelty. In conclusion, ketamine (which contributes to the impairment of memory trace stored in the hippocampus) may be generated from GABAA receptors of CA1 neurons and their blockade could prevent these effects.

Response to spatial and nonspatial change in wild (WWCPS) and Wistar rats

Response to spatial and nonspatial change in wild (WWCPS) and Wistar rats The purpose of the experiment was to investigate the effects of domestication on exploration in rats. The comparison was made between wild Warsaw-Wild-Captive-Pisula-Stryjek (WWCPS) rats and Wistar laboratory rats. The study used a purpose-built maze divided into zones connected with a corridor. Objects were placed in two out of four zones. Their location and shape were subject to experimental manipulation. Transporter used to move rats to the maze provided the opportunity for spontaneous exploration of the experimental arena. Rats were subjected to a series of 10 sessions (habituation), followed by a spatial or nonspatial change in the experimental arena, after which another 5 experimental sessions were conducted. The study revealed that wild rats had much higher exploration latency than their laboratory counterparts. At each analyzed stage, WWCPS rats spent much more time in the transporter than Wistar rats. Wistar rats spent much more time during the experiment on object interaction in the experimental arena. In post-manipulation sessions, however, it was wild rats that explored object zones relatively longer than laboratory rats. No differences in the animals' behavior depending on the type of change were observed. Results suggest that wild rats tend to explore much more cautiously than laboratory rats and are more sensitive to changes in their environment. The underlying cause of these differences is likely to be the higher level of stress in wild rats, resulting from threats in their natural habitat.

Reversibility of object recognition but not spatial memory impairment following binge-like alcohol exposure in rats

Excessive alcohol use leads to neurodegeneration in several brain structures including the hippocampal dentate gyrus and the entorhinal cortex. Cognitive deficits that result are among the most insidious and debilitating consequences of alcoholism. The object exploration task (OET) provides a sensitive measurement of spatial memory impairment induced by hippocampal and cortical damage. In this study, we examine whether the observed neurotoxicity produced by a 4-day binge ethanol treatment results in long-term memory impairment by observing the time course of reactions to spatial change (object configuration) and non-spatial change (object recognition). Wistar rats were assessed for their abilities to detect spatial configuration in the OET at 1 week and 10 weeks following the ethanol treatment, in which ethanol groups received 9–15 g/kg/day and achieved blood alcohol levels over 300 mg/dl. At 1 week, results indicated that the binge alcohol treatment produced impairment in both spatial memory and non-spatial object recognition performance. Unlike the controls, ethanol treated rats did not increase the duration or number of contacts with the displaced object in the spatial memory task, nor did they increase the duration of contacts with the novel object in the object recognition task. After 10 weeks, spatial memory remained impaired in the ethanol treated rats but object recognition ability was recovered. Our data suggest that episodes of binge-like alcohol exposure result in long-term and possibly permanent impairments in memory for the configuration of objects during exploration, whereas the ability to detect non-spatial changes is only temporarily affected.

THE EFFECT OF TASK EXPERIENCE, LONG-TERM DIETARY RESTRICTION AND AGING ON PERFORMANCE IN REFERENCE AND WORKING MEMORY TASKS: A LONGITUDINAL AND CROSS-SECTIONAL DESIGN STUDY

The purpose of this study was to examine the effect of task experience, long-term dietary restriction and aging on spatial cognition. In experiment 1, nineteen rats were divided into restricted (n = 10) or ad libitum feeding (n = 9) groups at 2.5 months of age, then repeatedly trained in Morris water maze task (reference memory task) and delayed-matching-to-place (DMTP) task (working memory task). Dietary conditions did not affect in performing both tasks. However, deteriorated effect of aging was found in performing DMTP task. These results suggest that repeated task experiences protect rats from age-related reference memory deficits, but not from working memory deficits. Experiment 2 compared the performance of young (n = 8) and aged (n = 4) rats in object exploration task. Young rats reacted to both spatial and nonspatial changes in objects, whereas aged rats reacted only to nonspatial change. Thus, it is suggested that the ability to recognize spatial changes is impaired in aged rats.

Mice with reduced NMDA receptor glycine affinity model some of the negative and cognitive symptoms of schizophrenia

Schizophrenic patients demonstrate prominent negative and cognitive symptoms that are poorly responsive to antipsychotic treatment. Abnormal glutamatergic neurotransmission may contribute to these pathophysiological dimensions of schizophrenia. We examined the involvement of the glycine coagonist site on the N-methyl-D: -aspartate receptor (NMDAR) glycine coagonist site in the modulation of negative and cognitive endophenotypes in mice. Behavioral phenotypes relevant to schizophrenia were assessed in Grin1(D481N) mice that have reduced NMDAR glycine affinity. Grin1(D481N) mutant mice showed abnormally persistent latent inhibition (LI) that was reversed by two agents that enhance NMDAR glycine site function, D: -serine (600 mg/kg) and ALX-5407 (1 mg/kg), and by the classical atypical antipsychotic clozapine (3 mg/kg). Similarly, blockade of the NMDAR glycine site with the antagonist L-701,324 (5 mg/kg) induced persistent LI in C57BL6/J mice. In a social affiliations task, Grin1(D481N) mutant animals showed reduced social approach behaviors that were normalized by D: -serine (600 mg/kg). During a nonassociative spatial object recognition task, mutant mice demonstrated impaired reactivity to a spatial change that was reversible by D: -serine (300 and 600 mg/kg) and clozapine (0.75 mg/kg). In contrast, responses to social novelty and nonspatial change remained unaffected, indicating that the Grin1(D481N) mutation induces selective deficits in sociability and spatial discrimination, while leaving intact the ability to react to novelty. Genetic and pharmacologically induced deficiencies in glycine binding appear to model the impairments in behavioral flexibility, sociability, and spatial recognition related to the negative and cognitive symptoms of schizophrenia. Antipsychotics that target the NMDAR glycine site may be beneficial in treating such psychiatric symptoms.

Delay-dependent involvement of the rat entorhinal cortex in habituation to a novel environment

Evidence has accumulated that the entorhinal cortex (EC) is involved in memory operations underlying formation of a long-term memory. Because entorhinal-lesioned rats are impaired for long delays in delayed matching and non-matching to sample tasks, it has been proposed that EC contributes to the maintenance of information in short-term memory. In the present study, we asked whether such a time-limited role applies also when learning complex spatial information in a novel environment. We therefore examined the effects of EC lesions on habituation in an object exploration task in which a delay of either 4min or 10min is imposed between successive sessions. EC-lesioned rats exhibited a deficit in habituation at 10min but not 4min delays. Following habituation, reactions to spatial change (object configuration) and non-spatial change (novel object) were also examined. EC-lesioned rats were impaired in detecting the spatial change but were able to detect a non-spatial change, irrespective of the delay. Overall, the results suggest that EC is involved in maintaining a large amount of novel, multidimensional information in short-term memory therefore enabling formation of long-term memory. Switching to a novelty detection mode would then allow the animal to rapidly adapt to environmental changes. In this mode, EC would preferentially process spatial information rather than non-spatial information.

Effects of feature-selective attention on auditory pattern and location processing

Recent neuroimaging studies have suggested that spatial versus nonspatial changes in acoustic stimulation are processed along separate cortical pathways. However, it has remained unclear in how far change-related responses are modulated by selective attention. Thus, we aimed at testing effects of feature-selective attention on the cortical representation of pattern and location of complex natural sounds using human functional magnetic resonance imaging (fMRI) adaptation. We consecutively presented the following pairs of animal vocalizations: (a) two identical animal vocalizations, (b) same animal vocalizations at different locations, (c) different animal vocalizations at the same location, and (d) different animal vocalizations at different locations. Subjects underwent this stimulation under two different task conditions requiring either to match sound identity or location. We observed significant fMRI adaptation effects within the bilateral superior temporal sulcus (STS), planum temporale (PT) and right anterior insula for location changes. For pattern changes, we found adaptation effects within the bilateral superior temporal lobe, in particular along the superior temporal gyrus (STG), PT and posterior STS, the bilateral anterior insula and inferior frontal areas. While the adaptation effects within the pattern-selective temporal lobe areas were robust to task requirements, adaptation within the more posterior location-selective areas was modulated by feature-specific attention. In contrast, inferior frontal cortex and anterior insular exhibited adaptation effects mainly during the location matching task. Given that the location matching task was significantly more difficult than the pattern matching, our data suggest that frontal and insular regions were modulated by task difficulty rather than feature-specific attention.

Spatial deficits in a mouse model of Parkinson disease

Accumulating evidence in humans demonstrated that visuo-spatial deficits are the most consistently reported cognitive abnormalities in Parkinson disease (PD). These deficits have been generally attributed to cortical dopamine degeneration. However, more recent evidence suggests that dopamine loss in the striatum is responsible for the visuo-spatial abnormalities in PD. Studies based on animal models of PD did not specifically address this question. Thus, the first goal of this study was to analyze the role of dopamine within the dorsal striatum in spatial memory. We tested bilateral 6-OHDA striatal lesioned CD1 mice in an object-place association spatial task. Furthermore, to see whether the effects were selective for spatial information, we measured how the 6-OHDA-lesioned animals responded to a non-spatial change and learned in the one-trial inhibitory avoidance task. The results demonstrated that bilateral (approximately 75%) dopamine depletion of the striatum impaired spatial change discrimination. On the contrary, no effect of the lesion was observed on non-spatial novelty detection or on passive avoidance learning. These results confirm that dopamine depletion is accompanied by cognitive deficits and demonstrate that striatal dopamine dysfunction is sufficient to induce spatial information processing deficits.

Dissociations of the medial and lateral perforant path projections into dorsal DG, CA3, and CA1 for spatial and nonspatial (visual object) information processing.

Medial perforant path plasticity can be attenuated by 2-amino-5-phosphonovaleric acid (APV) infusions, whereas lateral perforant path plasticity can be attenuated by naloxone infusions. The present experiment was designed to evaluate the role of each entorhinal efferent pathway into the dorsal hippocampus for detection of spatial and nonspatial (visual object) changes in the overall configuration of environmental stimuli. Dorsal dentate gyrus infusions of either APV or naloxone attenuated detection of a spatial change, whereas only naloxone infusions disrupted novel object detection. Either APV or naloxone infusions into dorsal CA3 disrupted both spatial and novel object detection. APV infusions into dorsal CA1 attenuated detection of a spatial change, whereas naloxone infusions into dorsal CA1 disrupted novel object detection. These data suggest that each dorsal hippocampal subregion processes spatial and nonspatial (visual object) information from perforant path efferents in a unique manner that is consistent with the intrinsic properties of each subregion.

D1 and D2 Receptor Antagonist Injections in the Prefrontal Cortex Selectively Impair Spatial Learning in Mice

The prefrontal cortex (PFC) is a cortical area involved in selecting and retaining information to produce complex behaviors. Within the PFC, the dopaminergic system plays an important role in information processing. Thus, the objective of this study was to test whether bilateral administration of the D1 and D2 receptor antagonists in the prelimbic region of the PFC influenced the performance of mice in a non-associative spatial learning task. CD1 mice were bilaterally microinjected in the PFC with either the D1 receptor antagonist, SCH23390 (SCH 6.25; 12.5; 50 ng), or the D2 receptor antagonist, sulpiride (SULP 12.5; 50; 100 ng) and placed into an open field containing five different objects. After three sessions of habituation two objects were repositioned (spatial change) and in the subsequent session one of the objects was substituted (non-spatial change). No significant alteration was observed in the habituation pattern of the animals after D1 or D2 receptor blockade. When two of the objects were displaced, control mice explored the displaced objects far more than the non-displaced ones, while mice treated with SCH or SULP spent a comparable amount of time re-exploring the two object categories. Conversely, DA antagonists had no effects on the discrimination of the new object. Thus, the administration of both SCH and SULP selectively impaired the ability of mice to discriminate a spatial change, without affecting any other behavioral parameter. These findings could provide a model to study the role of the PFC dopaminergic system in spatial learning and to study the neural mechanisms underlying cognitive and attention deficits often observed in psychiatric disorders.

Study of CA1 place cell activity and exploratory behavior following spatial and nonspatial changes in the environment

Changes in the spatial arrangement or identity of objects inside a familiar environment induce reexploration. The present study looks at modifications of place cell activity during such renewed exploration. Hungry rats foraged for food in a cylinder with a salient cue card attached to the wall and with two distinct objects at fixed positions on the floor relative to each other and to the cue card. Once a set of CA1 place cells was recorded in this standard configuration, additional sessions were done after two kinds of manipulation. In the first, the two objects were rotated as a rigid set 90 degrees counterclockwise around the cylinder center while leaving the cue card in place; this was considered a spatial change. The effects of rotating the objects were different for fields near the objects (near fields) and fields far from the objects (far fields). Object rotation altered most near fields in complex ways, including remapping and cessation of firing. Near fields that remained intact after object rotation underwent unpredictable rotations that frequently departed considerably from the expected value of 90 degrees CCW. In contrast, the only change induced in far fields was a reduction of discharge rate on day 1, but not day 2, exposures of the rat to the rotated objects. The effects on both near and far fields were reversed when the objects were returned to their standard position. In the second manipulation, substitution of one of the two familiar objects with a novel object, a nonspatial change, had no detectable effect on place cell activity, regardless of field location. The sensitivity of hippocampal place cells to spatial changes but not to nonspatial changes is in agreement with earlier results showing that hippocampal lesions abolish reexploration after spatial but not after nonspatial object manipulations. The fact that reexploration is accompanied by place cell changes after spatial but not nonspatial changes reinforces the role that the hippocampus is believed to play in navigational computing and is perfectly compatible with the idea that another brain structure, likely perirhinal cortex, is responsible for object recognition.

Comparison of the effects of entorhinal and retrosplenial cortical lesions on habituation, reaction to spatial and non-spatial changes during object exploration in the rat

This study was aimed at comparing the effects of damage to the entorhinal cortex and retrosplenial cortex on exploration and reaction-to-change in rats. Following habituation to a configuration of objects, a familiar object was displaced therefore producing a spatial change. A non-spatial change was made by substituting a familiar object by a novel object. Both entorhinal cortex lesions and retrosplenial cortex lesions elicited a deficit in the rat's reaction to a spatial change. In addition, rats with entorhinal lesions showed hypoactive object exploration and exhibited a mild deficit in reaction to a non-spatial change. This may reflect the importance of temporal cortical input in object recognition. Overall, these results suggest that the entorhinal cortex and the retrosplenial cortex contribute to the processing of the geometric properties of the environment and have thus close functional links.

Comparison of the effects of entorhinal and retrosplenial cortical lesions on habituation, reaction to spatial and non-spatial changes during object exploration in the rat

This study was aimed at comparing the effects of damage to the entorhinal cortex and retrosplenial cortex on exploration and reaction-to-change in rats. Following habituation to a configuration of objects, a familiar object was displaced therefore producing a spatial change. A non-spatial change was made by substituting a familiar object by a novel object. Both entorhinal cortex lesions and retrosplenial cortex lesions elicited a deficit in the rat's reaction to a spatial change. In addition, rats with entorhinal lesions showed hypoactive object exploration and exhibited a mild deficit in reaction to a non-spatial change. This may reflect the importance of temporal cortical input in object recognition. Overall, these results suggest that the entorhinal cortex and the retrosplenial cortex contribute to the processing of the geometric properties of the environment and have thus close functional links.

The effects of heavy particle irradiation on exploration and response to environmental change

Free radicals produced by exposure to heavy particles have been found to produce motor and cognitive behavioral toxicity effects in rats similar to those found during aging. The present research was designed to investigate the effects of exposure to 56Fe particles on the ability of male Sprague-Dawley rats to detect novel arrangements in a given environment. Using a test of spatial memory previously demonstrated to be sensitive to aging, open field activity and reaction to spatial and non-spatial changes were measured in a group that received a dose of 1.5 Gy ( n=10) of 56Fe heavy particle radiation or in non-radiated controls ( n=10). Animals irradiated with 1.5 Gy of 56Fe particles exhibited some age-like effects in rats tested, even though they were, for the most part, subtle. Animals took longer to enter, visited less and spent significantly less time in the middle and the center portions of the open field, independently of total frequency and duration of activity of both groups. Likewise, irradiated subjects spend significantly more time exploring novel objects placed in the open field than did controls. However, irradiated subjects did not vary from controls in their exploration patterns when objects in the open field were spatially rearranged. Thus, irradiation with a dose of 1.5 Gy of 56Fe high-energy particle radiation elicited age-like effects in general open field exploratory behavior, but did not elicit age-like effects during the spatial and non-spatial rearrangement tasks.

Effect of age on object exploration, habituation, and response to spatial and nonspatial change.

To measure their ability to detect novel arrangements in a given environment, young (6 months old) and senescent (22-24 months old) male F344 rats were repeatedly exposed to a given spatial configuration of objects contained in an open field. After the rats were habituated to the novel environment (1 trial with no objects, followed by 3 trials with 5 salient objects), the spatial arrangement of the objects was modified (2 trials), and object novelty was tested (2 trials) by substituting a familiar object with a new one at the same location (nonspatial change). The results indicated that the senescent rats explored old objects less than young rats, particularly on Trial 2. On the 1st trial with displaced objects (Trial 5), the senescent rats explored the displaced objects less than the young rats. However, when a new object was placed in the field (Trials 7-8), there were no age differences in new object exploration. These results suggest that senescent rats have decrements in the ability to build spatial representations of the environment and to use this information to detect such changes, even though object recognition is not impaired with age.

Effect of age on object exploration, habituation, and response to spatial and nonspatial change.

Effect of age on object exploration, habituation, and response to spatial and nonspatial change.

Effect of intra-accumbens dopamine receptor agents on reactivity to spatial and non-spatial changes in mice.

Some evidence suggests an involvement of nucleus accumbens in spatial learning. However, it is controversial whether the mesoaccumbens dopaminergic pathways play a specific role in the acquisition of spatial information. The goal of these experiments was to investigate the effect of dopaminergic manipulations in the nucleus accumbens on a non-associative task designed to estimate the ability to encode/transmit spatial and non-spatial information. The effects of focal administrations of the D1 and D2 dopamine receptor antagonists, SCH 23390 (6.25, 12.5, 50 ng/side) and sulpiride (12.5, 50, 100 ng/side), respectively, and dopamine (DA; 1.25 and 2.5 microg/side) into the nucleus accumbens were studied on reactivity to spatial and non-spatial changes in an open field with objects. Both SCH 23390 and sulpiride impaired reactivity to spatial change. However, several differences were found in the effects induced by the two DA antagonists. SCH 23390 did not affect locomotor activity and only slightly impaired exploration of the novel object. On the contrary, the D2 antagonist, induced a general, dose-dependent, impairment on all variables measured. Local administration of DA increased locomotor activity, but did not affect reactivity to spatial and non-spatial changes. These results demonstrate a facilitatory role of mesoaccumbens dopamine in the acquisition of spatial information. Moreover, they suggest that nucleus accumbens D1 DA receptors, play a more selective role in the modulation of spatial learning than accumbens D2 DA receptors.

Role of dopaminergic system in reactivity to spatial and non-spatial changes in mice.

While experimental evidence shows that dopamine (DA) systems have an important role in locomotor function and in motivation, their role in the reactivity to spatial and non-spatial novelty is less well established. In this study, we investigated the effects of dopaminergic pharmacological manipulation on the capability of CD1 mice to encode spatial and non-spatial information in an open field with objects. The effects of systemic administration of: (1) selective D1 and D2 antagonists (SCH23390, 0.015 mg/kg or 0.020 mg/kg; sulpiride, 10 mg/kg or 20 mg/kg); (2) direct and indirect DA agonists (apomorphine, 1 mg/kg or 2 mg/kg; amphetamine, 1 mg/kg or 2 mg/kg) were studied. On the one hand, systemic administration of either D1 or D2 antagonists induced a selective impairment in the detection of spatial change but did not affect reaction to non-spatial novelty. On the other hand, amphetamine induced a selective decrease in exploratory activity in the first three sessions. This decrease did not affect the ability of mice to react to spatial change, but a dose-dependent decrease was observed in reactivity to non-spatial novelty. Such an effect does not seem to be due to amphetamine-induced hyperactivity or to non-DA mechanisms, since apomorphine induced a similar neophobic profile, without affecting locomotion. Taken together, these results demonstrate that manipulations of DA transmission affect reactivity to spatial and non-spatial novelty. In particular, we suggest that these two behavioral responses are modulated in opposite ways by the DA system.

Spatial memory, habituation, and reactions to spatial and nonspatial changes in rats with selective lesions of the hippocampus, the entorhinal cortex or the subiculum

Various spatial memory deficits have been described in rats with damage to the hippocampal formation (including the subiculum and the entorhinal cortex) and particularly in rats with selective lesions of the hippocampus proper. So far, the involvement of the entorhinal cortex in spatial memory is still controversial and the role of the subiculum is poorly documented. The aim of the present study was to compare the behavioural effects of selective lesions of the hippocampus, the entorhinal cortex or the subiculum in (a) a water-maze task using testing procedures sensitive to the disruption of reference or working memory and (b) in an object exploration task designed to evaluate habituation and subsequently reactions to changes of the spatial layout of objects (spatial change) or to the substitution of a familiar object by a new one (nonspatial change). Our results showed several similarities between the behavioural consequences of damage to each of the three structures. A few differences were also noted. Hippocampal rats were impaired in all spatial tasks, but they reacted like controls to a nonspatial change. The rats sustaining lesions of the entorhinal cortex or the subiculum were not impaired in the reference-memory procedure of the water-maze task and showed a deficit in reacting to a nonspatial change. Overall, our results confirm the central role of the hippocampus in spatial memory and also suggest a role for the entorhinal cortex and the subiculum in processing spatial informations. In addition, they indicate that the entorhinal cortex and the subiculum may have a hippocampal-independent role in memory.

Involvement of glutamatergic and dopaminergic systems in the reactivity of mice to spatial and non-spatial change.

Injections of glutamatergic NMDA as well as dopaminergic antagonists produce selective place- but not cue-learning deficits in associative spatial tasks. The present work was aimed at examining if the blockade of NMDA and dopaminergic receptors interferes with the encoding of spatial information in a non-associative task specifically designed for rodents. CD1 mice injected with MK-801 (0.1 and 0.25 mg/kg), haloperidol (0.04 and 0.08 mg/kg), a combination of the lower doses of each drug (haloperidol: 0.04 mg/kg and MK-801: 0.1 mg/kg) or saline were placed in an open field containing five objects and their reactivity to the displacement (spatial change) or the substitution (non-spatial change) of some of these objects was examined. The results show that saline-injected mice reacted to spatial as to non-spatial change by increasing the time spent exploring the displaced objects or the substituted one. Both doses of MK-801 prevented mice from detecting spatial change but did not affect their reactivity to the novel object. Both doses of haloperidol abolished the reactivity of mice to spatial change but the higher dose of the drug also altered the reaction to non-spatial change. Taken together, the present results indicate that the blockade of dopaminergic or glutamatergic NMDA receptors abolishes the detection of spatial novelty. The well-documented impairing effects of haloperidol and MK-801 on spatial learning may, therefore, be the consequence of a drug-induced inability in forming and/or updating spatial representations. The effects of haloperidol was, however, less specific than that of MK-801, since haloperidol always modified activity together with the response to spatial change and, at the higher dose, abolished the detection of both spatial and non-spatial change. Finally, haloperidol pretreatment was found to enhance the effect of MK-801 thus suggesting a possible interaction between the two systems in modulating these behavioral responses.