Substrain- and sex-dependent differences in stroke vulnerability in C57BL/6 mice

Area of Science:

• Neuroscience
• Genetics
• Cardiovascular Research

Background:

• The C57BL/6 mouse is a widely used model in biomedical research.
• Distinct substrains of C57BL/6 mice are known to possess genetic and phenotypic variations.
• These variations can impact experimental outcomes, particularly in studies of neurological diseases like stroke.

Purpose of the Study:

• To compare stroke vulnerability across different C57BL/6 mouse substrains.
• To identify potential confounds in stroke research due to substrain variability.
• To determine the suitability of different substrains as controls for stroke studies.

Main Methods:

• Utilized a permanent distal middle cerebral artery and common carotid artery occlusion model in six C57BL/6 substrains (J, JEiJ, ByJ, NCrl, NJ, NTac).
• Quantified mean infarct volume and analyzed infarct size distribution.
• Assessed potential contributing factors such as posterior communicating artery patency, MCA anatomy, and penumbral blood flow.

Main Results:

• Mean infarct volume was nearly two-fold smaller in J, JEiJ, and ByJ substrains compared to NCrl, NJ, and NTac (N-lineage) mice.
• Sex-dependent differences in infarct size were observed in J and ByJ substrains, with females having smaller infarcts, but not in NCrl and NJ mice.
• Substrain and sex differences were primarily attributed to a higher proportion of small infarcts in the J and ByJ substrains.

Conclusions:

• Significant genetic variability exists among C57BL/6 substrains, impacting stroke vulnerability.
• Failure to match substrain backgrounds can introduce confounds in stroke research, especially when comparing genetically modified strains.
• N-lineage C57BL/6 substrains, with their larger and more homogeneous infarcts, may be preferable for future experimental stroke studies.