Chronic sensitization to serotonin 1A and 7 receptors agonist 8-OH-DPAT induces compulsive checking and perseverative behavior. As such, it has been used to model obsessive-compulsive disorder (OCD)-like behavior in mice and rats. In this study, we tested spatial learning in the 8-OH-DPAT model of OCD and the effect of co-administration of memantine and riluzole-glutamate-modulating agents that have been shown to be effective in several clinical trials. Rats were tested in the active place avoidance task in the Carousel maze, where they learned to avoid the visually imperceptible shock sector. All rats were subcutaneously injected with 8-OH-DPAT (0.25 mg/kg) or saline (control group) during habituation. During acquisition, they were pretreated with riluzole (1 mg/kg), memantine (1 mg/kg), or saline solution 30 min before each session and injected with 8-OH-DPAT ("OH" groups) or saline ("saline" groups) right before the experiment. We found that repeated application of 8-OH-DPAT during both habituation and acquisition significantly increased locomotion, but it impaired the ability to avoid the shock sector. However, the application of 8-OH-DPAT in habituation had no impact on the learning process if discontinued in acquisition. Similarly, memantine and riluzole did not affect the measured parameters in the "saline" groups, but in the "OH" groups, they significantly increased locomotion. In addition, riluzole increased the number of entrances and decreased the maximum time avoided of the shock sector. We conclude that monotherapy with glutamate-modulating agents does not reduce but exacerbates cognitive symptoms in the animal model of OCD.

• Klíčová slova
• 8-OH-DPAT, memantine, memory, obsessive-compulsive disorder, riluzole, spatial learning,
• MeSH
• 8-hydroxy-2-(di-N-propylamino)tetralin škodlivé účinky   farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• krysa rodu Rattus MeSH
• memantin farmakologie   MeSH
• modely nemocí na zvířatech MeSH
• obsedantně kompulzivní porucha * chemicky indukované   farmakoterapie   patofyziologie   MeSH
• paměť účinky léků   MeSH
• potkani Long-Evans MeSH
• prostorové učení účinky léků   MeSH
• riluzol farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 8-hydroxy-2-(di-N-propylamino)tetralin MeSH
• memantin MeSH
• riluzol MeSH

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.

• Klíčová slova
• autism, chronic bacterial infection, development, lipopolysaccharide, macrocephaly, maternal immune activation, parvalbumin-positive interneurons, prenatal infection, schizophrenia, sex differences,
• MeSH
• chování zvířat * MeSH
• imunohistochemie MeSH
• imunomodulace * MeSH
• interneurony metabolismus   MeSH
• krysa rodu Rattus MeSH
• lipopolysacharidy imunologie   MeSH
• matka - expozice noxám MeSH
• mikroglie imunologie   metabolismus   MeSH
• mozek imunologie   metabolismus   MeSH
• parvalbuminy metabolismus   MeSH
• sexuální faktory MeSH
• sociální chování MeSH
• těhotenství MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• lipopolysacharidy MeSH
• parvalbuminy MeSH

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins are key to the development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating semaphorin 3A (Sema3A) signaling; however, nothing is known about its role in synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that CRMP2 has a moderate effect on Sema3A-dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and the corpus callosum. Surprisingly, crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which is consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). We demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2-/- mice display ASD-related social behavior changes in the early postnatal period as well as in adults. Together, we demonstrate that CRMP2 mediates Sema3F-dependent synapse pruning and its dysfunction shares histological and behavioral features of ASD.

• Klíčová slova
• axon guidance, collapsin response mediator protein 2, dendritic spines, semaphorins, synapse pruning,
• MeSH
• dendritické trny MeSH
• membránové proteiny fyziologie   MeSH
• mezibuněčné signální peptidy a proteiny genetika   MeSH
• myši knockoutované MeSH
• myši MeSH
• neurony MeSH
• neuroplasticita MeSH
• poruchy autistického spektra * MeSH
• proteiny nervové tkáně genetika   fyziologie   MeSH
• semaforiny * MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• collapsin response mediator protein-2 MeSH Prohlížeč
• membránové proteiny MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• proteiny nervové tkáně MeSH
• Sema3f protein, mouse MeSH Prohlížeč
• semaforiny * MeSH

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.

• Klíčová slova
• Alzheimer's disease, amyloid precursor protein, circadian system, cognition, rat, social behavior, transgenic,
• Publikační typ
• časopisecké články MeSH

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.

• Klíčová slova
• animal model, behavior, chronic treatment, dizocilpine, rats, schizophrenia, western blot,
• Publikační typ
• časopisecké články MeSH

Muscarinic acetylcholine receptors (mAChRs) have been found to regulate many diverse functions, ranging from motivation and feeding to spatial navigation, an important and widely studied type of cognitive behavior. Systemic administration of non-selective antagonists of mAChRs, such as scopolamine or atropine, have been found to have adverse effects on a vast majority of place navigation tasks. However, many of these results may be potentially confounded by disruptions of functions other than spatial learning and memory. Although studies with selective antimuscarinics point to mutually opposite effects of M1 and M2 receptors, their particular contribution to spatial cognition is still poorly understood, partly due to a lack of truly selective agents. Furthermore, constitutive knock-outs do not always support results from selective antagonists. For modeling impaired spatial cognition, the scopolamine-induced amnesia model still maintains some limited validity, but there is an apparent need for more targeted approaches such as local intracerebral administration of antagonists, as well as novel techniques such as optogenetics focused on cholinergic neurons and chemogenetics aimed at cells expressing metabotropic mAChRs.

• Klíčová slova
• acetylcholine, behavior, biperiden, learning, memory, receptor, rodents, scopolamine,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Alzheimer's disease (AD) is one of the most serious human, medical, and socioeconomic burdens. Here we tested the hypothesis that a rat model of AD (Samaritan; Taconic Pharmaceuticals, USA) based on the application of amyloid beta42 (Abeta42) and the pro-oxidative substances ferrous sulfate heptahydrate and L-buthionine-(S, R)-sulfoximine, will exhibit cognitive deficits and disruption of the glutamatergic and cholinergic systems in the brain. Behavioral methods included the Morris water maze (MWM; long-term memory version) and the active allothetic place avoidance (AAPA) task (acquisition and reversal), testing spatial memory and different aspects of hippocampal function. Neurochemical methods included testing of the NR1/NR2A/NR2B subunits of NMDA receptors in the frontal cortex and CHT1 transporters in the hippocampus, in both cases in the right and left hemisphere separately. Our results show that Samaritan rats(™) exhibit marked impairment in both the MWM and active place avoidance tasks, suggesting a deficit of spatial learning and memory. Moreover, Samaritan rats exhibited significant changes in NR2A expression and CHT1 activity compared to controls rats, mimicking the situation in patients with early stage AD. Taken together, our results corroborate the hypothesis that Samaritan rats are a promising model of AD in its early stages.

• Klíčová slova
• Alzheimer’s disease, animal model, cognition, hippocampus, learning and memory, neurochemistry of the acetylcholine system, sporadic AD,
• Publikační typ
• časopisecké články MeSH

Dopamine plays a role in generating flexible adaptive responses in changing environments. Chronic administration of D2-like agonist quinpirole (QNP) induces behavioral sensitization and stereotypical behaviors reminiscent of obsessive-compulsive disorder (OCD). Some of these symptoms persist even after QNP discontinuation. In QNP-sensitization, perseverative behavior has often been implicated. To test the effect of QNP-sensitization on reversal learning and its association with perseveration we selected an aversively motivated hippocampus-dependent task, active place avoidance on a Carousel. Performance was measured as the number of entrances into a to-be-avoided sector (errors). We tested separately QNP-sensitized rats in QNP-drugged and QNP-undrugged state in acquisition and reversal tasks on the Carousel. In acquisition learning there were no significant differences between groups and their respective controls. In reversal, QNP-sensitized drugged rats showed a robust but transient increase in number of errors compared to controls. QNP-sensitized rats in an undrugged state were not overtly different from the control animals but displayed an altered learning manifested by more errors at the beginning compensated by quicker learning in the second session compared to control animals. Importantly, performance was not associated with perseveration in neither QNP-sensitized drugged nor QNP-sensitized undrugged animals. The present results show that chronic QNP treatment induces robust reversal learning deficit only when the substance is continuously administered, and suggest that QNP animal model of OCD is also feasible model of cognitive alterations in this disorder.

• Klíčová slova
• behavior, cognitive coordination, flexibility, obsessive–compulsive disorder, quinpirole, rat, reversal,
• Publikační typ
• časopisecké články MeSH

The present study describes a task testing the ability of rats to trigger operant behavior by their relative spatial position to inaccessible rotating objects. Rats were placed in a Skinner box with a transparent front wall through which they could observe one or two adjacent objects fixed on a slowly rotating arena (d = 1 m) surrounded by an immobile black cylinder. The direction of arena rotation was alternated at a sequence of different time intervals. Rats were reinforced for the first bar-press that was emitted when a radius separating the two adjacent objects or dividing a single object into two halves (pointing radius) entered a 60 degrees sector of its circular trajectory defined with respect to the stationary Skinner box (reward sector). Well trained rats emitted 62.1 +/- 3.6% of responses in a 60 degrees sector preceding the reward sector and in the first 30 degrees of the reward sector. Response rate increased only when the pointing radius was approaching the reward sector, regardless of the time elapsed from the last reward. In the extinction session, when no reward was delivered, rats responded during the whole passage of the pointing radius through the former reward sector and spontaneously decreased responding after the pointing radius left this area. This finding suggests that rats perceived the reward sector as a continuous single region. The same results were obtained when the Skinner box with the rat was orbiting around the immobile scene. It is concluded that rats can recognize and anticipate their position relative to movable objects.

• MeSH
• chování zvířat * MeSH
• krysa rodu Rattus MeSH
• odměna MeSH
• operantní podmiňování * MeSH
• potkani Long-Evans MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

The spatial orientation of vertebrates is implemented by two complementary mechanisms: allothesis, processing the information about spatial relationships between the animal and perceptible landmarks, and idiothesis, processing the substratal and inertial information produced by the animal's active or passive movement through the environment. Both systems allow the animal to compute its position with respect to perceptible landmarks and to the already traversed portion of the path. In the present study, we examined the properties of substratal idiothesis deprived of relevant exteroceptive information. Rats searching for food pellets in an arena formed by a movable inner disk and a peripheral immobile belt were trained in darkness to avoid a 60 degrees sector; rats that entered this sector received a mild foot shock. The punished sector was defined in the substratal idiothetic frame, and the rats had to determine the location of the shock sector with the use of substratal idiothesis only, because all putative intramaze cues were made irrelevant by angular displacements of the disk relative to the belt. Striking impairment of place avoidance by this "shuffling procedure" indicates that effective substratal idiothesis must be updated by exteroceptive intramaze cues.

• MeSH
• krysa rodu Rattus MeSH
• plnění a analýza úkolů MeSH
• podněty * MeSH
• potkani Long-Evans MeSH
• prostorové chování * MeSH
• reverzní učení MeSH
• učení vyhýbat se MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH