Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems @UniTn, Rovereto, Italy.
PLoS One. 2013 Oct 16;8(10):e76655. doi: 10.1371/journal.pone.0076655. eCollection 2013.
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.
BTBR T+tf/J（BTBR）小鼠表现出明显的行为缺陷，类似于自闭症的定义症状，这一特征促使该模型在临床前自闭症研究中得到广泛应用。由于神经行为特征是根据参考人群来描述的，因此许多研究人员已经检查并描述了 BTBR 小鼠的行为，以对比 C57BL/6J（B6）小鼠的行为，B6 是一种具有高社交性和低自我梳理行为的小鼠品系。为了探究这种比较对于自闭症研究的转化相关性，我们使用磁共振成像（MRI）来绘制两种品系的多个形态解剖和功能神经影像学读数图谱，这些图谱在患者群体中得到了广泛应用。弥散张量纤维束成像证实了之前关于 BTBR 小鼠胼胝体发育不全和海马连合缺失的报告，并揭示了主要皮质白质束的头尾向重新组织。在前连合、腹内侧丘脑和位于第三脑室上方的一种品系特异性白质结构中发现了完整的半球间束。BTBR 还表现出额皮质、枕皮质和丘脑灰质体积减少，以及与对照 B6 小鼠相比皮质厚度广泛减少。内侧前额叶和岛叶皮质观察到灰质体积和厚度增加的焦点。使用脑血容量加权 fMRI 进行静息状态大脑活动映射显示，BTBR 小鼠的皮质-丘脑功能降低，下丘脑和背侧海马的活动增加。总的来说，我们的结果显示，BTBR 小鼠的大脑相对于对照 B6 小鼠存在明显的功能和结构异常。观察到的大而广泛的白质和灰质异常似乎不符合自闭症患者通常观察到的神经解剖改变。额皮质代谢减少具有潜在的转化相关性，因为这一特征重现了先前报告的临床观察结果。
