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

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 观察儿童或年轻动物的人会注意到，对世界的了解在很大程度上取决于他们的存在。 事实上，对人类和其他灵长类动物的研究表明，运动皮层（M1） 工作记忆、同理心和语言。运动功能障碍是否会导致 认知和情感缺陷发生在神经发育障碍（NDD）？相反，可以 改善运动功能改善NDD表型的其他方面？我的实验室最近的工作提供了 有证据表明情况可能是这样。 我们一直在研究Rett综合征（RTT），这是由X- 连锁基因甲基CpG结合蛋白2（MECP 2），是NDD的主要单基因原因，影响1/ 10 000个活产女婴。这种表型在出生后发病是惊人的：受影响的女孩似乎发展为 正常情况下，在生命的头一两年达到适当的里程碑， 获得技能和发展运动，认知和社会异常。男性和女性Mecp 2- 缺陷小鼠复制了这种自然史，延迟发作强烈表明，尽管MeCP 2是 它在早期发育中表达，在维持成熟神经元方面具有额外的、目前尚不清楚的功能 和突触连接。因此，我们开始提出两个问题：1）MeCP 2缺乏如何影响 运动回路水平的学习过程，2）运动学习是否会产生超越运动回路水平的有益影响。 学到的特殊技能？我们使用钙双光子成像同时记录兴奋性活动， 第2/3和5a层，而8周龄的野生型和无效雄性小鼠学习适应在一个 经过两周的电脑跑步训练。我们发现，在第2/3层的M1神经元的一个亚组， 和5a加强了它们的功能连接，而其余的种群则降低了功能连接。 连接性，可能保持学习新技能的灵活性。MeCP 2的损失会减弱，但不会 取消这种重组：尽管在无效小鼠中跨层连接要低得多， 在无效M1回路中神经元对之间的功能连接持续的时间是WT中的一半，无效M1回路中的神经元对之间的功能连接持续的时间是WT中的一半。 M1回路保留了足够的可塑性来支持运动技能学习。此外，经过训练的null小鼠表现出的 焦虑样行为，寿命比未经训练的小鼠长约20%（手稿正在重新审查）。这是所有的 更值得注意的是，整个大脑因MeCP 2的丢失而受到干扰。这项工作为 目前的建议，试图了解皮质输入和抑制神经元的贡献， 学习过程中L2/3可塑性，确定运动学习对女性Mecp 2杂合子M1的影响 小鼠，并阐明如何'正常'的M1电路实际上是在前驱RTT小鼠。