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Basic evaluation of the effect of chronic NMDA glutamate receptor (NMDAR) blockade on the hippocampal long-term potentiation (LTP) was performed in an animal model of inborn olivo-cerebellar degeneration (Lurcher mutant mice, LMM). NMDA receptor antagonist MK-801 was administered to mice in the dose 0.2 mg/kg of body weight, daily during two periods of their ontogeny: D5-D26 and D91-D111. In the consecutive 15 days some behavioral characteristics were studied using special methods for physical activity testing. Then LTP was investigated in LMM and also in their healthy littermates which served as controls (wild-type, WT). LTP in animals pre-treated with MK-801 showed significant long-term suppression of NMDAR activity, in both WT and LMM despite certain small differences between them. Our results show that cerebellar pathology on one hand and a physical activity on the other hand can influence the LTP in hippocampal region. It can be concluded that the results support the ideas of close functional cooperation between the brain structures which are involved in mechanisms of learning and memory.

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Possible effect of trophic factors from embryonic cerebellar graft transplanted in adult Lurcher mutant mice on LTP as electrophysiological marker of learning and memory process was studied. Also the combination of the transplantation and long-term forced motor training was investigated. An evaluation of LTP ability in four animal groups (transplanted, sham-operated, with and without forced motor activity) and comparison among them showed the highest LTP improvement in the group with combination of both influences (ie. transplantation and motor training).

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The effect of single dose of NMDA glutamate receptor blockage administration on the hippocampal LTP was evaluated in animal model of inborn cerebellar degeneration. We compared the level of possible LTP blockade in two groups of animals, Lurcher mutant mice and their healthy littermates which served as controls. In the second part of the study we tested group of mice which were influenced repeatedly by the same NMDA blocker (MK-801) during behavioral experiments. Our results suggest a similar effect of blockade either after single or chronic MK-801 administration; both of them practically disrupted LTP generation with differences between healthy and neurodegenerative animals.

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Possible influence of embryonic cerebellar graft transplanted into the adult neurodegenerative brain in Lurcher mutant mice on long-term potentiation (LTP) in hippocampus was investigated. Evaluation of LTP ability and comparison with the tests of motor learning suggests similarities between magnitude of LTP and criteria of motor learning. Also interstrain differences were described. Our results support ideas about tight cooperation among brain structures which are involved in mechanisms of learning and memory.

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A direct registration of brain cortical and hippocampal activity during a high-frequency electromagnetic field (HF EMF) exposure was performed. All experimental procedures were done under urethane anaesthesia (20%, 2 g/kg i.p.) in Lurcher mutant mice, wild type (healthy littermates) were used as controls. Experimental animals were exposed to the HF EMF with frequency corresponding to cellular phones. Our method is based on the use of gel electrodes (silicon tubes or glass microcapillaries filled with agar) where the connection with classical electrodes is located out of HF EMF space. ECoG evaluation showed a distinct shift to lower frequency components but clear effect has been observed only in wild type (healthy) mice whereas in Lurcher mutant mice only gentle differences between frequency spectra were found. Measurement of hippocampal rhythmicity showed gentle changes with increase of higher frequencies (i.e. opposite effect than in cortex) and changes in theta oscillations registered from a dentate gyrus and CA1 area in both types of animals (healthy and mutant). These findings support the idea about possible influencing the central nervous system by HF EMF exposure and support also some recent results about possible health risks resulting from cellular phones use.

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Four-day-old rat pups were taught to avoid an electrified grid under the influence of increased nitric oxide availability in brain (by a nitric oxide substrate L-arginine) that alleviated learning or decreased nitric oxide (due to the action of a blocker of nitric oxide synthase nitro-L-arginine) that impaired learning. Three hours after criteria meeting, the pups were killed for analysis of nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase content in brain cells and neuropil. In the cingulate gyrus, NADPH-diaphorase-positive staining was increased after L-arginine, but an opposite picture was observed in hippocampus and basal ganglia, i.e. an increase after the blocker nitro-L-arginine. A noteworthy accumulation of NADPH-diaphorase in hippocampal cells might be tentatively explained by the blocking effect of nitro-L-arginine not allowing NADPH-diaphorase to leave the cells. Application of L-arginine or nitro-L-arginine provoked only minor changes in the studied structures of non-learned pups with the exception of hippocampus where nitro-L-arginine increased the width of neuropil, but to a lesser degree than in learned animals. These results clearly show that both manipulations, i.e. drug application and learning, only have a significant effect on the changes in NADPH-diaphorase positivity in brain neurons.

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Taking into account our previous results on dopamine and nitric oxide effects on neonatal inhibitory learning and memory in rats, the mutual interactions of the two molecules were studied in this experimental paradigm. Both increased dopamine content and nitric oxide bioavailability in the brain after application of dopamine and L-arginine as substrate for nitric oxide synthase solutions into lateral cerebral ventricles improved learning and 24 h memory. Joint application of dopamine and L-arginine yielded still more improvement. Learning and memory processing were dose dependently enhanced by D1 receptor agonists as well, whereas D1 receptor antagonists had an opposite and also dose-dependent effect. Dopamine or D1 receptor agonists administered together with nitro-L-arginine, a nitric oxide synthase inhibitor that impaired learning and memory due to a decreased nitric oxide availability, antagonized the effect of nitro-L-arginine, as did L-arginine. D1 receptor antagonists impaired both learning and memory, and L-arginine rendered learning values normal. The dopamine and D1 receptor-agonist effect on 24 h memory was concentration dependent, and their higher concentrations substantially increased the retention indexes. The intimate mechanisms of these interactions are to be identified in further experiments.

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The impact of nitric oxide on learning, memory processing and retrieval was studied in the neonatal rats. For comparison, spontaneous motor activity and changes of brain temperature were also studied after nitric oxide manipulations in identical age groups. The nitric oxide availability was either increased by a systemic or intracerebroventricular application of L-arginine, a substrate of nitric-oxide synthase, or decreased by nitro-L-arginine, its inhibitor. L-arginine, 20 mM or nitro-L-arginine, 10 or 5 mM were given intraperitoneally, 1 ml/100 g weight, or in the amounts of 11 into both lateral cerebral ventricles. Intact and saline injected pups were used as controls. Spontaneous motor behavior of newborn pups were not unambiguously affected by nitric oxide, and the same applies to changes of brain and body temperature or heart rate. In no case any correlation with changes of learning and/or memory could be established. Learning was dose dependently impaired relative to controls by intraperitoneal application of nitroarginine. L-arginine only slightly decreased numbers of trials to both criteria and partially abolished the blocking effect of nitroarginine on nitric oxide synthase. With the use of intracerebroventricular injections the positive impact of L-arginine on learning became highly significant. In 24-h memory, intraperitoneal injections of L-arginine enhanced the retention indexes. The impairing effect of nitro-L-arginine significantly increased with delaying after-learning application intervals, being more pronounced at the 3-h than at 0-h interval. Here also, its effect was partially abolished by L-arginine. Effects of nitric-oxide availability in brain after intracerebroventricular application of these substances at 16 various post-learning intervals were assessed on memory processing and retrieval. A general enhancing effect of increased nitric-oxide supply on 24-h retention indexes was found through all studied intervals, which was not, however, monotonous, but several peaks appeared with application at 3, 6, 18 and 23.5 h after learning. On the other hand, the suppressive effect of NArg was not evident relative to saline before the 6-h post-learning injection delay. These results show that nitric oxide exerts a considerable central modulatory effect on learning, memory processing and retrieval at the very early postnatal period of the rat. The efficiency of nitric-oxide manipulations depends on its actual bioavailability in the brain and the stage of memory processing.

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