Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss.
Behavioral flexibility in a mouse model of developmental cerebellar Purkinje cell loss.
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DOI：
10.1016/j.nlm.2010.05.010
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发表时间：
2010-09
影响因子：
2.7
通讯作者：
Mittleman, Guy
中科院分区：
文献类型：
--
作者：
Dickson, Price E.;Rogers, Tiffany D.;Del Mar, Nobel;Martin, Loren A.;Heck, Detlef;Blaha, Charles D.;Goldowitz, Daniel;Mittleman, Guy
虽然行为不稳定性和浦肯野细胞丢失在自闭症中都得到了很好的证实，但尚不清楚这些现象是否存在因果关系。使用小鼠模型，我们测试了小脑发育异常（包括浦肯野细胞丢失）导致行为异常的假设。具体地，我们在lurcher（Lc/+）突变胚胎和野生型（+/+）对照胚胎之间制备聚集嵌合体（Lc/+ Participate +/+）。Lurcher小鼠出生后失去100%的浦肯野细胞，而嵌合小鼠失去不同数量的浦肯野细胞。我们测试了这些小鼠的收购和一系列逆转的操作性条件性视觉歧视，测试啮齿动物的行为灵活性。在逆转1和2期间，所有组的小鼠犯下了类似数量的“持续性”错误（在会话表现≤ 40%正确时犯下的错误）。然而，与对照组和嵌合体相比，Lurchers犯下的“学习”错误（在会话表现正确率在41%至85%之间时犯下的错误）数量明显更多，并且大多数无法通过逆转3。在逆转3和4，嵌合体，作为一个群体，犯了更多的“持续性”，但不是“学习”的错误比对照组，虽然比较浦肯野细胞的数量和性能在个别小鼠显示，与浦肯野细胞较少的嵌合体作出更多的“学习”错误，并有较短的响应延迟比嵌合体与更多的浦肯野细胞。这些数据表明，发展小脑浦肯野细胞的损失可能会影响更高层次的认知过程，以前已被证明是由前额叶皮层介导的，通常是缺乏自闭症谱系障碍。
Although behavioral inflexibility and Purkinje cell loss are both well established in autism, it is unknown if these phenomena are causally related. Using a mouse model, we tested the hypothesis that developmental abnormalities of the cerebellum, including Purkinje cell loss, result in behavioral inflexibility. Specifically, we made aggregation chimeras (Lc/+↔+/+) between lurcher (Lc/+) mutant embryos and wildtype (+/+) control embryos. Lurcher mice lose 100% of their Purkinje cells postnatally, while chimeric mice lose varying numbers of Purkinje cells. We tested these mice on the acquisition and serial reversals of an operant conditional visual discrimination, a test of behavioral flexibility in rodents. During reversals 1 and 2, all groups of mice committed similar numbers of “perseverative” errors (those committed while session performance was ≤ 40% correct). Lurchers, however, committed a significantly greater number of “learning” errors (those committed while session performance was between 41% and 85% correct) than both controls and chimeras, and most were unable to advance past reversal 3. During reversals 3 and 4, chimeras, as a group, committed more “perseverative”, but not “learning” errors than controls, although a comparison of Purkinje cell number and performance in individual mice revealed that chimeras with fewer Purkinje cells made more “learning” errors and had shorter response latencies than chimeras with more Purkinje cells. These data suggest that developmental cerebellar Purkinje cell loss may affect higher level cognitive processes which have previously been shown to be mediated by the prefrontal cortex, and are commonly deficient in autism spectrum disorders.
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通讯作者：
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