Altered structural connectome in adolescent socially isolated mice Cirong Liu a,b,c , Yonghui Li a , Timothy J. Edwards a , Nyoman D. Kurniawan d , Linda J. Richards a,e , Tianzi Jiang a,b,c,f, ⁎ a Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia b Brainnetome Center, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China c National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China d The Centre for Advanced Imaging, The University of Queensland, Brisbane, QLD 4072, Australia e The School of Biomedical Sciences, The University of Queensland, Brisbane, QLD 4072, Australia f Key Laboratory for NeuroInformation of Ministry of Education, School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, China abstract article info Article history: Received 11 February 2016 Revised 11 June 2016 Accepted 18 June 2016 Available online 20 June 2016 Social experience is essential for adolescent development and plasticity of social animals. Deprivation of the ex- perience by social isolation impairs white matter microstructures in the prefrontal cortex. However, the effect of social isolation may involve highly distributed brain networks, and therefore cannot be fully explained by a change of a single region. Here, we compared the connectomes of adolescent socially-isolated mice and normal-housed controls via diffusion magnetic resonance imaging. The isolated mice displayed an abnormal connectome, characterized by an increase in degree and reductions in measures such as modularity, small- worldness, and betweenness. The increase in degree was most evident in the dorsolateral orbitofrontal cortex, entorhinal cortex, and perirhinal cortex. In a connection-wise comparison, we revealed that most of the abnormal edges were inter-modular and inter-hemispheric connections of the dorsolateral orbitofrontal cortex. Further tractography-based analyses and histological examinations revealed microstructural changes in the forceps minor and lateral-cortical tracts that were associated with the dorsolateral orbitofrontal cortex. These changes of connectomes were correlated with fear memory deficits and hyper-locomotion activities induced by social iso- lation. Considering the key role of the orbitofrontal cortex in social behaviors, adolescent social isolation may pri- marily disrupt the orbitofrontal cortex and its neural pathways thereby contributing to an abnormal structural connectome. © 2016 Elsevier Inc. All rights reserved. Keywords: Brain network Connectome Structural connectivity Diffusion MRI Orbitofrontal cortex Social deprivation 1. Introduction Social experience is important for normal brain development and plasticity of social animals, particularly during adolescence. Social isola- tion not only induces stress but also deprives the animal of essential ex- periences required for normal brain maturation and plasticity (Blakemore and Mills, 2014; Fuhrmann et al., 2015), which have been studied extensively in rodent animal models (Buwalda et al., 2011). Re- cent studies have begun to examine the effect of social isolation on white matter development: social isolation during the first two weeks post-weaning causes detrimental hypo-myelination in the medial pre- frontal cortex (PFC) (Makinodan et al., 2012), and chronic social isola- tion during adolescence and young adulthood causes similar effects (Liu et al., 2012). However, the effect of social isolation may involve highly distributed brain regions, and therefore cannot be fully explained by a change to a single brain region. Instead of limiting analysis to particular regions or tracts, we can model the complex system as a large-scale network or connectome that fully describes the structural architecture of the brain (Sporns et al., 2005). Recent advances in diffusion magnetic resonance imaging (dMRI) and tractography have enabled the connectivity profiles of the entire brain to be mapped, and have greatly promoted the exploration of the human structural connectome (Sporns et al., 2005). These dMRI-based studies of the human connectome have deepened our un- derstanding of normal brain development and neurodevelopmental disorders such as depression, schizophrenia, and autism (Griffa et al., 2013; Zuo et al., 2012). In contrast to the multitude of discoveries re- garding the human connectome, only one dMRI-based study investi- gated the maturation of the mouse structural connectome, which quantified the brain changes in connectivity during development and revealed a nonlinear relationship between network measures and age (Ingalhalikar et al., 2015). In this study, we investigated how social isolation during adolescent development affected brain's structural connectome. We acquired high- NeuroImage 139 (2016) 259–270 ⁎ Corresponding author at: Queensland Brain Institute, The University of Queensland, Brisbane, QLD 4072, Australia; Brainnetome Center, National Laboratory of Pattern Recognition, Institute of Automation, Chinese Academy of Sciences, Beijing 100190, China. E-mail address: jiangtz@nlpr.ia.ac.cn (T. Jiang). http://dx.doi.org/10.1016/j.neuroimage.2016.06.037 1053-8119/© 2016 Elsevier Inc. All rights reserved. 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