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In this paper, the data are presented concerning different reactions to seven daily injections of atomoxetine in two mouse strains differing in relative brain weight. Atomoxetine affected the performance in a puzzle-box cognitive test in a complicated way—the large brain mice were less successful at task solutions (presumably because they were not afraid of the brightly lit test box), while the small brain strain of atomoxetine treated mice solved the task more successfully. The behavior of all atomoxetine treated animals was more active in an aversive situation (an unescapable slippery funnel, (analogous to the Porsolt test) and the time of immobility decreased significantly in all atomoxetine treated mice. The general patterns of behavioral reactions to atomoxetine in the cognitive test and other interstrain differences demonstrated in these experiments made it possible to suggest that differences in ascending noradrenergic projections between the two strains used exist. Further analysis of the noradrenergic system in these strains is needed (and further analysis of the effects of drugs which affect noradrenergic receptors). [ABSTRACT FROM AUTHOR]

The selection of mice for high ("plus") and low ("minus") scores in the puzzle-box test was performed over five generations. This test evaluates the success (or failure) in finding the underpass, leading to the dark part of the box, when it is blocked. This means that the mouse is either able or unable to operate the "object permanence rule" (one of the index's cognitive abilities). For the "+" strain, animals were bred who solved the test when the underpass test blocked with a plug; the "−" strain comprised those who were unable to solve this task. In mice of the "+" strain, the proportion of animals that was able to solve "plug" stages of the test was higher than in the "−" strain and in the non-selected genetically heterogeneous population. The "+" mice ate significantly more new food in the hyponeophagia test. Animals of both strains demonstrated the ability to "manipulate" the plug blocking the underpass, touching the plug with their paws and muzzle, although the majority of "−" mice were unable to open the underpass effectively. Thus, mice of both selected strains demonstrated that they were able to understand that the underpass does exist, but only "+"-strain animals (at least the majority of them) were able to realize the solution. The selection for plug-stage solution success affected the mouse's ability to open the hidden underpass. [ABSTRACT FROM AUTHOR]

Neuroinflammation plays an important role in epileptogenesis, however, most studies are performed using pharmacological models of epilepsy, while there are only few data available for non-invasive, including genetic, models. The levels of a number of pro-inflammatory cytokines were examined in the Krushinsky–Molodkina (KM) rat strain with high audiogenic epilepsy (AE) proneness (intense tonic seizure fit in response to loud sound) and in the control strain "0" (not predisposed to AE) using multiplex immunofluorescence magnetic assay (MILLIPLEX map Kit). Cytokine levels were determined in the dorsal striatum tissue and in the brain stem. Background levels of IL-1β, IL-6, and TNF-α in the dorsal striatum of the KM rats were significantly lower than in the rats "0" (by 32.31, 27.84, and 38.87%, respectively, p < 0.05, 0.05, and 0.01), whereas no inter-strain differences in the levels of these metabolites were detected in the brain stem in the "background" state. Four hours after sound exposure, the TNF-α level in the dorsal striatum of the KM rats was significantly lower (by 38.34%, p < 0.01) than in the "0" rats. In the KM rats, the dorsal striatal levels of IL-1β and IL-6 were significantly higher after the sound exposure and subsequent seizure fit, compared to the background (35.29 and 50.21% increase, p < 0.05, 0.01, respectively). In the background state the IL-2 level in the KM rats was not detected, whereas after audiogenic seizures its level was 14.01 pg/ml (significant difference, p < 0.01). In the KM rats the brain stem levels of IL-1β and TNF-α after audiogenic seizures were significantly lower than in the background (13.23 and 23.44% decrease, respectively, p < 0.05). In the rats of the "0" strain, the levels of cytokines in the dorsal striatum after the action of sound (which did not induce AE seizures) were not different from those of the background, while in the brain stem of the "0" strain the levels of IL-1β were lower than in the background (40.28%, p < 0.01). Thus, the differences between the background levels of cytokines and those after the action of sound were different in the rats with different proneness to AE. These data suggest involvement of the analyzed cytokines in pathophysiology of the seizure state, namely in AE seizures. [ABSTRACT FROM AUTHOR]

Variations in the extent of adult neurogenesis and natural and experimental factors controlling it have been described in laboratory animals. The wide range of variation seen even within a species, the mouse, raises the question as to which rates of neurogenesis can be expected in natural populations. Answering this question is important to evaluate the functional significance of adult neurogenesis under natural conditions and to define the factors controlling it. To address this issue, we investigated four species of wild-living rodents and outbred laboratory mice using markers for proliferating cells, Ki-67, and developing neurons, doublecortin and NeuroD. We found about four times as many Ki-67-positive cells per mm3 granule cell layer in two wood mouse species (Muridae; Apodemus spp.) than in bank and pine voles (Arvicolidae; Clethrionomys glareolus and Microtus subterraneus). Laboratory mice show proliferation rates between wood mice and voles. Markers for developing neurons, NeuroD and doublecortin, reflect the findings of proliferation activity. Hippocampal cell proliferation decreases dramatically with age in wild-living species. The onset of the downregulation varies among species. It occurs late in the life span of the yellow-necked wood mouse. In aged animals, the number of proliferating cells per mm3 granule cell layer is reduced to 19% of the adult value. Downregulation occurs early in pine voles, in which cell proliferation in adult animals is reduced to 33% of juvenile values. Proliferation and age-dependent changes along the deep border of the alveus and angular bundle follow those of the dentate gyrus. We conclude that cell proliferation and neurogenesis in the dentate gyrus vary significantly among wild-living rodents, and that they are downregulated with age, but at species-specific time points. © 2004 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

The expression of glial cell line-derived neurothrophic factor (GDNF) transcript forms pre-(α)pro-gdnf, pre-(β)pro-gdnf, and their common region m-gdnf in the pons as well as the inferior (IC) and superior colliculi in Krushinsky–Molodkina (KM) rats and in the strain "0" was analyzed by quantitative real-time polymerase chain reaction (PCR) in the control (unstimulated KM and "0" rats) and 1.5, 4.5, and 8 h after auditory stimulation. Such stimulation induced audiogenic seizures (AS) in KM rats. Audiogenic seizure was not observed in "0" rats, which was obtained by selection for the absence of AS in a population of F2 hybrids between KM and Wistar rats not predisposed to AS. A significant drop in the level of all transcripts was observed 1.5 h after auditory stimulation in both KM and "0" rats. In most cases, the average expression of α and β isoforms and m-region 4.5 h after stimulation was greater than those after 1.5 and 8 h. At the same time, the expression of pre-(β)pro-gdnf in the IC of KM rats 4.5 h after the stimulation was significantly lower than after 1.5 or 8 h. This work presents the first demonstration of different time courses of expression of the α and β GDNF isoforms during physiological processes in genotype-specific pathology. • The GDNF isoforms in brainstem of audiogenic seizure-prone rat were examined. • Audiogenic seizure correlates with abnormal pre-(β)pro-gdnf expression in midbrain. • The diverse expression of GDNF α- and β-isoforms in vivo is firstly shown. [ABSTRACT FROM AUTHOR]

The role of brain and liver mitochondria at epileptic seizure was studied on Krushinsky-Molodkina (KM) rats which respond to sound with an intensive epileptic seizure (audiogenic epilepsy). We didn't find significant changes in respiration rats of brain and liver mitochondria of KM and control rats; however the efficiency of АТР synthesis in the KM rat mitochondria was 10% lower. In rats with audiogenic epilepsy the concentration of oxidative stress marker malondialdehyde in mitochondria of the brain (but not liver) was 2-fold higher than that in the control rats. The rate of HO generation in brain mitochondria of КМ rats was twofold higher than in the control animals when using NAD-dependent substrates. This difference was less pronounced in liver mitochondria. In KM rats, the activity of mitochondrial ATP-dependent potassium channel was lower than in liver mitochondria of control rats. The comparative study of the mitochondria ability to retain calcium ions revealed that in the case of using the complex I and complex II substrates, permeability transition pore is easier to trigger in brain and liver mitochondria of KM and КМs rats than in the control ones. The role of the changes in the energetic, oxidative, and ionic exchange in the mechanism of audiogenic epilepsy generation in rats and the possible correction of the epilepsy seizures are discussed. [ABSTRACT FROM AUTHOR]

Background: Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity. Methods: Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM × Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated. Results: Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS. Conclusions: Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity. [ABSTRACT FROM AUTHOR]

Summary Deletion of the p66Shc gene results in lean and healthy mice, retards aging, and protects from aging-associated diseases, raising the question of why p66Shc has been selected, and what is its physiological role. We have investigated survival and reproduction of p66Shc−/− mice in a population living in a large outdoor enclosure for a year, subjected to food competition and exposed to winter temperatures. Under these conditions, deletion of p66Shc was strongly counterselected. Laboratory studies revealed that p66Shc−/− mice have defects in fat accumulation, thermoregulation, and reproduction, suggesting that p66Shc has been evolutionarily selected because of its role in energy metabolism. These findings imply that the health impact of targeting aging genes might depend on the specific energetic niche and caution should be exercised against premature conclusions regarding gene functions that have only been observed in protected laboratory conditions. [ABSTRACT FROM AUTHOR]

Daily patterns of animal behavior are potentially of vast functional importance. Fitness benefits have been identified in nature by the association between individual timing and survival or by the fate of individuals after experimental deletion of their circadian pacemaker. The recent advances in unraveling the molecular basis of circadian timing enable new approaches to natural selection on timing. The investigators report on the effect and fate of the mutant Per2Brdm1 allele in 4 replicate populations of house mice in a seminatural outside environment over 2 years. This allele is known to compromise circadian organization and entrainment and to cause multiple physiological disturbances. Mice (N = 250) bred from Per2Brdm1 heterozygotes were implanted subcutaneously with transponders and released in approximately Mendelian ratios in four 400 m2 pens. An electronic system stored the times of all visits to feeders of each individual. The study first demonstrates that mice are not explicitly nocturnal in this natural environment. Feeding activity was predominantly and sometimes exclusively diurnal and spread nearly equally over day and night under the protective snow cover in winter. The effect of Per2Brdm1 on activity timing is negligible compared to seasonal changes in all genotypes. Second, the Per2Brdm1 allele did not have persistent negative effects on fitness. In the first year, the allele gradually became less frequent by reducing survival. New cohorts captured had the same Per2Brdm1 frequency as the survivors from previous cohorts, consistent with an absence of an effect on reproduction. In the second year, the allele recovered to about its initial frequency (0.54). These changes in selective advantage were primarily due to female mice, as females lived longer and the sex ratio dropped to about 25% males in the population. While it is unknown which selective advantage led to the recovery, the results caution against inferences from laboratory experiments on fitness consequences in the natural environment. It also demonstrates that the activity of mice, while strictly nocturnal in the laboratory, may be partially or completely diurnal in the field. The new method allows assessment of natural selection on specific alleles on a day-today basis. [ABSTRACT FROM PUBLISHER]

Abstract: Our previous work has revealed very high baseline neurogenesis in the dentate gyrus of wood mice as compared particularly to bank voles; a difference which may be related to learning capacity. This study explored whether the newly-developed Intellicage system could be used to compare these species in simple spatial learning paradigms. The Intellicage is essentially a group-housing cage that also allows continuous automatic recording of each individual’s behaviour. Seven wild-caught bank voles (Clethrionomys glareolus) were compared with seven wild-caught long-tailed wood mice (Apodemus sylvaticus) in the Intellicage system over 9 days. During the first 90min after entering the cage, the wood mice were substantially more exploratory than the bank voles (P = 0.003). Over subsequent days, both species showed nocturnal activity increases with voles being 3.7 times more active overall. In the spatial learning paradigms, there were significant species-by-time interactions with wood mice outperforming bank voles on both place learning (P = 0.027) and subsequent reversal (P = 0.006). Conclusions are firstly that the wood mice show superior learning abilities in this paradigm, and secondly that the Intellicage serves as a valuable cognitive testing arena for small wild rodents, or for circumstances where cognition must be compared independent of different responses to handling or novel environments. [Copyright &y& Elsevier]

Principal component analysis of behavioural measures together with body and brain weight of hybrid F2 mice crosses between two lines selected for large (LB) and small (SB) brain weight yielded eight-factor solution explaining 75.1% of total variance. Two of eight factors had sufficient loading on brain weight and several behavioural measures. The factor analysis showed that, among F2 hybrids, mice with larger brain weight were characterised, in open-field test, by higher scores of locomotion in the periphery of arena and of rearing, as well as less frequent grooming and freezing than mice with smaller brain weight. F2 hybrids with larger brain weight moved faster and displayed stereotyped behaviour in the cross-maze test more frequently. In general, this diversity is in accord with the behaviour differences between parent LB and SB lines. The results show that, in mice fear-anxiety and stereotypic behaviours, which are known to interfere with normal exploration and learning of the environment, are causally connected with brain weight. [Copyright &y& Elsevier]