Differential learning abilities of 129T2/Sv and C57BL/6J mice as assessed in three water maze protocols

Knockout mice are generated by using ES cells from 129 mouse strains and are frequently backcrossed with other strains, like C57BL/6. It is important to characterise the physiological and, in particular, the behavioural profile of each strain in order to correctly analyse the functional contribution of a single gene mutation on the 'cognitive' phenotype. The present study compared 129T2/Sv (129) and C57BL/6J (C57) mice in three different spatial learning protocols in the water maze, using a hidden platform. In the 'standard' reference memory protocol, 129 and C57 attained an equivalent level of performance as assessed by accuracy in reaching the platform (path length), despite a faster swim speed exhibited by C57 mice. In a stepwise learning task, C57 mice showed poorer performances over all stages of learning. However they performed better than 129 in a massed learning protocol which taxes short-term memory, and in which they exhibited lower levels of perseveration. The results emphasize the importance of using various tasks differing in cognitive demand, but using the same experimental environment and motivation, in order to 1) evaluate strain- or mutation-dependent learning abilities, and 2) dissociate the roles played by cognitive and non-cognitive factors in the behavioural requirements of the tasks.     

Performance of F2 B6x129 hybrid mice in the Morris water maze, latent inhibition and prepulse inhibition paradigms: Comparison with C57Bl/6J and 129sv inbred mice

Assessment of cognition and information processing in mice is an important tool in preclinical research that focuses on the development of cognitive enhancing drugs. Analysis of transgenic (TG) and knockout (KO) mice is usually performed on a F2 B6x 129 background. In the present study, we have compared performance of F2 B6x 129 hybrid mice (F2 mice) with that of the two parental inbred strains (C57Bl/6J and 129sv mice), and a wild-type (WT) strain (with a combined B6x 129 background) in three cognitive/information processing paradigms. It was found that the F2 mice outperformed either of the parental strains and provide a control sample with good baseline performance in the Morris water maze (MWM). Reliable deficits could be obtained in learning and memory in this paradigm following injections with scopolamine (0.16 mg/kg) in the F2 mice, which can potentially be used to test effects of reference and novel compounds in order to develop cognitive enhancing drugs. Furthermore, it was shown that the four genotypes showed normal latent inhibition (LI) using the conditioned taste aversion (CTA) paradigm and exhibited no differences in prepulse inhibition (PPI) levels. Following the setup of these procedures in mice, we are now able to compare the effects of gene knockout/mutations used for target validation with results in the present study as a frame of reference.     

Cellular correlates of progressive hearing loss in 129S6/SvEv mice

Several strains of mice hear well initially but show progressive sensorineural hearing loss. Affected cochlear cell types include all those known to be affected in human age-related hearing loss (ARHL), or presbycusis. Thus these mice have been offered as models of human ARHL. At present, however, few mouse ARHL models are sufficiently well described to serve as the basis for specific hypotheses about human ARHL. We examined 1-month-old and 15-month-old 129S6/SvEv (129S6) mice and compared them with BALB/cJ and CBA/J mice. Age-related elevation of compound action potential thresholds was interpreted in the light of endocochlear potentials and changes in hair cells, afferent neurons, fibrocytes in spiral limbus and ligament, and supporting cells within the organ of Corti. Aging in 129S6 mice was associated with high-frequency hearing loss. Four components of age-related cochlear degeneration emerged from quantitative analyses, including 1) basal loss of outer hair cells; 2) basal loss of type IV fibrocytes in the spiral ligament; 3) apical loss of fibrocytes in spiral limbus, and 4) anomalies of supporting cells in the cochlear base. Although neuronal loss was not consistently found, two mice showed loss of afferent dendrites and cell bodies in the cochlear apex without inner hair cell loss. Despite multifaceted degeneration, hearing loss in 129S6 mice appears to be best explained by degenerative changes in outer hair cells and in the organ of Corti, conforming to human sensory ARHL. Age-related changes in the apical spiral limbus may promote pathology of the medial organ of Corti and eventual loss of afferent neurons, with possible implications for human neural ARHL.     

Age-related changes in the motricity of the inbred mice strains 129/sv and C57BL/6j

The development of motor skills was studied at different stages in the life of the mouse, focusing on three key aspects of motor development: early rhythmic motor activities prior to the acquisition of quadruped locomotion, motor skills in young adults, and the effect of aging on motor skills. The age-related development pattern was analysed and compared in two strains of major importance for genomic studies (C57Bl6/j and 129/sv). Early rhythmic air-stepping activities by l-dopa injected mice showed similar overall development in both strains; differences were observed with greater beating frequency and less inter-limb coordination in 129/sv, suggesting that 129/sv had a different maturation process. Performance on the rotarod by young adult C57Bl6/j gradually improved between 1 and 3 months, but then declined with age; performance on the treadmill also declined with an age-related increase in fatigability. Overall performance by 129/sv mice was lower than C57Bl6/j, and the age-related pattern of change was different, with 129/sv having relatively stable performance over time. Inter-strain differences and their possible causes, in particular the role of dopaminergic pathways, are discussed together with repercussions affecting mutant phenotyping procedures.     

Contrasting grooming phenotypes in C57Bl/6 and 129S1/SvImJ mice

Since C57 and 129 mice are the commonly used background strains, a better knowledge of all their behavioural characteristics is important in neuroscience research. Grooming is a complex and essential ritual in the rodent behavioural repertoire, normally proceeding in a cephalocaudal progression (paws-nose-face-body-legs-tail and genitals). Various stressors as well as genetic manipulations have been reported to alter mouse grooming and its patterning, underlying the importance of analysis of grooming behaviours in detail. Although strain differences between C57BL/6 and 129S1/SvImJ substrains have been assessed in many studies, no ethological analyses of their grooming have been performed. Here we show strain differences between these mice in spontaneous (novelty-induced) and artificial (water-induced) grooming. Overall, 129S1/SvImJ mice demonstrated less grooming activity, more interrupted and incomplete bouts, and more incorrect transitions (contrary to the cephalocaudal rule) between patterns, accompanied by lower vertical activity and higher defecation/urination in both tests. These results are consistent with general hypoactive anxious phenotype in 129S1/SvImJ mice and suggest that ethological analysis of mouse grooming may be used in neurobehavioural stress research, including behavioural phenotyping of both mutant and background mice.     

胶质瘤多药耐药细胞系C6／adr的建立及其耐药性逆转的研究

目的 研究胶质瘤多药耐药（ＭＤＲ）的发生机理及逆转方法。方法 建立了Ｃ６／ａｄｒ ＭＤＲ细胞系,经ＲＴ－ＰＣＲ及免疫组化染色分别研究了ｍｄｒ－１基因及Ｐ－糖蛋白（Ｐ－ｇｐ）的表达;采用ＭＴＴ药敏试验及ＨＰＬＣＡ测定细胞内阿霉素浓度的方法研究了异搏定、红霉素、潘生丁、Ｐ－ｇｐ单克隆抗体、复方丹参对ＭＤＲ的逆转作用。结果 Ｃ６／ａｄｒ ＭＤＲ细胞系ｍｄｒ－１基因阳性,Ｐ－ｇｐ高度表达。异搏定（２～６μ     

Differences in nociceptive behavioral performance between C57BL/6J, 129S6/SvEv, B6 129 F1 and NMRI mice

The interpretation of knockout and transgenic mouse studies in pain research critically depends on detailed knowledge of the performance profile of the background strains. Pain-related behavior was compared between four relevant mouse strains (C57BL/6J, 129S6/SvEv, B6 129 F1 and NMRI mice of both sexes) using an extended test battery that included an unusual variety of assays for thermal and mechanical acute nociception, and inflammatory and neuropathic pain. Strain- and gender-dependent differences were demonstrated in many of these nociceptive assays. Particularly, C57BL and 129 mice, which serve as the default genetic backgrounds for experiments in genetically altered mice, display quite different patterns of nociceptive performance. Compared to C57BL/6J mice, 129S6/SvEv animals are less sensitive to inflammatory pain conditions (thermal sensitivity after carrageenan subplantar injection; flinch behavior after formalin injection), while the opposite is observed in the neuropathic pain condition and the visceral pain model. These data may be of special interest for genetic studies, where issues related to the background phenotype may confound their interpretation.     

Radial maze performance in three strains of mice: role of the fimbria/fornix

The excitatory action of quinolinic acid has been examined on neurons in different parts of the rat CNS. When applied by microiontophoresis quinolinic acid excited cells in the cerebral cortex, hippocampus and neostriatum, but even when applied from electrodes which produced responses in these areas, quinolinic acid was ineffective in the cerebellum and spinal cord. Like most excitants tested in other studies, L-glutamate was excitatory to all cells examined. As an endogenous compound, therefore, quinolinic acid may merit special attention as a potential neurotransmitter in brain.     

LP-BM5 infection impairs spatial working memory in C57BL/6 mice in the Morris water maze

Previous studies show that the LP-BM5 murine leukemia virus causes an acquired immunodeficiency syndrome in C57BL/6 mice (MAIDS) and impairs learning and memory without gross motor impairment. To assess spatial working memory impairment after LP-BM5 infection and the time course of this impairment, we tested mice in a modified working-memory version of the Morris water maze. Twenty mice were inoculated with LP-BM5; controls received medium (Minimum Essential Medium). In the test procedure, animals had two 1-min training sessions to learn the position of a randomly placed hidden platform. Thirty seconds after the second training session, animals were placed in the maze without the platform, and time and pathlength spent in each quadrant of the maze were measured. For 9 weeks after LP-BM5 infection, both groups showed preference for the target quadrant compared to the opposite quadrant. At 10 and 11 weeks after infection, the LP-BM5 virus infected mice lost this target quadrant preference. We conclude that LP-BM5 infection impaired spatial working memory in a modified working-memory version of the Morris water maze test in C57BL/6 mice at 10 and 11 weeks after virus infection.     

Impaired water maze learning performance without altered dopaminergic function in mice heterozygous for the GDNF mutation

Exogenous glial cell line-derived neurotrophic factor (GDNF) exhibits potent survival-promoting effects on dopaminergic neurons of the nigrostriatal pathway that is implicated in Parkinson's disease and also protects neurons in forebrain ischemia of animal models. However, a role for endogenous GDNF in brain function has not been established. Although mice homozygous for a targeted deletion of the GDNF gene have been generated, these mice die within hours of birth because of deficits in kidney morphogenesis, and, thus, the effect of the absence of GDNF on brain function could not be studied. Herein, we sought to determine whether adult mice, heterozygous for a GDNF mutation on two different genetic backgrounds, demonstrate alterations in the nigrostriatal dopaminergic system or in cognitive function. While both neurochemical and behavioural measures suggested that reduction of GDNF gene expression in the mutant mice does not alter the nigrostriatal dopaminergic system, it led to a significant and selective impairment of performance in the spatial version of the Morris water maze. A standard panel of blood chemistry tests and basic pathological analyses did not reveal alterations in the mutants that could account for the observed performance deficit. These results suggest that endogenous GDNF may not be critical for the development and functioning of the nigrostriatal dopaminergic system but it plays an important role in cognitive abilities.     

Spatial learning and memory, maze running strategies and cholinergic mechanisms in two inbred strains of mice

The acquisition process of the radial maze task was studied in two inbred strains of mice, C57BL/6 and DBA/2. A quantitative and qualitative evaluation of performance was performed and the pretest level of activity was measured. The results showed a significant correlation between activity and performance since the highly active C57BL/6 mice exhibited better performance of the radial maze task than the less active DBA/2 mice. Moreover, for correct trials, strain-dependent maze-running strategies were observed: while both strains displayed about the same percentage of clockwise and spatial strategies, it was observed that among the spatial strategies C57BL/6 used a larger number of different correct solutions. Subsequently, the effect of scopolamine administration on working memory processes was assessed in sequential and discrete trials. A different reactivity of each strain to anti-cholinergic treatment was found in discrete trials since only DBA/2 mice were impaired. The effect of scopolamine is discussed in relation to the different models of information processing involved in learning and memorizing the experimental rule.     

BALB/c mice are not so bad in the Morris water maze

We compared the learning performances of BALB/c mice subjected to the Morris water spatial task under two different lighting conditions. In the first one, the experimental room was lit by neon tubes (direct and bright illumination) and in the second one by a halogen lamp directed to the roof (diffuse illumination). The scores of BALB/c mice in the diffuse illumination condition clearly demonstrated that these mice could learn to escape to a hidden platform while they could not under direct illumination condition. Moreover, they were able to acquire the task by means of spatial cues. These results are interpreted in terms of a decrease of anxiety levels.     

Effects of spaced learning in the water maze on development of dentate granule cells generated in adult mice

New dentate granule cells (GCs) are generated in the hippocampus throughout life. These adult‐born neurons are required for spatial learning in the Morris water maze (MWM). In rats, spatial learning shapes the network by regulating their number and dendritic development. Here, we explored whether such modulatory effects exist in mice. New GCs were tagged using thymidine analogs or a GFP‐expressing retrovirus. Animals were exposed to a reference memory protocol for 10–14 days (spaced training) at different times after newborn cells labeling. Cell proliferation, cell survival, cell death, neuronal phenotype, and dendritic and spine development were examined using immunohistochemistry. Surprisingly, spatial learning did not modify any of the parameters under scrutiny including cell number and dendritic morphology. These results suggest that although new GCs are required in mice for spatial learning in the MWM, they are, at least for the developmental intervals analyzed here, refractory to behavioral stimuli generated in the course of learning in the MWM. © 2015 Wiley Periodicals, Inc.     

Faster is not surer--a comparison of C57BL/6J and 129S2/Sv mouse strains in the watermaze.

In recent years the use of genetic manipulations to investigate the molecular mechanisms underlying learning and memory has become a common approach. In a great many cases, the spatial learning ability of mutant mice has been assessed using the Morris watermaze task. The performance of these mice may, however, be strongly influenced by their genetic background and, therefore, the interpretation of their phenotype requires a preliminary characterization of the parental strains. The present study compared 129S2/Sv and C57/BL/6J inbred mouse strains, which have been widely used in deriving lines of genetically modified mice, on the hidden platform version of the watermaze task. During acquisition, the C57 mice displayed shorter escape latencies to find the platform than the 129S2s. Further analysis revealed, however, that the C57 mice also swam faster than the 129S2s. The analysis of path lengths was thus a more reliable measure of spatial learning, and revealed an equal level of performance in the two strains. This conclusion was confirmed during the two probe trials with both strains showing a similar spatial preference for the training site. These results suggest that the 129S2 substrain is no less proficient than the C57 substrain in terms of spatial learning in the watermaze, and also demonstrates the importance of not relying solely on escape latency as a measure of watermaze performance.     

Differential learning strategies in spatial and nonspatial versions of the Morris water maze in the C57BL/6J inbred mouse strain

We recently developed a new nonspatial version of the Morris water maze that requires the use of four visually distinct intra-maze patterns to efficiently locate a hidden platform. The nonspatial version was designed to match the spatial version on complexity of cue usage, and differs only on spatiality of cues, thereby allowing more meaningful comparisons between the two versions. Following a previous experiment that demonstrated nonspatial learning with the BXSB inbred mouse strain, C57 inbred mice were tested in this study. They received spatial and nonspatial training in a counter-balanced order so that Test Order and information transfer could be assessed. Subjects that received spatial training first had superior performance in both the spatial and the nonspatial tasks when compared to mice that received nonspatial training first. The mice that received spatial training first used extra-maze cues as a spatial strategy. However, during nonspatial testing they did not use the intra-maze cues to locate the platform; instead, the mice used an egocentric strategy of circling through the platform annulus. Subjects that received spatial testing first were superior on the nonspatial task to those subjects that received nonspatial training first. Moreover, subjects that received nonspatial testing first were unable to learn the spatial version. Overall, C57 mice can learn both the spatial and nonspatial versions of the Morris maze presented here; however, the nonspatial version is more difficult and is solved using an egocentric strategy.     

Applications of the Morris water maze in the study of learning and memory

The Morris water maze (MWM) was described 20 years ago as a device to investigate spatial learning and memory in laboratory rats. In the meanwhile, it has become one of the most frequently used laboratory tools in behavioral neuroscience. Many methodological variations of the MWM task have been and are being used by research groups in many different applications. However, researchers have become increasingly aware that MWM performance is influenced by factors such as apparatus or training procedure as well as by the characteristics of the experimental animals (sex, species/strain, age, nutritional state, exposure to stress or infection). Lesions in distinct brain regions like hippocampus, striatum, basal forebrain, cerebellum and cerebral cortex were shown to impair MWM performance, but disconnecting rather than destroying brain regions relevant for spatial learning may impair MWM performance as well. Spatial learning in general and MWM performance in particular appear to depend upon the coordinated action of different brain regions and neurotransmitter systems constituting a functionally integrated neural network. Finally, the MWM task has often been used in the validation of rodent models for neurocognitive disorders and the evaluation of possible neurocognitive treatments. Through its many applications, MWM testing gained a position at the very core of contemporary neuroscience research.     

Water version of the radial-arm maze: Learning in three inbred strains of mice

The conventional land radial-arm maze has several disadvantages, including requiring a complicated automated apparatus, the elimination of odors as cues, and the use of food deprivation. We have created a water version of the maze, based on the principles of the land version, which maintains the advantages and excludes some of the disadvantages. In our maze, BXSB and C57BL/6 mice significantly reduced the number of working and reference memory errors committed over sessions, while NZB mice did not. For each strain, as the working memory ‘load' increased during a session, the number of errors increased. However, with practice the BXSB and C57BL/6 strains were able to handle this memory load more effectively. Mice were able to learn the maze without extensive adaptation, training, or testing and they did not exhibit ‘chaining'. This maze can also be considered to be an example of a water win-shift task that mice can easily learn. Therefore, the water version of the radial-arm maze can be a simple and useful tool for studying rodent learning and memory.