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PubMed2004

Electrolytic lesions of the ventral subiculum weakly alter spatial memory but potentiate amphetamine-induced locomotion.

Adult Long-Evans male rats were subjected to electrolytic lesions of the ventral subiculum, and tested for locomotor activity in the home cage, reference and working memory in the water maze, working memory in the radial maze, and D-amphetamine-induced locomotion (1mg/kg, i.p.). When compared to their sham-operated counterparts, lesioned rats showed nocturnal hyperactivity, no reference memory deficit, but working memory was impaired in the water maze and during the initial stage of radial-maze testing. Their locomotor responsiveness to D-amphetamine was exaggerated. Histological verifications confirmed lesions in the ventral subiculum. Material stained for acetylcholinesterase activity indicated septohippocampal and commissural/associational sprouting, accounting for partial damage to the perforant paths. These results showed that ventral subiculum lesions (i) do not alter the capability of rats to learn repeatedly presented spatial information, and (ii) impair, but do not prevent, spatial working memory, suggesting that the ventral subiculum is preferentially involved in short-term memory for spatial locations. Given the electrolytic nature of the lesion, the lesion-induced potentiation of the locomotor response to amphetamine is probably easier explained by partial disruption of the perforant paths than by damage to neurons of the ventral subiculum.

Acetylcholinesterase↗
PubMed2005

Working memory in the chick: parallel and lateralized mechanisms for encoding of object- and position-specific information.

Working memory of chicks was probed in a delayed-response task, with either object- or position-specific information available in order to locate a goal that had disappeared behind one of two screens in a test arena. When the position of the correct screen was the only available cue (i.e., the two screens were identical) binocular and monocular chicks could easily locate the goal, and the same occurred when the visual characteristics of the screens (no matter what their spatial position) were the only relevant information available and when object- and position-specific cues were both available and in agreement (i.e., the two screens were different and maintained fixed spatial locations). In contrast, when object- and position-specific cues were available but were put in conflict (the two screens were different and were swapped during the delay time) left-eyed and binocular chicks went to the correct position, whereas right-eyed chicks seemed to choose both the correct spatial position and the correct object cue to the same degree. When during the delay the correct screen was substituted by an entirely novel screen, no left-right asymmetry associated with response to novelty was observed; monocular chicks preferentially approached the novel screen in the correct position, whereas binocular chicks did not show any clear choice. The results suggest that both object- and position-specific information is available to the two cerebral hemispheres in working memory tasks; however, when a conflict between cues arises, the right hemisphere preferentially attends to position-specific cues, whereas the left hemisphere tends to attend to object-specific cues.

Animals↗
PubMed2005

Impaired memory and olfactory performance in NaSi-1 sulphate transporter deficient mice.

In the present study, NaSi-1 sulphate transporter knock-out (Nas1-/-) mice, an animal model of hyposulphataemia, were examined for spatial memory and learning in a Morris water maze, and for olfactory function in a cookie test. The Nas1-/- mice displayed significantly (P<0.05) increased latencies to find an escape platform in the reversal learning trials at 2 days but not 1 day after the last acquisition trial in a Morris water maze test, suggesting that Nas1-/- mice may have proactive memory interference. While the wild-type (Nas1+/+) mice showed a significant (P<0.02) decrease in time to locate a hidden food reward over four trials after overnight fasting, Nas1-/- mice did not change their performance, resulting in significantly (P<0.05) higher latencies when compared to their Nas1+/+ littermates. There were no significant differences between Nas1-/- and Nas1+/+ mice in the cookie test after moderate food deprivation. In addition, both Nas1-/- and Nas1+/+ mice displayed similar escape latencies in the acquisition phase of the Morris water maze test, suggesting that learning, motivation, vision and motor skills required for the task may not be affected in Nas1-/- mice. This is the first study to demonstrate an impairment in memory and olfactory performance in the hyposulphataemic Nas1-/- mouse.

Animals↗
PubMed2005

Effects of intraperitoneal lipopolysaccharide on Morris maze performance in year-old and 2-month-old female C57BL/6J mice.

Several studies have shown that systemic lipopolysaccharide (LPS) or interleukin-1beta (IL-1beta) may affect performance in various learning tasks, including the Morris water maze. In the current study, female C57BL/6J mice, either 2 months or 1 year of age, were given 5 days of testing followed by 3 days of rest, and then three additional days of testing. Mice either received a single LPS injection on day 1 and saline on days 2-5, LPS injections on days 1-5, or saline injections on days 1-5. Daily LPS administration significantly prolonged latency for the animals to find the platform, and decreased their swimming speed. Year-old mice treated with LPS each day also exhibited significantly higher levels of thigmotaxis in the maze. Despite effects on latency and swim speed, no effect of LPS treatment was observed for distance traveled to the platform or other measures that clearly indicate disruption of learning in the maze. On the other hand, age was a significant factor affecting both latency and distance, with older animals swimming greater distances to find the platform. Additionally, older animals were more adversely affected by daily LPS treatment. In this study, although LPS-induced performance impairments in the Morris water maze were noted, particularly in older animals, these effects were not clearly indicative of learning impairment per se.

Age Factors↗
PubMed2004

Systemic administration of MK-801, a non-competitive NMDA-receptor antagonist, elicits a behavioural deficit of rats in the Active Allothetic Place Avoidance (AAPA) task irrespectively of their intact spatial pretraining.

Spatial orientation is considered to be an animal model of human cognitive functions. Efficient navigation is believed to require a brain representation of the environment. The role of NMDA-receptor-dependent neurotransmission in encoding spatial representations has been intensively studied; however, its involvement in organizing spatial information into neural representations is poorly understood. We tested the effect of NMDA-receptor blockade on the performance of rats in Active Allothetic Place Avoidance (AAPA), a cognitive task which requires rats to separate two conflicting spatial reference frames (room and arena frames), when only the room frame is relevant for solution of the task. The NMDA-receptor blockade was achieved by systemic administration of either 0.15 mg/kg or 0.2 mg/kg of dizocilpine (MK-801), a non-competitive NMDA-receptor antagonist. Two distinct AAPA setups located in different rooms were used. The rooms had different layouts of robust extramaze landmarks. Intact rats were trained in the upstairs arena and, subsequently, they received saline or MK-801 and their performance was tested (reinforced retention). Re-acquisition of AAPA task in the downstairs room was then tested under saline or MK-801. MK-801 at the dose of 0.2 mg/kg was found to disrupt the reinforced retention of the AAPA. Re-acquisition of AAPA in the novel environment was impaired by both doses of MK-801. Taken together, administration of MK-801 causes an orientation deficit in the AAPA task irrespectively of the rats' prior intact pretraining. These results support the hypothesis that NMDA-receptors play a pivotal role in cognitive processes.

Analysis of Variance↗
PubMed2004

Effects of histamine H3 receptor antagonists in two models of spatial learning.

Despite the well-described attention and short-term memory enhancing effects of H3 receptor antagonists, and evidence to suggest a close relationship between central histaminergic and cholinergic systems, there is a paucity of evidence for a role for H3 receptor blockade in spatial learning. To address this, we investigated two H3 receptor antagonists in a visual discrimination water maze in rats, and in a Barnes circular maze in mice. Thioperamide and ciproxifan significantly attenuated a scopolamine-induced deficit in the water maze task, while only ciproxifan showed a modest attenuation in the Barnes maze. Taken together, these data suggest a role for H3 receptors in spatial learning that appears to be task-dependent.

Animals↗
PubMed2005

Age-progressing cognitive impairments and neuropathology in transgenic CRND8 mice.

Patients with Alzheimer's disease suffer from progressive cognitive impairments and show distinct post-mortem neuropathology, including beta-amyloid plaques. Transgenic (Tg) CRND8 mice carry a mutated human amyloid precursor protein gene and show age-related increases in beta-amyloid production and plaque deposition. It was previously reported that during the early stages of plaque deposition, Tg CRND8 mice demonstrated Morris maze impairments. However, it is unknown if Tg mice would be impaired at an earlier age prior to plaque deposition or more impaired at a later age with more extensive plaque deposition. In the current study, we describe Tg CRND8 age-progressing beta-amyloid neuropathology and cognitive abilities in greater detail. At all ages, Tg mice showed normal short-term memory in the Y-maze. Pre-plaque Tg and age-matched Non-Tg mice did not differ in learning the spatial Morris water maze. However, both early and late plaque Tg mice showed impairments during acquisition. In addition, although early plaque Tg mice performed well in the probe trial, late plaque Tg mice demonstrated impaired probe trial performance. Therefore compared to their Non-Tg littermates, Tg CRND8 mice demonstrate cognitive impairments that progressed with age and seemed to coincide with the onset of beta-amyloid plaque deposition.

Age Factors↗
PubMed2005

Effects of light stimulation of embryos on the use of position-specific and object-specific cues in binocular and monocular domestic chicks (Gallus gallus).

Chicks hatched from eggs incubated in the dark (D-chicks) or from eggs exposed to light during the last 3 days before hatching (L-chicks) were trained on day 4 to peck at small cones for food reinforcement. The cones had different patterns (checked or striped) and were located in different positions (either on the left or on the right of a rectangular arena) so as both object-specific (pattern) and position-specific cues could be used to discriminate cones that contained or that did not contain food. After learning, the position of the cones was reversed so that object- and position-specific cues provided contradictory information. No effect of light incubation was observed in binocular chicks that chose cones on the basis of object-specific cues. Monocular D-chicks also tended to approach and peck the cones with the correct pattern in the wrong position, whereas monocular L-chicks did not show any clear choice. Initial choices for one side or other of the arena were mostly determined by the first side visible through the non-occluded eye in D-chicks, particularly when using their left eye. These results suggest that light exposure of the embryo makes neural mechanisms that do not receive direct visual input (i.e., those of the occluded side) more available to be used in assessment of novelty.

Analysis of Variance↗
PubMed2005

Metabotropic glutamate receptor 1 blockade impairs acquisition and retention in a spatial Water maze task.

Metabotropic glutamate receptors, including the mGlu1 receptor, have received considerable attention as potential targets for anxiolytic, antidepressant, antipsychotic and antinociceptive drugs. mGlu1 receptors have also been suggested to play a role in the modulation of cognitive processes, but knowledge is still very limited. In the present study the effects of the selective mGlu1 receptor antagonist 3,4-dihydro-2H-pyrano[2,3]beta-quinolin-7-yl)(cis-4-methoxycyclohexyl)methanone (JNJ16259685, 0.63-10 mg/kg s.c.) on more or less spatially demanding learning and spatial memory (retention and re-acquisition) were investigated in mice performing in a water maze. Selective mGlu1 receptor blockade with JNJ16259685 impaired spatial acquisition processes, irrespective of spatial load, as well as spatial re-acquisition, already at the lowest dose tested (0.63 mg/kg). In contrast, effects on spatial retention performance were relatively mild in mice that had learned to locate the position of the escape platform prior to treatment. Thigmotaxic behaviour and locomotor activity appeared to be unaffected by JNJ16259685. These data suggest that blockade of the mGlu1 receptor primarily affects learning of new information, but leaves retention of spatial information relatively unaffected. Blockade of the mGlu5 receptor with MPEP also impaired spatial learning, although only at the highest dose tested (10 mg/kg). An ex vivo receptor occupancy study in rats revealed that MPEP occupied central mGlu5 receptors with an ED(50) of 2.0 mg/kg one hour after subcutaneous administration. This is 50-150 times higher than the ED(50) reported for JNJ16259685 at central mGlu1 receptors and suggests that one reason why the two compounds cause cognitive effects at different doses might be due to differences in central mGlu receptor occupancy, rather than fundamentally different roles of mGlu1 and mGlu5 receptors in the modulation of cognitive function.

Animals↗
PubMed2005

Inactivation of the rat dorsal striatum impairs performance in spatial tasks and alters hippocampal theta in the freely moving rat.

We analysed the interaction between the dorsal striatum (motor coordination and planning) and the hippocampus (sensory information processing and integration) during performance of goal-directed tasks. The performance of rats that had been injected with different doses of the D(2)-antagonist Sulpiride into the dorsal striatum was tested in an egocentric 4-arm maze task that tests striatal functions. Furthermore, hippocampal EEGs were recorded before, during and after inactivation of the dorsal striatum via injections of Sulpiride of rats that were performing a continuous alternation task. Injection of 5 microl of 100 mM Sulpiride increased the number of errors committed in the egocentric 4-arm maze (p < 0.01), indicating that the dorsal striatum is involved in motor control and motor memory recall in such a task. In the recording study, the same dose of Sulpiride injected into the dorsal striatum had powerful effects on the hippocampal EEG. The main activity in the theta range (5-10 Hz) was shifted from higher frequencies in the 8-10 Hz range to lower frequencies in the 5-7 Hz range (p < 0.005). The impairment in the behavioural egocentric task after Sulpiride injection, and the effects of Sulpiride on hippocampal theta shows that there is a functional interaction between the dorsal striatum and the hippocampus. While the dorsal striatum coordinates the execution of complex motor programs, the hippocampus integrates spatial and other sensory information required for the planning and execution of goal-directed movements.

Analysis of Variance↗
PubMed2005

Normal attention orienting but abnormal stimulus alerting and conflict effect in combined subtype of ADHD.

Recent pharmacological studies in animals and neuroimaging studies in normal humans suggest that the spatial and nonspatial cues in tasks measuring reflexive attention may be modulated by different neurotransmitter systems. The efficiency with which attention is oriented to explicit spatial cues may be altered by manipulating levels of brain acetylcholine, whereas reactions to nonspatial cues may be influenced by altering brain noradrenaline levels but not acetylcholine levels. In humans, however, previous attention studies have implicated dopamine when either explicit or implicit cueing is used. Some of the differences between animal and human work may be due to inadequate testing of nonspatial cues. To remedy this, we tested adult humans with ADHD that were primarily inattentive (ADHD/I) or combined inattentive/hyperactive (ADHD/C) and controls with the Attention Network Task that assesses both reflexive and voluntary attention and explicitly tests nonspatial cueing. Our results showed that spatial orienting in both subtypes was no different than controls. However, ADHD/C but not ADHD/I subjects had significantly slowed response times to nonspatial cues and cues with spatial conflict. Stimulant medication in a subset of ADHD/C subjects reduced these deficits to control levels. Based on these results, we conclude that ADHD/C subjects orient the focus of their attention normally but are impaired in their reactions both to abrupt visual cues and those that contain conflicting spatial cues.

Adolescent↗
PubMed2006

Extensive enriched environments protect old rats from the aging dependent impairment of spatial cognition, synaptic plasticity and nitric oxide production.

In aged rodents, neuronal plasticity decreases while spatial learning and working memory (WM) deficits increase. As it is well known, rats reared in enriched environments (EE) show better cognitive performances and an increased neuronal plasticity than rats reared in standard environments (SE). We hypothesized that EE could preserve the aged animals from cognitive impairment through NO dependent mechanisms of neuronal plasticity. WM performance and plasticity were measured in 27-month-old rats from EE and SE. EE animals showed a better spatial WM performance (66% increase) than SE ones. Cytosolic NOS activity was 128 and 155% higher in EE male and female rats, respectively. Mitochondrial NOS activity and expression were also significantly higher in EE male and female rats. Mitochondrial NOS protein expression was higher in brain submitochondrial membranes from EE reared rats. Complex I activity was 70-80% increased in EE as compared to SE rats. A significant increase in the area of NADPH-d reactive neurons was observed in the parietotemporal cortex and CA1 hippocampal region of EE animals.

Aging↗
PubMed2006

Analysis of spatial orientation strategies of male and female Wistar rats in a Morris water escape task.

In the present study we investigated spatial navigation in male and female Wistar rats in the Morris water escape task. Rats were subjected to procedures which required the use of a place (PLACE), cue (CUE) and egocentric (EGO) response to learn the task efficiently. In a first experiment rats were successively tested in the PLACE, CUE and EGO condition and in a second experiment the order of tasks was reversed. The first experiment showed that female rats swam longer distances and took more time to find the platform in the PLACE task. Further, the female rats spent less time near the previous platform position than the male rats during probe trial. No sex difference was found in the CUE and EGO task. In the second experiment, the female rats took longer to find the platform than the male rats in the EGO task. In the CUE and PLACE task no differences between the sexes was found during acquisition. However, the male rats spent more time near the previous platform position than the female rats during the probe trial of the PLACE task. On basis of present data it is concluded that the use of a PLACE-based strategy is better in male Wistar rats. CUE learning is not sex-dependent. The ability to use EGO strategies appears not to be different between male and female Wistar rats, but appears dependent on pre-exposure to the task.

Analysis of Variance↗
PubMed2006

Deficits in acquisition of spatial learning after dorsomedial telencephalon lesions in goldfish.

Acquisition of spatial learning is an important function of mammalian hippocampus. In order to identify the brain areas in teleost fish that are homologous to mammalian hippocampus, the present study examined the effects of lesions in the dorsal area of the caudal telencephalon of goldfish (Carassius auratus) on the acquisition of spatial learning. An open-field maze that was similar to the dry version of the Morris water maze was used. The task consisted of habituation and postoperative training to reach the position of the bait. Extramaze cues were visible in the habituation sessions in experiment 1, while they were blocked and not visible in the habituation sessions in experiment 2. Only in experiment 2, there was a significant deficit in the performance in the training sessions in the goldfish with damage to the dorsomedial area of the caudal telencephalon (DM). These data showed that blocking of the extramaze cues in the habituation sessions caused deficits in postoperative acquisition of spatial learning in the training sessions in the goldfish with DM lesions. Latent learning in the habituation sessions, however, eliminated the effects of the DM lesions on spatial learning. The present study suggests that the DM plays a critical role in acquisition of spatial learning.

Analysis of Variance↗
PubMed2006

Functional inactivation of orexin 1 receptors in CA1 region impairs acquisition, consolidation and retrieval in Morris water maze task.

Orexin containing neurons in the lateral hypothalamic area (LHA) produce orexin-A (hypocretin-1) and orexin-B (hypocretin-2) and send their axons to the hippocampus, which predominantly expresses orexin 1 receptors (OX1Rs) showing a higher affinity to orexin-A. Recent studies have shown that central administration of orexin-A has an effect on learning and memory but literature concerning the role of orexinergic system in cognition remains controversial. Therefore, we examined the effect of pre-training, post-training and pre-probe trial intrahippocampal CA1 administration of a selective OX1R the orexin 1 receptor antagonist SB-334867-A (1.5, 3, 6 microg/0.5 microl) on acquisition, consolidation and retrieval in a single-day testing version of Morris water maze (MWM) task. Our results show that, SB-334867-A impaired acquisition, consolidation and retrieval of MWM task as compared with the control group. This drug had no effect on escape latency of a non-spatial visual discrimination task. Therefore, it seems that endogenous orexins, especially orexin-A, play an important role in spatial learning and memory in the rat.

Analysis of Variance↗
PubMed2006

Effects of sex on object recognition and spatial navigation in humans.

Human tests designed to mirror rodent tests of object recognition and spatial navigation were administered to adult cognitively healthy humans. Facial recognition was also assessed. There was no sex difference in facial recognition, consistent with earlier studies. In the object recognition test, the test-retest NINL total scores during the same visit were highly correlated, comparable to the test-retest correlations obtained in the established facial recognition test. There were no effects of sex on object recognition. However, in the spatial navigation test, there were effects of sex on spatial learning and memory during the session with the hidden, but not visible, target. These tests might be useful to compare assessments of object recognition and spatial learning and memory in humans and animal models.

Adult↗
PubMed2006

Anastrozole improved testosterone-induced impairment acquisition of spatial learning and memory in the hippocampal CA1 region in adult male rats.

Neurohormones like testosterone and estrogen have an important role in learning and memory. Many biological effects of androgens in the brain require the local conversion of these steroids to an estrogen. The current research has conducted to assess the effect of testosterone, estrogen and aromatase inhibitor (anastrozole) on spatial discrimination of rats, using Morris water maze and also the pathway of the effect of testosterone by using anastrozole. Adult male rats were bilaterally cannulated into CA1 region of hippocampus and divided into 15 groups. Different groups received DMSO 0.5 microl and DMSO 0.5 microl + DMSO 0.5 microl as control groups and different doses of testosterone enanthate (TE) (20, 40 and 80 microg/0.5 microl), estradiol valerat (EV) (1, 2.5, 5, 10, and 15 microg/0.5 microl), anastrozole (An) (0.25, 0.5, 1 microg/0.5 microl), TE 80 microg/0.5 microl + anastrozole 0.5 microg/0.5 microl and EV 15 microg/0.5 microl + anastrozole 0.5 microg/0.5 microl all days before training. TE and EV were injected 30-35 min before training and anastrozole was injected 25-30 min before training. Our results have shown both TE 80 microg/0.5 microl and EV 15 microg/0.5 microl groups increase in escape latency and traveled distance to find invisible platform. Also we have shown that anastrozole dose dependently decreases escape latency and traveled distance. We resulted that both TE and EN impaired acquisition of spatial learning and memory but anastrozole improved it. Anastrozole also could be buffered TE-induced impairment effect but not EV.

Analysis of Variance↗
PubMed2006

Disconnection of the hippocampal-prefrontal cortical circuits impairs spatial working memory performance in rats.

There is a unidirectional, ipsilateral and monosynaptic projection from the hippocampus to the prefrontal cortex. The cognitive function of hippocampal-prefrontal cortical circuit is not well established. In this paper, we use muscimol treated rats to investigate the roles of the hippocampal-prefrontal cortical circuits in spatial working memory, as assessed with a delayed spatial alternation task. First of all, the effect of muscimol on EEG power of infusion area was observed for confirmation of the dosage of muscimol to inhibit the function of infusion area. The results show that the EEG power of the ventral hippocampus and the prelimbic area of the prefrontal cortex were inhibited by local infusion of muscimol (0.5 microg in 0.25 microl PBS) into the above areas, respectively. Delayed alternation performance was significantly impaired when muscimol at this dosage was infused (1) bilaterally into the ventral hippocampus, (2) bilaterally into the prelimbic area, (3) unilaterally into the ventral hippocampus and simultaneously contralaterally into the prelimbic area. Infusion of muscimol either unilaterally into the ventral hippocampus or unilaterally into the prelimbic area did not impair delayed alternation performance. The present results suggest that any structures in this circuit is damaged or inhibited bilaterally, the spatial working memory will be disrupted. It means the hippocampal-prefrontal cortical circuit plays an important role in spatial working memory.

Animals↗