Department of Psychology, Azusa Pacific University, Azusa, CA 91702, USA.
Eur J Neurosci. 2010 Feb;31(3):544-55. doi: 10.1111/j.1460-9568.2009.07073.x. Epub 2010 Jan 25.
Repetitive behaviors and hyperactivity are common features of developmental disorders, including autism. Neuropathology of the cerebellum is also a frequent occurrence in autism and other developmental disorders. Recent studies have indicated that cerebellar pathology may play a causal role in the generation of repetitive and hyperactive behaviors. In this study, we examined the relationship between cerebellar pathology and these behaviors in a mouse model of Purkinje cell loss. Specifically, we made aggregation chimeras between Lc/+ mutant embryos and +/+ embryos. Lc/+ mice lose 100% of their Purkinje cells postnatally due to a cell-intrinsic gain-of-function mutation. Through our histological examination, we demonstrated that Lc/+<-->+/+ chimeric mice have Purkinje cells ranging from zero to normal numbers. Our analysis of these chimeric cerebella confirmed previous studies on Purkinje cell lineage. The results of both open-field activity and hole-board exploration testing indicated negative relationships between Purkinje cell number and measures of activity and investigatory nose-poking. Additionally, in a progressive-ratio operant paradigm, we found that Lc/+ mice lever-pressed significantly less than +/+ controls, which led to significantly lower breakpoints in this group. In contrast, chimeric mice lever-pressed significantly more than controls and this repetitive lever-pressing behavior was significantly and negatively correlated with total Purkinje cell numbers. Although the performance of Lc/+ mice is probably related to their motor deficits, the significant relationships between Purkinje cell number and repetitive lever-pressing behavior as well as open-field activity measures provide support for a role of cerebellar pathology in generating repetitive behavior and increased activity in chimeric mice.
重复行为和多动是发育障碍的常见特征，包括自闭症。小脑的神经病理学也是自闭症和其他发育障碍的常见现象。最近的研究表明，小脑病理学可能在重复和多动行为的产生中起因果作用。在这项研究中，我们在浦肯野细胞缺失的小鼠模型中研究了小脑病理学与这些行为之间的关系。具体来说，我们在 Lc/+ 突变胚胎和 +/+ 胚胎之间制作了聚集嵌合体。Lc/+ 小鼠由于内在获得性功能突变，在出生后会失去 100%的浦肯野细胞。通过我们的组织学检查，我们证明了 Lc/+<-->+/+ 嵌合体小鼠的浦肯野细胞数量从零到正常不等。我们对这些嵌合体小脑的分析证实了先前关于浦肯野细胞谱系的研究。开放式活动和孔板探索测试的结果表明，浦肯野细胞数量与活动和探究性鼻刺测度之间呈负相关。此外，在渐进式比率操作范式中，我们发现 Lc/+ 小鼠的 lever-pressing 显著少于 +/+ 对照组，这导致该组的 breakpoints 显著降低。相比之下，嵌合体小鼠 lever-pressing 明显多于对照组，这种重复 lever-pressing 行为与总浦肯野细胞数量呈显著负相关。尽管 Lc/+ 小鼠的表现可能与它们的运动缺陷有关，但浦肯野细胞数量与重复 lever-pressing 行为以及开放式活动测度之间的显著关系为小脑病理学在产生重复行为和增加嵌合体小鼠活动中的作用提供了支持。
