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

项目总结 意义：神经电路组装需要依赖活动的电路架构精细化(例如 可塑性)产生刻板印象的行为。神经元特别容易受到功能和结构上的影响 早期发育窗口期的可塑性称为关键期。显然，未能终止是至关重要的 在动物模型和人类中，时期可塑性都会对成熟的回路功能产生不利影响(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。这条通往独立的道路 获奖提案寻求了解促进关键期的细胞和分子机制 闭合，并定义关键周期如何塑造电路体系结构，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 华盛顿大学医学院凯利·蒙克博士的实验室里的神经科学，在那里她使用了Forward和 反向遗传策略以发现髓鞘形成的调节因素(NS087801)。然后，她加入了 著名神经生物学家Chris Doe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中的可塑性，并发现了一系列星形胶质细胞衍生的分子 关键期关闭监管机构(NS098690)。在这项提案中，阿克曼博士将把她目前的技能扩展到 分子遗传学、实时成像和电路分析，包括电生理学和单细胞培训 RNAseq(ScRNAseq)，对她来说是两种全新的技术。此外，她将使用两个模型系统(Fly和 斑马鱼)，以确定这些新的、星形胶质细胞衍生的因子如何限制运动神经回路的可塑性(目标1)，以 定义关键期对电机电路连接性、功能和行为的影响(目标2)，以及 确定脊椎动物运动回路的可塑性如何在发育过程中受到限制(目标3)。 职业发展：除了无名氏博士的持续指导外，应聘者还组建了一个 来自俄勒冈大学和其他地方的杰出导师和合作者组成的团队。在接受指导的过程中 在阶段，候选人将从Dion Dickman博士(南加州大学)那里接受NMJ电生理学培训，以确定如何 运动神经元在关键期所经历的活动水平决定了运动输出和行为。 这种培训对于将来在考生自己的实验室中研究马达电路功能是必不可少的。此外，她还 聚集了来自斑马鱼社区的当地顾问团队，朱迪思·艾森博士和亚当·米勒博士，他 在斑马鱼电机电路领域拥有40年的经验。艾森博士和米勒博士将协助培训 ，并将从一个互补的角度提供关键的职业发展建议 经验丰富的(艾森博士)和最近成立(米勒博士)的首席研究员。这项提案的资金将 让阿克曼博士具备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。

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.