Schmitt Lauren M, Arzuaga Anna L, Dapore Ashley, Duncan Jason, Patel Maya, Larson John R, Erickson Craig A, Sweeney John A, Ragozzino Michael E
Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Front Behav Neurosci. 2023 Jan 5;16:1074682. doi: 10.3389/fnbeh.2022.1074682. eCollection 2022.
Fragile X Syndrome (FXS) is a monogenic condition that leads to intellectual disability along with behavioral and learning difficulties. Among behavioral and learning difficulties, cognitive flexibility impairments are among the most commonly reported in FXS, which significantly impacts daily living. Despite the extensive use of the knockout (KO) mouse to understand molecular, synaptic and behavioral alterations related to FXS, there has been limited development of translational paradigms to understand cognitive flexibility that can be employed in both animal models and individuals with FXS to facilitate treatment development.
To begin addressing this limitation, a parallel set of studies were carried out that investigated probabilistic reversal learning along with other behavioral and cognitive tests in individuals with FXS and KO mice. Fifty-five adolescents and adults with FXS (67% male) and 34 age- and sex-matched typically developing controls (62% male) completed an initial probabilistic learning training task and a probabilistic reversal learning task.
In males with FXS, both initial probabilistic learning and reversal learning deficits were found. However, in females with FXS, we only observed reversal learning deficits. Reversal learning deficits related to more severe psychiatric features in females with FXS, whereas increased sensitivity to negative feedback (lose:shift errors) unexpectedly appear to be adaptive in males with FXS. Male KO mice exhibited both an initial probabilistic learning and reversal learning deficit compared to that of wildtype (WT) mice. Female KO mice were selectively impaired on probabilistic reversal learning. In a prepotent response inhibition test, both male and female KO mice were impaired in learning to choose a non-preferred spatial location to receive a food reward compared to that of WT mice. Neither male nor female KO mice exhibited a change in anxiety compared to that of WT mice.
Together, our findings demonstrate strikingly similar sex-dependent learning disturbances across individuals with FXS and KO mice. This suggests the promise of using analogous paradigms of cognitive flexibility across species that may speed treatment development to improve lives of individuals with FXS.
脆性X综合征（FXS）是一种单基因疾病，会导致智力残疾以及行为和学习困难。在行为和学习困难中，认知灵活性受损是FXS中最常报告的问题之一，这对日常生活有重大影响。尽管基因敲除（KO）小鼠被广泛用于了解与FXS相关的分子、突触和行为改变，但用于理解认知灵活性的转化范式的发展有限，这些范式可用于动物模型和FXS患者以促进治疗开发。
为了开始解决这一局限性，我们进行了一系列平行研究，调查了FXS患者和KO小鼠的概率性逆向学习以及其他行为和认知测试。55名患有FXS的青少年和成年人（67%为男性）以及34名年龄和性别匹配的发育正常的对照者（62%为男性）完成了初始概率学习训练任务和概率性逆向学习任务。
在患有FXS的男性中，发现了初始概率学习和逆向学习缺陷。然而，在患有FXS的女性中，我们只观察到逆向学习缺陷。逆向学习缺陷与患有FXS的女性中更严重的精神症状有关，而对负面反馈（损失：转换错误）的敏感性增加在患有FXS的男性中似乎具有适应性。与野生型（WT）小鼠相比，雄性KO小鼠表现出初始概率学习和逆向学习缺陷。雌性KO小鼠在概率性逆向学习方面有选择性受损。在优势反应抑制测试中，与WT小鼠相比，雄性和雌性KO小鼠在学习选择非偏好的空间位置以获得食物奖励方面均受损。与WT小鼠相比，雄性和雌性KO小鼠的焦虑水平均未发生变化。
总之，我们的研究结果表明，患有FXS的个体和KO小鼠之间存在惊人相似的性别依赖性学习障碍。这表明跨物种使用类似的认知灵活性范式有望加快治疗开发，改善FXS患者的生活。
