Substrain-specific behavioral variation in female C57BL/6 and C57BL/10 mice

Celine L. St. Pierre; Natalia M. Gonzales; Greta Sokoloff; Oksana Polesskaya

doi:10.3389/fnbeh.2026.1805176

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Substrain-specific behavioral variation in female C57BL/6 and C57BL/10 mice

Journal article

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Substrain-specific behavioral variation in female C57BL/6 and C57BL/10 mice

Celine L. St. Pierre, Natalia M. Gonzales, Greta Sokoloff and Oksana Polesskaya

Frontiers in behavioral neuroscience, Vol.20, 1805176

04/01/2026

DOI: 10.3389/fnbeh.2026.1805176

PMID: 42063742

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Abstract

IntroductionInbred mouse strains are essential to biomedical research, yet accumulating mutations and substrain divergence introduce phenotypic variability that can confound experimental outcomes. This study investigates behavioral differences among 13 inbred mouse substrains: eight C57BL/6 (B6) and five C57BL/10 (B10), bred in-house to control for environmental effects.MethodsFemale F1 offspring underwent a standardized battery of behavioral assays—open field test (OFT), locomotor response to cocaine (LOCO), fear conditioning (FC), prepulse inhibition (PPI), and the forced swim test (FST)—chosen for their relevance to models of psychiatric and substance use disorders.ResultsSignificant substrain-specific differences were observed across all behaviors. In the OFT, B6 substrains such as C57BL/6J showed higher activity than others, while B10 substrains exhibited distinct edge-zone preference patterns. Cocaine-induced locomotor stimulation varied significantly among B6 substrains but not among B10. In FC, substrain differences emerged in pre-training, contextual, and cued freezing behavior, particularly among B10 substrains. PPI testing revealed substrain-dependent variation in acoustic startle responses, with C57BL/10J displaying consistently lower startle amplitudes. In the FST, substrain-specific differences in swimming velocity and high mobility duration and frequency were found within the B6 group, while swimming distance showed substrain variation within the B10 group.DiscussionThese findings demonstrate substantial phenotypic variability among closely related substrains, underscoring the critical importance of substrain selection in behavioral research. By focusing on female mice (a group underrepresented in prior work), this study addresses an essential gap and provides insights for researchers designing preclinical models of psychiatric disorders. The results provide the basis for studies in reduced complexity crosses to identify causal genetic variants underlying behavioral traits.

C57BL/10

C57BL/6

fear conditioning

forced swim test

locomotor response to cocaine

prepulse inhibition

Details

Title: Subtitle: Substrain-specific behavioral variation in female C57BL/6 and C57BL/10 mice
Creators: Celine L. St. Pierre - University of Chicago
Natalia M. Gonzales - University of Chicago
Greta Sokoloff - University of Iowa
Oksana Polesskaya - University of California San Diego
Resource Type: Journal article
Publication Details: Frontiers in behavioral neuroscience, Vol.20, 1805176
DOI: 10.3389/fnbeh.2026.1805176
PMID: 42063742
ISSN: 1662-5153
eISSN: 1662-5153
Publisher: Frontiers Media S.A
Language: English
Date published: 04/01/2026
Academic Unit: Psychological and Brain Sciences
Record Identifier: 9985154892602771

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