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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Available from: Michael Fanselow, Oct 05, 2015
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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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    ABSTRACT: High-fructose diets have been implicated in obesity via impairment of leptin signaling in humans and rodents. We investigated whether fructose-induced leptin resistance in mice could be used to study the metabolic consequences of fructose consumption in humans, particularly in children and adolescents. Male C57Bl/6 mice were weaned to a randomly assigned diet: high fructose, high sucrose, high fat, or control (sugar-free, low-fat). Mice were maintained on their diets for at least 14 weeks. While fructose-fed mice regularly consumed more kcal and expended more energy, there was no difference in body weight compared to control by the end of the study. Additionally, after 14 weeks, both fructose-fed and control mice displayed similar leptin sensitivity. Fructose-feeding also did not change circulating glucose, triglycerides, or free fatty acids. Though fructose has been linked to obesity in several animal models, our data fail to support a role for fructose intake through food lasting 3 months in altering of body weight and leptin signaling in mice. The lack of impact of fructose in the food of growing mice on either body weight or leptin sensitivity over this time frame was surprising, and important information for researchers interested in fructose and body weight regulation.
    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.
    Pharmacology Biochemistry and Behavior 05/2014; 124C. DOI:10.1016/j.pbb.2014.05.007 · 2.78 Impact Factor
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    • "In this study, we crossed tau-expressing mice to a C57BL/6NTac (B6/NTac) sub-strain while Bolmont et al. crossed tau-expressing mice to a C57BL/6 J (B6/J) sub-strain. The B6/NTac sub-strain from Taconic was originally derived from the B6/J strain from Jackson laboratory, but over time genetic and phenotypic differences have developed between the two sub-strains [36-38]. Although we detected significant, but relatively modest changes in the tauopathy of rTg4510 mice on a B6/NTac background, it is possible that modifiers of tauopathy exist on the B6/J strain. "
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    ABSTRACT: Cross-breeding of transgenic mice is commonly used to assess gene-gene interactions, particularly in the context of disease. Strain background changes can influence the phenotype of mouse models and can confound crossbreeding studies. We sought to determine if changing the strain background of a commonly used mouse model of tauopathy (rTg4510) would significantly impact the originally reported phenotype. On the original F1 FVB/N x 129S6 background, rTg4510 mice present with progressive cognitive decline, increased insoluble tau, robust tau pathology and age-dependent neurodegeneration. One of the most common strains in mouse modeling is C57BL/6. We and others have previously reported that this strain background alters the phenotypes of various models, including the JNPL3 model of tauopathy. To determine if the phenotype of rTg4510 mice was similarly affected by the introduction of the C57BL/6 background, we compared rTg4510 mice on the original F1 FVB/N x 129S6 background to rTg4510 mice on an F1 FVB/N x C57BL/6NTac (B6/NTac) background, herein termed rTg4510B6. Despite a small, but significant increase in soluble human tau levels, young rTg4510B6 mice had equivalent levels of tau phosphorylation, aggregation and cognitive impairments as age-matched rTg4510 mice. At 6.5 months of age, rTg4510B6 mice displayed hyperphosphorylated insoluble tau and robust cortical tau neuropathology that was equivalent to age-matched rTg4510 mice; however, 10.5-month-old rTg4510B6 mice had greater amounts of phospho-tau in the cortex and hippocampus when compared to age-matched rTg4510 mice. Non-transgenic (NT) littermates of rTg4510B6 (NTB6) mice also had greater amounts of cortical and hippocampal phospho-tau at 10.5 months of age when compared to NT littermates of rTg4510 mice. Additionally, older rTg4510B6 mice had gross forebrain neurodegeneration that was equivalent to age-matched rTg4510 mice. Overall, our data shows that introduction of the C57BL/6 strain into the rTg4510 mouse background modestly alters the tau pathology that was originally reported in rTg4510 on the F1 FVB/129 background. In contrast, behavioral and neurodegenerative outcomes were not altered. These studies support the use of the rTg4510 mouse model on a partial C57BL/6 strain background without losing fidelity of the phenotype and suggest that the C57BL/6 background does not inherently protect against tauopathy.
    Molecular Neurodegeneration 01/2014; 9(1):8. DOI:10.1186/1750-1326-9-8 · 6.56 Impact Factor
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