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The universe is asymmetric, the mouse brain too.1Cognitive Neuroscience, Donders Institute for Brain, Behaviour, and Cognition, Nijmegen, Netherlands, 2Max Planck Institute for Psycholinguistics, Nijmegen, Netherlands, 3Donders Institute for Brain, Behaviour, and Cognition, Nijmegen, Netherlands, 4Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada, 5Harvard Medical School, Boston, MA, United States, 6Brigham and Women's Hospital, Boston, MA, United States, 7Harvard University, Cambridge, MA, United States, 8Mouse Imaging Centre, Toronto, ON, Canada, 9Wellcome Centre for Integrative Neuroimaging, University of Oxford, Oxford, United Kingdom, 10Radboud University Medical Center, Nijmegen, Netherlands
Synopsis
Keywords: Small Animals, Brain, Asymmetry
Motivation: Exploring the mechanistic insights into the development of (altered) brain asymmetry in cognitive and psychiatric conditions requires the use of preclinical models. However, as asymmetry patterns are generally nuanced, even within human populations, substantial sample sizes are required to describe this phenomenon accurately.
Goal(s): Our goal was to explore the presence of brain asymmetry in the mouse overcoming the sample size limitations.
Approach: We leveraged a dataset encompassing MRI data from over 2000 mice.
Results: We found robust brain asymmetry in the mouse, as well as asymmetry patterns that differ from those observed in humans.
Impact: The mouse brain is asymmetric and there are some similarities between humans and mice, but species-specific asymmetry patterns need to be taken into account for translational research, reevaluating traditional assumptions and exploring the complexities of brain function across species.
Background
Hemispheric asymmetry is a fundamental characteristic of human brain organization, and altered asymmetry patterns have been implicated in various cognitive and neuropsychiatric disorders, including autism1,2. Interestingly, evidence shows that asymmetrical brain organization is not limited to humans3,4. Yet, asymmetry patterns are generally nuanced, even within human populations, and substantial sample sizes are required to describe this phenomenon accurately.Methods
In this pre-registered study, we used a mouse dataset from the Province of Ontario Neurodevelopmental Network (POND), which comprises structural MRI data from over 2000 mice, including genetic models for autism spectrum disorder, to reveal the scope and magnitude of hemispheric asymmetry in the mouse.We used a symmetrized version of the DSURQE ex-vivo MRI mouse brain atlas5 to determine regional volumes. These measurements were derived from Jacobian maps generated through non-linear deformations necessary to align with a template sourced from the POND repository. The DSURQE-label-atlas right hemisphere regions of interest (ROIs) were mirrored onto the left hemisphere to ensure that paired ROIs had the same nominal volumes in the template. The averaged Jacobians were multiplied with the region of interest volumes to obtain the individual ROI volumes. The asymmetry index (AI) was calculated as AI = (volumeright - volumeleft) / (volumeright + volumeleft). We estimated the effect size using Hedge’s g for each ROI pair using a one-sample parametric test and inferences were drawn based on 95th confidence intervals. Specifically, we thresholded the effect size if both 2.5% and 97.5% confidence intervals were either > 0 for positive effect size or < 0 for negative effect size. The processed data and code are made freely available (www.github.com/grandjeanlab/mouse_asymmetry).
Results
Our findings demonstrate the presence of robust hemispheric asymmetry in the mouse brain. We observed a rightward bias in anterior ROIs over left hemisphere regions in the wild-type mice (Figure 1A, green in the plot), while posterior parietal ROIs (Figure 1A, purple in the plot) showed a leftward bias. Highlighted ROIs exhibited small to very small effects (Hedge’s g < 0.2), e.g. the striatum (gwt > 0 = 0.240 [0.146, 0.334]), and cingulate cortex (gwt > 0 = -0.194 [-0.288, -0.100]), indicating a rightward and leftward bias respectively. Intriguingly, the rightward bias observed in the striatum (caudoputamen) was different compared with the observations in humans that reported a leftward bias in the putamen6,7, suggesting the existence of species-specific traits. Restricting the analysis to the isocortical region of interest exclusively to compare with previous human studies, we found a plausible effect along the anterior-posterior axis, with larger right hemispheric volumes towards the anterior pole and larger left hemispheric volumes toward the posterior pole (Figure 1B, slopeAI ~ Anterior-Posterior position = 1.64e-4 [-1.91e-6, 3.29e-4]). The asymmetry index bias was evenly distributed across sexes and sub-strains, adding confidence beyond the confidence intervals of the effect size and the sub-sampling correlations (Figure 2). Additionally, employing clustering analysis, we identified distinct asymmetry patterns in autism spectrum disorder models, a phenomenon that is also seen in atypically developing participants. The clusters identified here have the potential to explain phenotypic differences associated with syndromic autism and understand the biological context associated with the phenotype (Figure 3).Discussion
Consistently with the effects enumerated above, the AI was slightly biased towards positive values. We find subtle asymmetry in the mouse brain which is less pronounced compared to previous findings4. This is also reflected in poor parameter estimates when contrasting mouse models for autism spectrum disorders to their controls. Even so, the current finding is consistent with our expectations given the observations in humans1,2. Interestingly, the asymmetry patterns bear resemblance with those put forward in humans, suggesting an evolutionarily conserved pattern.Conclusion
Our study shows potential for the use of mouse models in studying the biological bases of typical and atypical brain asymmetry but also warrants caution as asymmetry patterns seem to differ between humans and mice.Acknowledgements
This project was supported by the Horizon Europe programs CANDY under grant agreement nos. 847818 to JG and JRH.References
1. Kong XZ, Mathias SR, Guadalupe T; ENIGMA Laterality Working Group; Glahn DC, Franke B, Crivello F, Tzourio-Mazoyer N, Fisher SE, Thompson PM, Francks C. Mapping cortical brain asymmetry in 17,141 healthy individuals worldwide via the ENIGMA Consortium. Proc Natl Acad Sci U S A. 2018 May 29;115(22).
2. Floris DL, Wolfers T, Zabihi M, Holz NE, Zwiers MP, Charman T, Tillmann J, Ecker C, Dell'Acqua F, Banaschewski T, Moessnang C, Baron-Cohen S, Holt R, Durston S, Loth E, Murphy DGM, Marquand A, Buitelaar JK, Beckmann CF; EU-AIMS Longitudinal European Autism Project Group. Atypical Brain Asymmetry in Autism-A Candidate for Clinically Meaningful Stratification. Biol Psychiatry Cogn Neurosci Neuroimaging. 2021 Aug;6(8):802-812.
3. Miletto Petrazzini ME, Sovrano VA, Vallortigara G, Messina A. Brain and Behavioral Asymmetry: A Lesson From Fish. Front Neuroanat. 2020 Mar 26;14:11.
4. Spring S, Lerch JP, Wetzel MK, Evans AC, Henkelman RM. Cerebral asymmetries in 12-week-old C57Bl/6J mice measured by magnetic resonance imaging. Neuroimage. 2010 Apr 1;50(2):409-15.
5. Dorr AE, Lerch JP, Spring S, Kabani N, Henkelman RM. High resolution three-dimensional brain atlas using an average magnetic resonance image of 40 adult C57Bl/6J mice. Neuroimage. 2008 Aug 1;42(1):60-9.
6. Guadalupe T et al. Human subcortical brain asymmetries in 15,847 people worldwide reveal effects of age and sex. Brain Imaging Behav. 2017 Oct;11(5):1497-1514.
7. Postema MC et al. Altered structural brain asymmetry in autism spectrum disorder in a study of 54 datasets. Nat Commun. 2019 Oct 31;10(1):4958.
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