Aberrant Somatosensory Processing and Connectivity in Mice Lacking Engrailed-2
Aberrant Somatosensory Processing and Connectivity in Mice Lacking Engrailed-2
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DOI：
10.1523/jneurosci.0612-18.2018
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发表时间：
2019-02-20
影响因子：
5.3
通讯作者：
Bozzi, Yuri
中科院分区：
文献类型：
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作者：
Chelini, Gabriele;Zerbi, Valerio;Bozzi, Yuri
对触觉刺激的过度反应和防御行为是自闭症谱系障碍（ASD）患者的常见症状。类似地，在缺乏ASD相关基因如Fmr 1（脆性X智力低下蛋白1）的小鼠中也描述了体感超敏反应。fmr 1基因敲除小鼠也显示感觉皮层区域之间的功能连接减少，这可能代表了它们超敏反应的内源性生物标志物。在这里，我们测量了Engrailed-2基因敲除（En 2（-/-））成年小鼠的全脑功能连接性，这些小鼠显示出Fmr 1表达较低以及Fmr 1基因敲除常见的解剖缺陷。成年En 2（-/-）小鼠基于MRI的静息态功能连接显示，躯体感觉-听觉/联想皮层和背侧丘脑的同步性显著降低，表明这些突变体存在异常的躯体感觉处理。因此，当在胡须滋扰测试中进行测试时，两种性别的En 2（-/-）而不是WT小鼠显示出响应于重复胡须刺激的恐惧行为。与WT同窝仔相比，进行该试验的En 2（-/-）小鼠在初级躯体感觉皮层的第IV层中表现出c-Fos阳性神经元（神经元活动的标志物）减少，基底外侧杏仁核中的免疫反应性细胞增加。相反，当在感觉迷宫中测试时，En 2（-/-）和WT小鼠在胡须引导的探索中花费了相当的时间，这表明胡须介导的行为在En 2突变体中被保留。因此，En 2（-/-）小鼠对躯体感觉刺激的恐惧反应伴随着感觉区域的基底连接减少，躯体感觉皮层的激活减少，基底外侧杏仁核的激活增加，这表明躯体感觉处理受损是缺乏ASD相关基因的小鼠的共同特征。
Overreactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such as Fmr1 (fragile X mental retardation protein 1). Fmr1 knock-out mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity in Engrailed-2 knock-out (En2(-/-)) adult mice, which show a lower expression of Fmr1 and anatomical defects common to Fmr1 knock-outs. MRI-based resting-state functional connectivity in adult En2(-/-) mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, En2(-/-) but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation. En2(-/-) mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala compared with WT littermates. Conversely, when tested in a sensory maze, En2(-/-) and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in En2 mutants. Therefore, fearful responses to somatosensory stimuli in En2(-/-) mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes.