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: 10597705
• 负责人: Hui Lu
• 金额: $ 47.86万
• 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/10597705
• 关键词: Affect; Affective; Animals; Anxiety; Attenuated; Behavior; Birth; Brain; Calcium; Child; Cognitive; Data; Development; Disease; Empathy; Female; Fiber; Foundations; Functional disorder; Genes; Heterozygote; Human; Image; Individual; Knockout Mice; Language; Learning; Learning Skill; Life; 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; improved; 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; skill acquisition; 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.

项目总结