Navigation in a Space With Moving Objects: Rats Can Avoid Specific Locations Defined With Respect to a Moving Robot.

Animals can organize their behavior with respect to other moving animals or objects; when hunting or escaping a predator, when migrating in groups or during various social interactions. In rats, we aimed to characterize spatial behaviors relative to moving objects and to explore the cognitive mechanisms controlling these behaviors. Three groups of animals were trained to avoid a mild foot-shock delivered in one of three positions: either in front, on the left side, or on the right side of a moving robot. We showed the rats can recognize and avoid these specific areas. The avoidance behavior specific for the left or right side of the robot demonstrated animals not only react to "simple" stimuli such as increasing noise level or growing retinal image of an approaching object, but they process their spatial position relative to the object. Using an all-white robot without prominent visual patterns that would distinguish its different sides, we showed that the behavior does not depend on responses to prominent visual patterns, but that the rats can guide their navigation according to geometrical spatial relationship relative to the moving object. Rats' competence for navigation in space defined by a moving object resembles navigation abilities in stationary space. Recording of hippocampal single unit activity during rat's interaction with the robot proved feasibility of the task to uncover neuronal mechanism of this type of navigation.

The McGill Transgenic Rat Model of Alzheimer's Disease Displays Cognitive and Motor Impairments, Changes in Anxiety and Social Behavior, and Altered Circadian Activity.

The McGill-R-Thy1-APP transgenic rat is an animal model of the familial form of Alzheimer's disease (AD). This model mirrors several neuropathological hallmarks of the disease, including the accumulation of beta-amyloid and the formation of amyloid plaques (in homozygous animals only), neuroinflammation and the gradual deterioration of cognitive functions even prior to plaque formation, although it lacks the tauopathy observed in human victims of AD. The goal of the present study was a thorough characterization of the homozygous model with emphasis on its face validity in several domains of behavior known to be affected in AD patients, including cognitive functions, motor coordination, emotionality, sociability, and circadian activity patterns. On the behavioral level, we found normal locomotor activity in spontaneous exploration, but problems with balance and gait coordination, increased anxiety and severely impaired spatial cognition in 4-7 month old homozygous animals. The profile of social behavior and ultrasonic communication was altered in the McGill rats, without a general social withdrawal. McGill rats also exhibited changes in circadian profile, with a shorter free-running period and increased total activity during the subjective night, without signs of sleep disturbances during the inactive phase. Expression of circadian clock gene Bmal1 was found to be increased in the parietal cortex and cerebellum, while Nr1d1 expression was not changed. The clock-controlled gene Prok2 expression was found to be elevated in the parietal cortex and hippocampus, which might have contributed to the observed changes in circadian phenotype. We conclude that the phenotype in the McGill rat model is not restricted to the cognitive domain, but also includes gait problems, changes in emotionality, social behavior, and circadian profiles. Our findings show that the model should be useful for the development of new therapeutic approaches targeting not only memory decline but also other symptoms decreasing the quality of life of AD patients.

Corrigendum: Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits.

[This corrects the article on p. 42 in vol. 9, PMID: 29487522.].

Mnemonic and behavioral effects of biperiden, an M1-selective antagonist, in the rat.

RATIONALE: There is a persistent pressing need for valid animal models of cognitive and mnemonic disruptions (such as seen in Alzheimer's disease and other dementias) usable for preclinical research. OBJECTIVES: We have set out to test the validity of administration of biperiden, an M1-acetylcholine receptor antagonist with central selectivity, as a potential tool for generating a fast screening model of cognitive impairment, in outbred Wistar rats. METHODS: We used several variants of the Morris water maze task: (1) reversal learning, to assess cognitive flexibility, with probe trials testing memory retention; (2) delayed matching to position (DMP), to evaluate working memory; and (3) "counter-balanced acquisition," to test for possible anomalies in acquisition learning. We also included a visible platform paradigm to reveal possible sensorimotor and motivational deficits. RESULTS: A significant effect of biperiden on memory acquisition and retention was found in the counter-balanced acquisition and probe trials of the counter-balanced acquisition and reversal tasks. Strikingly, a less pronounced deficit was observed in the DMP. No effects were revealed in the reversal learning task. CONCLUSIONS: Based on our results, we do not recommend biperiden as a reliable tool for modeling cognitive impairment.

Chronic MK-801 Application in Adolescence and Early Adulthood: A Spatial Working Memory Deficit in Adult Long-Evans Rats But No Changes in the Hippocampal NMDA Receptor Subunits.

The role of NMDA receptors in learning, memory and hippocampal function has long been recognized. Post-mortem studies have indicated that the expression or subunit composition of the NMDA glutamate receptor subtype might be related to the impaired cognitive functions found in schizophrenia patients. NMDA receptor antagonists have been used to develop animal models of this disorder. There is accumulating evidence showing that not only the acute but also the chronic application of NMDA receptor antagonists may induce schizophrenia-like alterations in behavior and brain functions. However, limited evidence is available regarding the consequences of NMDA receptor blockage during periods of adolescence and early adulthood. This study tested the hypothesis that a 2-week treatment of male Long-Evans and Wistar rats with dizocilpine (MK-801; 0.5 mg/kg daily) starting at postnatal days (PD) 30 and 60 would cause a long-term cognitive deficit and changes in the levels of NMDA receptor subunits. The working memory version of the Morris water maze (MWM) and active place avoidance with reversal on a rotating arena (Carousel) requiring cognitive coordination and flexibility probed cognitive functions and an elevated-plus maze (EPM) was used to measure anxiety-like behavior. The western blot method was used to determine changes in NMDA receptor subunit levels in the hippocampus. Our results showed no significant changes in behaviors in Wistar rats. Slightly elevated anxiety-like behavior was observed in the EPM in Long-Evans rats with the onset of treatment on PD 30. Furthermore, Long-Evans rats treated from PD 60 displayed impaired working memory in the MWM. There were; however, no significant changes in the levels of NMDA receptor subunits because of MK-801 administration. These findings suggest that a 2-week treatment starting on PD 60 in Long-Evans rats leads to long-term changes in working memory, but this deficit is not paralleled by changes in NMDA receptor subunits. These results support the face validity, but not construct validity of this model. We suggest that chronic treatment of adolescent and adult rats does not constitute a plausible animal model of schizophrenia.

Transient inactivation of the anterior cingulate cortex in rats disrupts avoidance of a dynamic object.

Although animals often learn and monitor the spatial properties of relevant moving objects such as conspecifics and predators to properly organize their own spatial behavior, the underlying brain substrate has received little attention and hence remains elusive. Because the anterior cingulate cortex (ACC) participates in conflict monitoring and effort-based decision making, and ACC neurons respond to objects in the environment, it may also play a role in the monitoring of moving cues and exerting the appropriate spatial response. We used a robot avoidance task in which a rat had to maintain at least a 25cm distance from a small programmable robot to avoid a foot shock. In successive sessions, we trained ten Long Evans male rats to avoid a fast-moving robot (4cm/s), a stationary robot, and a slow-moving robot (1cm/s). In each condition, the ACC was transiently inactivated by bilateral injections of muscimol in the penultimate session and a control saline injection was given in the last session. Compared to the corresponding saline session, ACC-inactivated rats received more shocks when tested in the fast-moving condition, but not in the stationary or slow robot conditions. Furthermore, ACC-inactivated rats less frequently responded to an approaching robot with appropriate escape responses although their response to shock stimuli remained preserved. Since we observed no effect on slow or stationary robot avoidance, we conclude that the ACC may exert cognitive efforts for monitoring dynamic updating of the position of an object, a role complementary to the dorsal hippocampus.

Scopolamine disrupts place navigation in rats and humans: a translational validation of the Hidden Goal Task in the Morris water maze and a real maze for humans.

RATIONALE: Development of new drugs for treatment of Alzheimer's disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research. OBJECTIVES: We present validation of a place-navigation task, a Hidden Goal Task (HGT) based on the Morris water maze (MWM), in comparable animal and human protocols. METHODS: We used scopolamine to model cognitive dysfunction similar to that seen in AD and donepezil, a symptomatic medication for AD, to assess its potential reversible effect on this scopolamine-induced cognitive dysfunction. We tested the effects of scopolamine and the combination of scopolamine and donepezil on place navigation and compared their effects in human and rat versions of the HGT. Place navigation testing consisted of 4 sessions of HGT performed at baseline, 2, 4, and 8 h after dosing in humans or 1, 2.5, and 5 h in rats. RESULTS: Scopolamine worsened performance in both animals and humans. In the animal experiment, co-administration of donepezil alleviated the negative effect of scopolamine. In the human experiment, subjects co-administered with scopolamine and donepezil performed similarly to subjects on placebo and scopolamine, indicating a partial ameliorative effect of donepezil. CONCLUSIONS: In the task based on the MWM, scopolamine impaired place navigation, while co-administration of donepezil alleviated this effect in comparable animal and human protocols. Using scopolamine and donepezil to challenge place navigation testing can be studied concurrently in animals and humans and may be a valid and reliable model for translational research, as well as for preclinical and clinical phases of drug trials.

Can rats solve the active place avoidance task without the room-bound cues?

The active place avoidance task is used in the research of spatial cognition. Rats are trained on a rotating arena to avoid an aversive stimulus delivered in a part of the room while being transported toward it by the arena rotation. The task tests the ability of rats to navigate with respect to distal cues in the room and to ignore confusing cues on the arena. The demand for cue segregation makes the task suitable for studying neural mechanisms responsible for cognitive coordination. An incidental observation made in our laboratory implied that overtrained rats may be able to solve the task without the room-bound cues. The aim of this study was to test this observation. The room-bound cues were hidden by switching off the lights. Rats trained only in darkness did not learn the task at all. Rats that were initially pre-trained in light performed considerably better. In a few exceptional dark sessions they even reached the level of performance observed in light. The rats needed the aversive stimuli to keep off the to-be-avoided sector. Without them, they continued their behavior, but with no spatial relationship to the to-be-avoided sector. We conclude that rats are able to solve the place avoidance task without the room-bound cues, but not as efficiently as in their presence.

Comparison of Long-Evans and Wistar rats in sensitivity to central cholinergic blockade with scopolamine in two spatial tasks: an active place avoidance and the Morris water maze.

Place navigation is essential for an animal's survival and this behavior has attracted the attention of scientists focused on the neural and neuropharmacological bases of learning and memory. Many navigational tests are employed today, such as the Morris water maze (MWM) which demands a precise representation of an unmarked place. Another spatial paradigm is the active place avoidance task. It requires mainly cognitive coordination in contrast to the MWM. Various rat strains are used in the research of animal models of cognitive impairments. The aim of this study was to compare sensitivity to the administration of higher doses (1.5mg/kg and 3mg/kg) of the central cholinergic blocker, scopolamine in outbred Long-Evans and Wistar rats. The results showed that while Wistar rats were more strongly affected by cholinergic blockade in the active place avoidance than Long-Evans rats, no differences were seen in the MWM. Long-Evans rats also showed better baseline performance in the active place avoidance and visible platform versions of the MWM (the latter suggesting better vision). This study demonstrated task-specific inter-strain differences in sensitivity to central cholinergic blockade in an active place avoidance task requiring cognitive coordination.

Visuospatial working memory is impaired in an animal model of schizophrenia induced by acute MK-801: an effect of pretraining.

Deficient working memory was proposed as an endophenotype of schizophrenia. Such deficits are also commonly found in animal models of schizophrenia-like behavior of various origins. An allothetic place avoidance alternation task was proposed as a behavioral test of visuospatial working memory. This study tested the hypothesis that working memory in this test would be impaired by acute pre-test treatment with MK-801 (dizocilpine) in an animal model possessing high phenomenological and predictive validity. Furthermore, the study sought to determine the effect of pretraining to the task prior to treatment on the subsequent learning in the animal model. The results show that both doses of MK-801 (0.12 mg/kg and 0.15 mg/kg) significantly impaired working memory in the alternation paradigm, and both doses also increased locomotor activity. Notably, in previously pretrained animals, the significant effect of MK-801 on working memory was absent, despite persistent hyperlocomotion. These results showed that a deficit in working memory was detectable in this animal model of schizophrenia-like behavior, but its occurrence depended on the previous experience of animals with familiarization in the task.

Two learning tasks provide evidence for disrupted behavioural flexibility in an animal model of schizophrenia-like behaviour induced by acute MK-801: a dose-response study.

Schizophrenia is a chronic and devastating illness. Exact causes of the disease remain elusive; however, neurodevelopmental changes in the brain glutamate system are recognized to play an important role. Several animal models of the disease are induced by a systemic blockade of N-methyl-d-aspartate (NMDA) receptors. This study examined the animal model of schizophrenia-like behaviours induced by acute treatment with MK-801, a non-competitive NMDA-receptor antagonist. Behavioural flexibility is an ability to adapt to the changes in environment, and schizophrenia is often accompanied by its decrease. The study tested the effect of MK-801 on behavioural flexibility in an active place avoidance task and the Morris water maze (MWM). Flexibility was tested under reversal conditions, i.e., after changing the location of the target. Each spatial task addressed different functions; continuous coordinate-frame segregation was present in the active place avoidance and precise place representation in the MWM. Results showed that reversal was altered in both tasks by MK-801 at doses of 0.10-0.15 mgkg(-1). Some impairment was observed in the active place avoidance task at 0.08 mgkg(-1). Swimming towards a visible platform was impaired only by the highest dose (0.15 mgkg(-1)). The results demonstrate that a significant impairment of behavioural flexibility accompanies this acute animal model of schizophrenia-like behaviours, and that active place avoidance had higher sensitivity for such deficits than the MWM. This suggests the usefulness of the reversal paradigm in both tasks for examining novel drugs with antipsychotic and procognitive actions.