Elsevier

NeuroImage

Volume 139, 1 October 2016, Pages 259-270
NeuroImage

Altered structural connectome in adolescent socially isolated mice

https://doi.org/10.1016/j.neuroimage.2016.06.037Get rights and content

Abstract

Social experience is essential for adolescent development and plasticity of social animals. Deprivation of the experience 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 isolation. Considering the key role of the orbitofrontal cortex in social behaviors, adolescent social isolation may primarily disrupt the orbitofrontal cortex and its neural pathways thereby contributing to an abnormal structural connectome.

Introduction

Social experience is important for normal brain development and plasticity of social animals, particularly during adolescence. Social isolation not only induces stress but also deprives the animal of essential experiences 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). Recent 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 prefrontal cortex (PFC) (Makinodan et al., 2012), and chronic social isolation 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 understanding 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 regarding the human connectome, only one dMRI-based study investigated 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-resolution ex-vivo dMRI from normal-housed controls and socially isolated C57BL/6 mice. Based on dMRI, we created an atlas and performed probabilistic tractography to construct the structural connectome. The structural connectomes of the two groups were then compared via graph-theory approaches (network-wise comparisons) (Rubinov and Sporns, 2010) and network based statistics (connection-wise comparisons) (Zalesky et al., 2010). We then investigated the association between properties of the structural connectome and behavioral phenotypes. Finally, we performed tractography-based analyses and histology to examine the white matter tracts that may contribute to the abnormal structural connectome. These comprehensive analyses allow us to fully describe the structural connectome in socially isolated mice and facilitate the understanding of social experience in adolescent brain development and plasticity.

Section snippets

Animals

Thirty-two C57BL/6 mice (18 males and 14 females) were divided into two groups: control (C; 10 males and 7 females) and socially isolated (I; 8 males and 7 females). Mice in the control group were group-housed in standard transparent plastic cages (3 or 4 mice per cage), while mice in the isolated group were housed separately (1 mouse per cage) from postnatal day 35 (P35) for 4 weeks. Behavioral tests were performed from P57 to P61, including an open-field test (1 day), a Y-maze spontaneous

Abnormal structural connectome in socially isolated mice

We constructed structural connectomes of mouse brains (Fig. 1C–D) and examined the effect of social isolation on network measures by two-way ANOVA (Fig. 2A). Socially isolated mice had a higher network degree than controls (F(1,20) = 29.32, p < 0.001, corrected), suggesting a higher overall connectivity probability in socially isolated mice. Contrary to the degree, socially isolated mice showed significant reduction relative to controls in betweenness (F(1,20) = 110.44, p < 0.001, corrected),

Discussion

Based on diffusion MRI and probabilistic tractography, we have identified the abnormal patterns in the structural connectome of socially isolated mice, characterized by reduced modularity and increased inter-hemispheric connections from prefrontal regions. These abnormalities were correlated with behavioral deficits caused by the social isolation, and the white matter changes in the forceps minor and lateral-cortical tracts contributed to the abnormal connectome. These results suggest that

Conflict of Interest

The authors declare no competing financial interests.

Acknowledgements

This work was supported by the National Basic Research Program of China (973 program; 2011CB707800), the Strategic Priority Research Program of the Chinese Academy of Sciences (Grant No. XDB02030300), the Natural Science Foundation of China (91132301), and a National Health and Medical Research Council (NHMRC) Australia project grant 1043045 (LJR). LJR is supported by an NHMRC Principal Research Fellowship and TJE is supported by a PhD student Australian Postgraduate Award from the Australian

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