Behavioral Differences among C57BL/6 Substrains: Implications for Transgenic and Knockout Studies

Department of Human Genetics, University of Chicago, Chicago, Illinois 60637, USA.
Journal of neurogenetics (Impact Factor: 1.27). 02/2008; 22(4):315-31. DOI: 10.1080/01677060802357388
Source: PubMed


Separate breeding colonies of C57BL/6 ("B6") mice maintained at the Jackson Laboratories ("J") and NIH ("N") have led to the emergence of two distinct substrains of C57BL/6 mice: C57BL/6J and C57BL/6N. Molecular genetic studies indicate simple sequence-length polymorphisms, single-nucleotide polymorphisms, and copy-number variants among B6 substrains that may contribute to phenotypic differences. We examined differences in motor coordination, pain sensitivity, and conditional fear in the C57BL/6J strain and three N strains: C57BL/6NCrl (Charles River), C57BL/6NTac (Taconic), and C57BL/6NHsd (Harlan Sprague Dawley). Male C57BL/6J mice demonstrated enhanced motor coordination, as measured by the rotarod assay, markedly enhanced pain sensitivity in two assays of acute thermal nociception (e.g., tail withdrawal and hot plate), and a reduced level of conditional fear. The tail withdrawal result was confirmed in a separate laboratory. We also provide a table reviewing previously reported behavioral differences among various B6 substrains and discuss the significance of environmental differences due to obtaining mice form different vendors. These data may be seen as a potential problem and as a potential opportunity. Great care must be taken when working with mice engineered by using B6 embryonic stem cell lines because control groups, backcrosses, and intercrosses could inadvertently introduce behaviorally significant polymorphic alleles or environmental confounds. On the other hand, deliberate crosses between B6 substrains may provide an opportunity to map polymorphic loci that contribute to variability in a trait on largely homogenous backgrounds, which has the potential to improve mapping resolution and aid in the selection of candidate genes.

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    • "Zurita and colleagues (2011) showed that the C57BL/ 6JBomTac mouse harbors three substrain-specific SNPs that are not present in other C57BL/6J mice, and these might be responsible for the differences. Interestingly, previous studies have reported that the C57BL/6J mouse has better motor coordination than the 6N substrains in the rotarod test (Bryant et al. 2008; Matsuo et al. 2010), which is consistent with our finding demonstrating that 6JBomTac mice showed longer latency to falling in the rotarod test (Figure 2). "
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    ABSTRACT: The C57BL/6 is one of the most frequently used mouse strains in neuroscience. Although it is well recognized that genetic background has a critical impact on the behavior and physiology of different strains of mice, the differences among substrains of C57BL/6 are not well appreciated. Here, we compared three substrains of C57BL/6 (C57BL/6NCrljOri, C57BL/6NTacSam, and C57BL/6JBomTac) in a series of behavioral tasks examining both general behavior, and learning and memory. In addition, we have also performed electrophysiological analyses including long-term potentiation (LTP) in the hippocampus, which is considered a cellular mechanism for learning and memory. We found that there are significant differences between C57BL/6JBomTac and the other two substrains in their behavioral phenotypes, including motor coordination, anxiety, and freezing in classical fear conditioning. However, the three substrains show comparable levels of hippocampal LTP. Our findings provide guidelines for choosing the most appropriate substrain for the intended studies.
    Animal cells and systems the official publication of the Zoological Society of Korea 04/2015; 19(3):1-7. DOI:10.1080/19768354.2015.1023830 · 0.44 Impact Factor
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    • "Further, even the same strain purchased from different vendors (i.e. different substrains) can exhibit different phenotypes or drug sensitivities [33]–[35]. While C57BL/6 mice from Harlan were used for experiment #1 (C57Bl/6H), C57Bl/6 mice from Jackson labs was used in experiment #2 (C57Bl/6J). "
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    PLoS ONE 09/2014; 9(9):e107206. DOI:10.1371/journal.pone.0107206 · 3.23 Impact Factor
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    • "Consistent response of specific mice strains to treatments is a clear necessity when using animal models to study underlying mechanisms of disease and treatment or when screening novel compounds (Gould, 2006; Gould et al., 2007; Can et al., 2013). Significant efforts are invested to identify the best strains to be used for modeling specific domains of disease or specific classes of drugs (Tejani-Butt et al., 2003; Crowley et al., 2005; Brimberg et al., 2007; Gould et al., 2007; Bryant et al., 2008; Milner and Crabbe, 2008; Kara and Einat, 2013). For example, and in the context of lithium action, common mice strains were evaluated in the forced swim test to examine the drug's antidepressant-like effect (Can et al., 2013) and similar work was also performed in the amphetamine-induced hyperactivity test (Gould et al., 2007). "
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    ABSTRACT: Animal models are crucial components in the search for better understanding of the biological bases of psychiatric disorders and for the development of novel drugs. Research, in general, and research with animal models, in particular, relies on the consistency of effects of investigated drugs or manipulations across experiments. In that context, it had been noted that behavioral responses to lithium in ICR (CD-1) mice from Harlan Israel have changed across the last years. To examine this change, the present study compared the effect of lithium treatment in ICR mice from Harlan Israel with the ICR mice from Harlan USA. The mice were treated with chronic oral lithium. Their lithium serum levels were measured and their behavior in the forced swim test (FST) was evaluated. The mice were also treated with [(3)H]-inositol ICV and lithium injection and their frontal cortex [(3)H]-phosphoinositol accumulation was measured. Results show that lithium serum levels in Israeli mice were significantly lower compared with the USA mice, that lithium had no behavioral effect in the Israeli mice but significantly reduced FST immobility time of the USA mice, and that phosphoinositol accumulation was much more strongly affected by lithium in the USA mice compared with the Israeli mice. These results suggest that the Israeli Harlan colony of ICR mice changed significantly from the original ICR colony in Harlan USA and that the differences might be related to absorption or secretion of lithium.
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