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 儿童或幼小动物的观察者会注意到，关于世界的学习在很大程度上依赖于 能够在里面移动。事实上，对人类和其他灵长类动物的研究表明，运动皮质(M1)是 涉及工作记忆、同理心和语言。运动功能障碍是否会导致各种 发生在神经发育障碍(NDD)中的认知和情感缺陷？相反，是否可以 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 这可能是事实的证据。 我们一直在研究雷特综合征(RTT)，它是由X-基因功能缺失突变引起的。 连锁基因甲基CpG结合蛋白2(MECP2)，是新城疫的主要单基因原因，影响1 活产女婴1万人。这种表型在出生后表现得很突出：受影响的女孩似乎会发展成 正常情况下，在生命的头一两年达到适当的里程碑，然后才会退化，损失最大 获得技能，并发展运动、认知和社交异常。男性和女性MeCP2- 缺陷小鼠复制了这一自然历史，延迟发病强烈表明，尽管MeCP2是 它是从早期发育而来的，在维持成熟神经元方面具有额外的、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)MeCP2缺乏如何影响 在运动电路水平上的学习过程，以及2)运动学习是否会产生超越 学到了什么特别的技能？我们使用钙双光子成像技术同时记录了 层2/3和5a，而8周龄的野生型和空白雄性小鼠学习适应在 计算机化的跑轮超过两周的训练。我们发现第2/3层的M1神经元的一个亚群 和5a增强了它们的功能连接，而其余的种群功能减少了 连接性，可能会保持学习新技能的灵活性。MeCP2的丢失会减弱，但不会 废除这种重组：尽管空鼠的跨层连接性要低得多，而且 Null M1回路中神经元对之间的功能连接持续的时间是WT的一半，即Null M1回路保留了足够的可塑性来支持运动技能的学习。此外，训练有素的空白小鼠表现出更少的 焦虑类行为，比未经训练的小鼠多活约20%(手稿正在重新审查中)。这就是所有 更值得注意的是，由于MeCP2的缺失，整个大脑都受到了干扰。这项工作奠定了 目前的建议，试图了解皮质输入和抑制性神经元对 学习中的L2/3可塑性，确定运动学习对女性MeCP2杂合子M1的影响 并阐明了症状前RTT小鼠的M1回路实际上是多么的“正常”。