Examining litter specific variability in mice and its impact on neurodevelopmental studies

• Published in: NeuroImage (Orlando, Fla.) Vol. 269; p. 119888
• Main Authors: Valiquette, Vanessa, Guma, Elisa, Cupo, Lani, Gallino, Daniel, Anastassiadis, Chloe, Snook, Emily, Devenyi, Gabriel A., Chakravarty, M. Mallar
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2023; Elsevier Limited; Elsevier
• Subjects: Animals; Behavior; Child development; Computer Simulation; Female; Inbreeding; Litter; Litter Size; Magnetic resonance imaging; Mice; Mice, Inbred C57BL; Mouse model; Neurodevelopment; Partial Least Squares; Power analysis; Pregnancy; Principal Component Analysis; Risk factors; MRI; PND; PPI; BFL; LV; LMER; FDR; MnCl2; MAGeT; AIC; OFT; Principal Component Analysis; GD; dB; MBT; EE; MM; SS; MIA; Power analysis; PLSC; KW; HPA-axis; PCA; MEMRI; PC; Magnetic resonance imaging; Partial Least Squares; Neurodevelopment; Mouse model; SAL
• ISSN: 1053-8119; 1095-9572
• DOI: 10.1016/j.neuroimage.2023.119888

•Starting in adolescence, a litter-effect is observed in mice brain and behaviors.•Variables patterns complexity explaining litter-effects increase within lifespan.•More litters of smaller size improve statistical power for litter modulated models.•The litter-effect and sex-effect are closely intertwined.•Litter modulated brain regions overlap with regions associated to social behaviors. Our current understanding of litter variability in neurodevelopmental studies using mice may limit translation of neuroscientific findings. Higher variance of measures across litters than within, often termed intra-litter likeness, may be attributable to both pre- and postnatal environment. This study aimed to assess the litter-effect within behavioral assessments (2 timepoints) and anatomy using T1-weighted magnetic resonance images across 72 brain region volumes (4 timepoints) (36 C57bl/6J inbred mice; 7 litters: 19F/17M). Between-litter comparisons of brain and behavioral measures and their associations were evaluated using univariate and multivariate techniques. A power analysis using simulation methods was then performed on modeled neurodevelopment and to evaluate trade-offs between number-of-litters, number-of-mice-per-litter, and sample size. Our results show litter-specific developmental effects, from the adolescent period to adulthood for brain structure volumes and behaviors, and for their associations in adulthood. Our power simulation analysis suggests increasing the number-of-litters in experimental designs to achieve the smallest total sample size necessary for detecting different rates of change in specific brain regions. Our results demonstrate how litter-specific effects may influence development and that increasing the litters to the total sample size ratio should be strongly considered when designing neurodevelopmental studies.