Impact of C57BL/6 substrain on sex-dependent differences in mouse stroke models

We have recently found significant variation in stroke vulnerability among substrains of C57BL/6 mice, observing that commonly used N-lineage substrains exhibit larger infarcts than C57BL/6J and related substrains. Parallel variation was also seen with respect to sex differences in stroke vulnerability, in that C57BL/6 mice of the N-lineage exhibited comparable infarct sizes in males and females, whereas infarcts tended to be smaller in females than in males of J-lineage substrains. This adds to the growing list of recognized phenotypic and genetic differences among C57BL/6 substrains. Although no previous studies have explicitly compared substrains with respect to sex differences in stroke vulnerability, unrecognized background mismatch has occurred in some studies involving control and genetically modified mice. The aims of this review are to: present the evidence for associated substrain- and sex-dependent differences in a mouse permanent occlusion stroke model; examine the extent to which the published literature in other models compares with these recent results; and consider the potential impact of unrecognized heterogeneity in substrain background on the interpretation of studies investigating the impact of genetic modifications on sex differences in stroke outcome. Substrain emerges as a critical variable to be documented in any experimental stroke study in mice.