Neuroanatomical Asymmetry Across Species: From Mice to Macaques to Human Insights

Abstract

How left-right anatomical asymmetry is established in the human brain is a major unanswered question in the field of laterality. Efforts to address this area of brain development are limited by the scarcity of animal models with such asymmetries, particularly for mammals whose brain structure and development are most similar to that of humans. Identifying patterns of anatomical brain asymmetry in other mammalian species would lay the groundwork for pursuing mechanistic studies of the molecular and cellular processes underlying its generation. Here, I led two studies using automated image analysis to perform extensive characterization of anatomical brain asymmetry in two key mammalian species of interest: mice (M. musculus) and rhesus macaques (M. mulatta). Using seven separate mouse datasets totaling over 3500 animals, I identified a global anterior-posterior asymmetry pattern in the mouse brain but the absence of regional asymmetries at individual structures. Anterior regions in the mouse brain are greater in volume and surface area on the right compared to left and are shifted anteriorly on the right compared to left. Posterior regions are greater in volume and surface area on the left compared to right and are shifted anteriorly on the left compared to right. In macaques, using seven datasets totaling nearly 700 animals, I identified 80 regional asymmetries, including a right hemisphere frontal lobe expansion and right-larger auditory regions, which are present as early as 1 month after birth and persist into adulthood. Yet, in contrast to mice, I observe no global asymmetry pattern in macaques. Extensive use of cross-validation demonstrates the results to be reproducible across independent datasets, across two different image modalities in mice, and across two different image registration software. Together, my studies establish high-confidence, atlas-based patterns for studying neuroanatomical asymmetry in both mice and macaques, robust to numerous biological and technical variables. These atlas-based patterns can serve as a foundation for future studies examining the action of genetic factors in neuroanatomical asymmetry, characterizing the underlying cellular architecture, or further probing the relationship between anatomical and functional brain asymmetries. Yet, interrogating these patterns also reveals three significant observations that advance our understanding of brain laterality. 1) The presence of human-like regional asymmetries in macaques but not mice suggests this aspect of laterality may have emerged within the primate lineage. 2) The mouse results show no relationship between anatomical asymmetries and known mouse functional asymmetries, indicating that functional asymmetry can be decoupled from macro-anatomical asymmetry. 3) The regional pattern of anatomical asymmetry in macaques is not correlated at all with that seen in humans, suggesting that, although some instances of consistent asymmetries may exist across species, the regional patterns are generally not evolutionarily conserved. Finally, my findings in mice reconcile two previously published studies on the question of neuroanatomical asymmetry in mice which on their surface, appeared to show major differences in their findings but which co-exist within the results of my analysis. Overall, my thesis research has provided a foundation for future cellular-level studies and advanced evolutionary understanding of anatomical left-right asymmetry.