Understanding the effects of motor learning in wild-type and Mecp2-deficient mice

了解野生型和 Mecp2 缺陷小鼠运动学习的影响

• 批准号: 10446459
• 负责人: Hui Lu
• 金额: $ 49.1万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446459
• 关键词: Affect; Affective; Animals; Anxiety; Attenuated; Behavior; Birth; Brain; Calcium; Child; Cognitive; Data; Development; Disease; Empathy; Female; Fiber; Foundations; Functional disorder; Genes; Human; Image; Individual; Knockout Mice; Language; Learning; Life; Light; Link; Manuscripts; Memory; Methyl-CpG-Binding Protein 2; Motor; Motor Cortex; Motor Skills; Mus; Mutant Strains Mice; Natural History; Nature; Neurodevelopmental Disorder; Neurons; Onset of illness; Phenotype; Population; Population Decreases; Primates; Process; Rest; Rett Syndrome; Running; Short-Term Memory; Social Interaction; Speed; Subgroup; Synapses; Time; Training; Wild Type Mouse; Work; anxiety-like behavior; cell type; cognitive skill; computerized; flexibility; girls; inhibitory neuron; insight; juvenile animal; loss of function mutation; male; motor control; motor disorder; motor function improvement; motor learning; motor skill learning; mutant; postnatal; response; skills; social; somatosensory; two-photon; Affect; Affective; Animals; Anxiety; Attenuated; Behavior; Birth; Brain; Calcium; Child; Cognitive; Data; Development; Disease; Empathy; Female; Fiber; Foundations; Functional disorder; Genes; Human; Image; Individual; Knockout Mice; Language; Learning; Life; Light; Link; Manuscripts; Memory; Methyl-CpG-Binding Protein 2; Motor; Motor Cortex; Motor Skills; Mus; Mutant Strains Mice; Natural History; Nature; Neurodevelopmental Disorder; Neurons; Onset of illness; Phenotype; Population; Population Decreases; Primates; Process; Rest; Rett Syndrome; Running; Short-Term Memory; Social Interaction; Speed; Subgroup; Synapses; Time; Training; Wild Type Mouse; Work; anxiety-like behavior; cell type; cognitive skill; computerized; flexibility; girls; inhibitory neuron; insight; juvenile animal; loss of function mutation; male; motor control; motor disorder; motor function improvement; motor learning; motor skill learning; mutant; postnatal; response; skills; social; somatosensory; two-photon

Project Summary Observers of children or young animals will notice how much learning about the world depends on being able to move within it. Indeed, studies in humans and other primates have shown that the motor cortex (M1) is involved in working memory, empathy, and language. Could motor dysfunction contribute to the various cognitive and affective deficits that occur in neurodevelopmental disorders (NDD)? Conversely, could improving motor function improve other aspects of NDD phenotypes? Recent work from my lab provides evidence that this may be the case. We have been studying Rett Syndrome (RTT), which is caused by loss-of-function mutations in the X- linked gene methyl CpG-binding protein 2 (MECP2) and is a leading monogenetic cause of NDD, affecting 1 in 10,000 live female births. The phenotype is striking for its postnatal onset: affected girls appear to develop normally and reach the appropriate milestones for the first year or two of life before they regress, losing most acquired skills and developing motor, cognitive, and social abnormalities. Both male and female Mecp2- deficient mice replicate this natural history, and the delayed onset strongly suggests that although MeCP2 is expressed from early development, it has additional, as-yet unclear functions in maintaining mature neurons and synaptic connections. We therefore set out to ask two questions: 1) how does MeCP2 deficiency affect the process of learning at the motor circuit level, and 2) would motor learning exert beneficial effects beyond the particular skill learned? We used calcium two-photon imaging to simultaneously record excitatory activity in layers 2/3 and 5a while 8-week old wild type and null male mice learned to adapt to changing speeds on a computerized running wheel over two weeks of training. We found that a subgroup of M1 neurons in layers 2/3 and 5a strengthen their functional connectivity while the rest of the population decreases functional connectivity, likely to maintain flexibility for learning new skills. Loss of MeCP2 attenuates but does not abolish this reorganization: although cross-layer connectivity was much lower in the null mice, and the functional connections between neuronal pairs in the null M1 circuit last half as long as those in WT, the null M1 circuit retains enough plasticity to support motor skill learning. Moreover, trained null mice showed less anxiety-like behavior and lived ~20% longer than untrained mice (manuscript under re-review). This is all the more remarkable given that the entire brain is disrupted by loss of MeCP2. This work laid the foundation for the current proposal, which seeks to understand the contributions of cortical inputs and inhibitory neurons to L2/3 plasticity during learning, determine the effects of motor learning on M1 in female Mecp2 heterozygous mice, and shed light on how 'normal' the M1 circuit actually is in presymptomatic RTT mice.

项目摘要 儿童或年轻动物的观察者会注意到，关于世界的学习量取决于多少 能够在其中移动。实际上，对人类和其他灵长类动物的研究表明，运动皮层（M1）是 参与工作记忆，同理心和语言。电动机功能障碍会导致各种 神经发育障碍（NDD）中出现的认知和情感缺陷？相反，可以 改善运动功能改善了NDD表型的其他方面？我实验室的最新工作提供 证据表明可能是这种情况。 我们一直在研究RETT综合征（RTT），这是由X-的功能丧失突变引起的 链接的基因甲基CpG结合蛋白2（MECP2），是NDD的主要单基因原因，影响1 10,000名活着的女性出生。该表型因其产后发作而引人注目：受影响的女孩似乎正在发展 通常，在回归前的第一年或两年的生活中达到适当的里程碑，失去了最多的里程碑 获得了技能，发展运动，认知和社会异常。男性和女性MECP2- 缺乏小鼠复制了这种自然史，延迟的发作强烈表明，尽管MECP2是 从早期开发中表达，它在维持成熟神经元方面具有额外的，尚未清楚的功能 和突触连接。因此，我们着手提出两个问题：1）MECP2缺乏症如何影响 在运动电路级别学习过程，2）运动学习会产生有益的效果 学到了特定的技能？我们使用钙的两光子成像同时记录 层2/3和5a，而8周的野生型和无效的雄性小鼠学会了适应一个变化的速度 计算机运行方向盘在两周的训练中。我们发现在2/3层中的M1神经元子组 5A增强其功能连接，而其余人口降低了功能 连通性，可能会保持学习新技能的灵活性。 MECP2的损失减弱，但没有 废除这种重组：虽然无效小鼠的跨层连通性要低得多，而 NULL M1电路中的神经元对之间的功能连接在wt中，null中的功能连接 M1电路保留足够的可塑性以支持运动技能学习。此外，训练有训练的零小鼠显示较少 类似焦虑的行为，比未经训练的小鼠长约20％（在重新审查下手稿）。这就是全部 鉴于MECP2的丧失会破坏整个大脑。这项工作为 当前的提案旨在了解皮质输入和抑制性神经元对 学习过程中的L2/3可塑性，确定运动学习对M1的影响女性MECP2杂合子 小鼠，并阐明了M1电路实际上是在预症状RTT小鼠中的“正常”。