Dataset Information

Characterization of behavioral phenotypes in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorder under social housing conditions using the multiple animal positioning system.

ABSTRACT: The BTBR T+ Itpr3tf/J (BTBR) mouse strain is a widely used model of autism spectrum disorder (ASD). The BTBR mice display behavior consistent with the three diagnostic categories of ASD. However, the behavioral phenotypes of the BTBR mice in a long-term group housing setting are largely unknown because conventional behavioral tests for ASD model mice are designed for use under simplified artificial conditions over a short observation period. In this study, we applied a newly developed assay system, the Multiple Animal Positioning System (MAPS), to quantify behaviors under group housing conditions over four days of continuous observation. Using MAPS, we showed that in a group housing condition, the BTBR mice exhibited lower activity levels in the dark phase and alteration of social behavior in comparison with the C57BL/6J mice. The phenotypes of the BTBR mice were affected by co-housing with the C57BL/6J mice for four days, but the influence was weak and limited. Our results by MAPS differ from those obtained using conventional behavioral tests. The present study demonstrated that MAPS would be useful for evaluating the usual/natural behaviors of various animal models in detail and under more ethological conditions.

SUBMITTER: Endo N

PROVIDER: S-EPMC6699967 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Characterization of behavioral phenotypes in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorder under social housing conditions using the multiple animal positioning system.

Endo Nozomi N Makinodan Manabu M Somayama Nami N Komori Takashi T Kishimoto Toshifumi T Nishi Mayumi M

Experimental animals 20190322 3

The BTBR T+ Itpr3tf/J (BTBR) mouse strain is a widely used model of autism spectrum disorder (ASD). The BTBR mice display behavior consistent with the three diagnostic categories of ASD. However, the behavioral phenotypes of the BTBR mice in a long-term group housing setting are largely unknown because conventional behavioral tests for ASD model mice are designed for use under simplified artificial conditions over a short observation period. In this study, we applied a newl ...[more]

PMID: 30905912

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Project description:The ketogenic diet (KD) has been utilized as a dietary therapeutic for nearly a century. One experimental model particularly responsive to the KD is the BTBRT+tf/j (BTBR) mouse, which displays phenotypic characteristics of autism spectrum disorder (ASD) and insulin resistance. Recently, the study of impaired mitochondrial function has become a focal point of research investigating the pathophysiology of ASD. As highly dynamic organelles, mitochondria undergo constant fluctuations in morphology, biogenesis, and quality control in order to maintain cellular homeostasis. An important modifier of mitochondrial dynamics is energy availability. Therefore, the aim of this study was to examine the impact of a KD on mitochondrial dynamics in the liver and brain (prefrontal cortex) of the BTBR mouse model of ASD. Juvenile male C57Bl/6 (B6) and BTBR mice were age-matched to 5 weeks of age before being fed standard chow (CD, 13% kcal fat) or a KD (75% kcal fat) for 10-14 days. Analysis of brain tissue identified differences in mitochondrial gene expression but no correlation with protein levels. Unlike in the brain, KD led to decreased levels of mitochondrial proteins in the liver, despite increased gene expression. Consistent with decreased mitochondrial proteins, we also observed decreased mtDNA for all mice on the KD, demonstrating that the KD reduces the total amount of mitochondria in the liver. In order to explain the discrepancy between protein levels and gene expression, we investigated whether mitochondrial turnover via mitophagy was increased. To this end, we examined expression levels of the mitophagy regulator BNIP3 (BCL2/adenovirus E1B 19 kd-interacting protein 3). BNIP3 gene and protein expression were significantly elevated in liver of KD animals (p < 0.05), indicating the potential activation of mitophagy. Therefore, consumption of a KD exerts highly tissue-specific effects, ultimately increasing mitochondrial turnover in the liver, while gene and protein expression in the brain remaining tightly regulated.

Project description:BTBR T+tf/J (BTBR) mice display prominent behavioural deficits analogous to the defining symptoms of autism, a feature that has prompted a widespread use of the model in preclinical autism research. Because neuro-behavioural traits are described with respect to reference populations, multiple investigators have examined and described the behaviour of BTBR mice against that exhibited by C57BL/6J (B6), a mouse line characterised by high sociability and low self-grooming. In an attempt to probe the translational relevance of this comparison for autism research, we used Magnetic Resonance Imaging (MRI) to map in both strain multiple morpho-anatomical and functional neuroimaging readouts that have been extensively used in patient populations. Diffusion tensor tractography confirmed previous reports of callosal agenesis and lack of hippocampal commissure in BTBR mice, and revealed a concomitant rostro-caudal reorganisation of major cortical white matter bundles. Intact inter-hemispheric tracts were found in the anterior commissure, ventro-medial thalamus, and in a strain-specific white matter formation located above the third ventricle. BTBR also exhibited decreased fronto-cortical, occipital and thalamic gray matter volume and widespread reductions in cortical thickness with respect to control B6 mice. Foci of increased gray matter volume and thickness were observed in the medial prefrontal and insular cortex. Mapping of resting-state brain activity using cerebral blood volume weighted fMRI revealed reduced cortico-thalamic function together with foci of increased activity in the hypothalamus and dorsal hippocampus of BTBR mice. Collectively, our results show pronounced functional and structural abnormalities in the brain of BTBR mice with respect to control B6 mice. The large and widespread white and gray matter abnormalities observed do not appear to be representative of the neuroanatomical alterations typically observed in autistic patients. The presence of reduced fronto-cortical metabolism is of potential translational relevance, as this feature recapitulates previously-reported clinical observations.

Dataset Information

Characterization of behavioral phenotypes in the BTBR T+ Itpr3tf/J mouse model of autism spectrum disorder under social housing conditions using the multiple animal positioning system.

Publications

Characterization of behavioral phenotypes in the BTBR T<sup>+</sup> Itpr3<sup>tf</sup>/J mouse model of autism spectrum disorder under social housing conditions using the multiple animal positioning system.

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