Department of Neuroscience, The Ohio State University Wexner Medical Center, Columbus, OH, 43210, USA.
Cerebellum. 2012 Dec;11(4):982-1001. doi: 10.1007/s12311-012-0368-4.
We previously reported motor and non-motor enhancements in a mouse mutant with an inactivated Purkinje cell-specific gene, Pcp2(L7), that encodes a GoLoco domain-containing modulator of Gi/o protein-coupled receptors. Effects included elevated learning asymptote with repeated rotarod training, increased acquisition rate in tone-cued fear conditioning (FC), and subtle male-specific changes in both acoustic startle habituation and pre-pulse inhibition. We have further analyzed this mutant strain this time with a focus on male-female differences, and here we report a sex-dependent anxiety-like phenotype: male mutants are less anxious, and female mutants are more anxious, than same-sex wild types. Similarly, the fear responses measured during the tone in FC acquisition are decreased in male mutants and increased in female mutants relative to same-sex wild types. Overall, the dynamics of both acquisition and extinction of FC is affected in mutants but memory was not affected. In the social realm, compositional analysis of sociability and preference for social novelty data supports that both L7 genotype and sex contribute to these behaviors. These results provide direct evidence of emotional functions of the cerebellum due to the unambiguous cerebellar specificity of Pcp2(L7) expression and the lack of any confounding motor defects in the mutant. We attempt to synthesize these new data with what is previously known both about Pcp2(L7) and about the effects of sex and sex hormones on anxiety and fear behaviors: specifically, L7 is a bidirectional and sex-dependent damper that regulates the amplitude and/or rate of sensorimotor responses, potentially acting as a mood stabilizer.
我们之前报道过一种在浦肯野细胞特异性基因 Pcp2(L7)失活的小鼠突变体中出现的运动和非运动增强现象，该基因编码 Gi/o 蛋白偶联受体的 GoLoco 结构域调节剂。这些影响包括通过重复旋转杆训练提高学习渐近线、在音调提示恐惧条件反射（FC）中提高获得率，以及在声起始习惯化和前脉冲抑制方面出现微妙的雄性特异性变化。这次我们进一步分析了这个突变体菌株，重点关注雌雄间的差异，在此我们报告了一个性别依赖的焦虑样表型：雄性突变体比同性别野生型更不焦虑，而雌性突变体则更焦虑。类似地，在 FC 获得过程中测量的恐惧反应在雄性突变体中减少，而在雌性突变体中增加，与同性别野生型相比。总体而言，FC 的获得和消退的动力学在突变体中受到影响，但记忆不受影响。在社交领域，社交性和对社会新颖性数据的偏好的组成分析支持 L7 基因型和性别都对这些行为有贡献。这些结果提供了小脑情绪功能的直接证据，因为 Pcp2(L7)的表达具有明确的小脑特异性，并且突变体中没有任何混杂的运动缺陷。我们尝试将这些新数据与以前已知的 Pcp2(L7)以及性别和性激素对焦虑和恐惧行为的影响综合起来：具体来说，L7 是一种双向的、依赖于性别的阻尼器，调节感觉运动反应的幅度和/或速率，可能作为一种情绪稳定剂。
