The role of astrocyte-neuron signaling in closing a critical period required for motor circuit structure, function, and behavior

星形胶质细胞-神经元信号传导在关闭运动回路结构、功能和行为所需的关键时期中的作用

• 批准号: 10188928
• 负责人: Sarah D Ackerman
• 金额: $ 18.06万
• 依托单位: UNIVERSITY OF OREGON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10188928
• 关键词: Ablation; Address; Adult; Affect; Animal Model; Architecture; Astrocytes; Award; Axon; Behavior; Binding; Biological Assay; Biological Models; Brain; CRISPR/Cas technology; Communities; Cytoskeleton; Data; Dendrites; Development; Drosophila genus; Electrophysiology (science); Ensure; Environment; Epilepsy; Failure; Fishes; Funding; Future; Genes; Genetic; Goals; Hour; Human; Image; Individual; Laboratories; Learning; Life; Link; Locomotion; Memory; Mentors; Mentorship; Microtubule Polymerization; Microtubules; Modeling; Molecular; Molecular Genetics; Morphology; Motor; Motor Neurons; Motor output; Muscle; Mutation; Neurodevelopmental Disorder; Neuronal Plasticity; Neurons; Neurosciences; Oregon; Output; Pathway interactions; Pharmacology; Phase; Physiological; Physiology; Principal Investigator; Research; Role; Seasons; Series; Shapes; Signal Transduction; Stereotyped Behavior; Structure; Synapses; Synaptic plasticity; System; Techniques; Testing; Time; Training; Universities; Vertebrates; Work; Zebrafish; autism spectrum disorder; behavior change; career development; cell type; critical period; defined contribution; experience; experimental study; fly; genetic approach; medical schools; motor behavior; myelination; nervous system disorder; neural circuit; novel; optogenetics; programs; reverse genetics; single-cell RNA sequencing; skills; synaptogenesis; time use; transcriptome sequencing

PROJECT SUMMARY Significance: Neural circuit assembly requires activity-dependent refinement of circuit architecture (e.g. plasticity) to produce stereotyped behavior. Neurons are particularly susceptible to functional and structural plasticity during early developmental windows called critical periods. It is clear that failure to terminate critical period plasticity adversely affects mature circuit function in both animal models and humans (e.g. autism and epilepsy), yet the mechanisms that close critical periods are largely unknown. This Pathway to Independence Award proposal seeks to understand the cellular and molecular mechanisms that promote critical period closure, and to define how critical periods shape circuit architecture to ensure proper locomotor behavior. Candidate and environment: Dr. Ackerman was trained in molecular genetics and developmental neuroscience in the laboratory of Dr. Kelly Monk at WashU School of Medicine, where she used forward and reverse genetic strategies to uncover regulators of myelination (NS087801). She then joined the laboratory of the renowned neurobiologist Dr. Chris Doe (UO, HHMI/NAS). Here, she defined a novel critical period of plasticity in the developing Drosophila motor circuit, and uncovered a series of astrocyte-derived molecular regulators of critical period closure (NS098690). In this proposal, Dr. Ackerman will extend her current skills in molecular genetics, live imaging, and circuit analysis to include training in electrophysiology and single cell RNAseq (scRNAseq), two completely new techniques for her. Further, she will use two model systems (fly and zebrafish) to determine how these novel, astrocyte-derived factors restrict motor circuit plasticity (Aim 1), to define how the critical period contributes to motor circuit connectivity, function, and behavior (Aim 2), and to determine how motor circuit plasticity is developmentally constrained in vertebrates (Aim 3). Career development: In addition to continued mentorship by Dr. Doe, the candidate has assembled an exceptional team of mentors and collaborators from the University of Oregon and beyond. During the mentored phase, the candidate will train in NMJ electrophysiology from Dr. Dion Dickman (USC) in order to define how the level of activity experienced by motor neurons during the critical period shapes motor output and behavior. This training is essential for future studies of motor circuit function in the candidate's own lab. Further, she has gathered a local team of advisors from the zebrafish community, Dr. Judith Eisen and Dr. Adam Miller, who have a combined 40 years of experience in zebrafish motor circuits. Drs. Eisen and Miller will facilitate training in scRNAseq, and will provide critical career development advice from the complementary perspectives of a seasoned (Dr. Eisen) and recently-established (Dr. Miller) principal investigator. Funding of this proposal will equip Dr. Ackerman with the unique skillset required to launch a robust and successful research program that pushes the boundaries of our understanding of circuit plasticity, from molecules to behavior.

项目摘要 重要性：神经电路组装需要依赖于活动的电路架构的细化（例如， 可塑性）产生刻板行为。神经元特别容易受到功能和结构的影响， 可塑性在早期发育窗口称为关键时期。很明显，未能终止关键 周期可塑性不利地影响动物模型和人类中的成熟回路功能（例如自闭症和 癫痫），但关闭关键时期的机制在很大程度上是未知的。通往独立的道路 该奖项旨在了解促进关键时期的细胞和分子机制 闭合，并定义关键时期如何塑造电路架构，以确保正确的运动行为。 候选人和环境：阿克曼博士接受过分子遗传学和发育方面的培训。 在华盛顿大学医学院的凯利·蒙克博士的实验室里， 反向遗传策略以揭示髓鞘形成的调节因子（NS 087801）。然后她加入了 著名的神经生物学家克里斯·多伊博士（UO，HHMI/NAS）。在这里，她定义了一个小说的关键时期， 在发育中的果蝇运动回路的可塑性，并揭示了一系列星形胶质细胞衍生的分子 关键期关闭监管机构（NS 098690）。在这项提案中，阿克曼博士将扩大她目前的技能， 分子遗传学，实时成像和电路分析，包括电生理学和单细胞 RNAseq（scRNAseq），两种全新的技术。此外，她将使用两个模型系统（苍蝇和 斑马鱼），以确定这些新的，星形胶质细胞衍生的因素如何限制运动回路可塑性（目的1）， 定义关键期如何促进运动回路连接、功能和行为（目标2），以及 确定运动回路可塑性在脊椎动物中是如何受到发育限制的（目标3）。 职业发展：除了继续接受多伊博士的指导外，候选人还组建了一个 来自俄勒冈州及其他大学的杰出导师和合作者团队。在指导期间， 阶段，候选人将接受Dion Dickman博士（USC）的NMJ电生理学培训，以确定如何 运动神经元在关键期经历的活动水平形成运动输出和行为。 这项培训对于将来在候选人自己的实验室中研究运动电路功能至关重要。此外，她 当地组建了一个由斑马鱼社区顾问组成的团队，朱迪思·艾森博士和亚当·米勒博士，他们 拥有40年的斑马鱼马达电路经验Drs. Rewen和米勒将协助培训 在scRNAseq，并将提供关键的职业发展建议，从互补的角度来看， 经验丰富的（Dr. Rewen）和最近成立的（Dr.米勒）首席研究员。该提案的资金将 为阿克曼博士提供启动强大而成功的研究计划所需的独特技能， 推动了我们对电路可塑性的理解，从分子到行为。