The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice
The within-subject application of diffusion tensor MRI and CLARITY reveals brain structural changes in Nrxn2 deletion mice
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弥散张量 MRI 和 CLARITY 的受试者体内应用揭示了 Nrxn2 缺失小鼠的大脑结构变化
DOI：
10.1101/300806
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
Pervolaraki E
中科院分区：
文献类型：
--
作者：
Pervolaraki E
在已知的许多增加自闭症谱系障碍风险的基因突变中，很大一部分集中在突触蛋白上。神经毒素（NRXN）就是这样一个突触前蛋白家族，最近的遗传和小鼠证据表明nrxn2在产生改变的社会行为中起着致病作用。自闭症一直被认为是一种非典型连通性障碍，然而单基因突变如何影响这种连通性仍未得到充分研究。为了解决这个问题，我们利用弥散张量MRI （DTI）和高分辨率3D成像技术对同一只小鼠的光学清除（CLARITY）脑组织进行了微观结构和结构连通性的定量分析，并将其应用于thenrxn2 α敲除（KO）模型。方法采用9.4T MRI对nrxn2 α - ko小鼠固定脑进行DTI，定量观察社会相关脑区弥散特性。然后对同一组织进行免疫标记轴突和细胞体的CLARITY，并对其进行定量。结果dti显示杏仁核（包括基底外侧核）、前扣带皮层、眶额皮质和海马的各向异性分数降低，表观扩散系数增加。nrxn2 α - ko小鼠的前扣带皮层和眶额皮层径向扩散率显著增加，杏仁核和眶额皮层之间的束也显著增加。使用CLARITY，我们发现杏仁核、眶额皮层和前扣带皮层的轴突方向发生了显著改变，这与细胞密度无关。结论我们的研究结果表明，删除一个神经rexin基因（Nrxn2α）会导致大脑社会相关区域的非典型结构连接。更一般地说，我们结合了受试者内部DTI和CLARITY方法，提出了一种新的、更敏感的方法来揭示自闭症大脑中迄今为止无法检测到的差异。
BackgroundOf the many genetic mutations known to increase the risk of autism spectrum disorder, a large proportion cluster upon synaptic proteins. One such family of presynaptic proteins are the neurexins (NRXN), and recent genetic and mouse evidence has suggested a causative role forNRXN2in generating altered social behaviours. Autism has been conceptualised as a disorder of atypical connectivity, yet how single-gene mutations affect such connectivity remains under-explored. To attempt to address this, we have developed a quantitative analysis of microstructure and structural connectivity leveraging diffusion tensor MRI (DTI) with high-resolution 3D imaging in optically cleared (CLARITY) brain tissue in the same mouse, applied here to theNrxn2αknockout (KO) model.MethodsFixed brains ofNrxn2αKO mice underwent DTI using 9.4T MRI, and diffusion properties of socially-relevant brain regions were quantified. The same tissue was then subjected to CLARITY to immunolabel axons and cell bodies, which were also quantified.ResultsDTI revealed decreases in fractional anisotropy and increases in apparent diffusion coefficient in the amygdala (including the basolateral nuclei), the anterior cingulate cortex, the orbitofrontal cortex and the hippocampus. Radial diffusivity of the anterior cingulate cortex and orbitofrontal cortex was significantly increased inNrxn2αKO mice, as were tracts between the amygdala and the orbitofrontal cortex. Using CLARITY, we find significantly altered axonal orientation in the amygdala, orbitofrontal cortex and the anterior cingulate cortex, which was unrelated to cell density.ConclusionsOur findings demonstrate that deleting a single neurexin gene (Nrxn2α) induces atypical structural connectivity within socially-relevant brain regions. More generally, our combined within-subject DTI and CLARITY approach presents a new, more sensitive method of revealing hitherto undetectable differences in the autistic brain.
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影响因子：
120.7
作者：
Sandin, Sven;Lichtenstein, Paul;Kuja-Halkola, Ralf;Larsson, Henrik;Hultman, Christina M.;Reichenberg, Abraham
通讯作者：
Reichenberg, Abraham
扩散张量成像的区域特异性分析表明，自闭症谱系障碍中的广泛白质妥协。
DOI：
10.1111/j.1469-7610.2010.02342.x
发表时间：
2011-03
期刊：
Journal of child psychology and psychiatry, and allied disciplines
影响因子：
--
作者：
Shukla DK;Keehn B;Müller RA
通讯作者：
Müller RA
DOI：
10.1037/h0058870
发表时间：
1954-01-01
期刊：
JOURNAL OF COMPARATIVE AND PHYSIOLOGICAL PSYCHOLOGY
影响因子：
--
作者：
ROSVOLD, HE;MIRSKY, AF;PRIBRAM, KH
通讯作者：
PRIBRAM, KH
影响因子：
3.5
作者：
Boyle, Martine Isabel;Jespersgaard, Cathrine;Tumer, Zeynep
通讯作者：
Tumer, Zeynep
影响因子：
2.9
作者：
Noriuchi, Madoka;Kikuchi, Yoshiaki;Kamio, Yoko
通讯作者：
Kamio, Yoko