CAREER: Structural and Functional Plasticity Induced By Loss of a Co-Innervating Neuron

职业：共同神经神经元丧失引起的结构和功能可塑性

• 批准号: 2048080
• 负责人: Robert Carrillo
• 金额: $ 120.59万
• 依托单位: University of Chicago
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2048080&HistoricalAwards=false
• 关键词: CAREER; Structural; Functional; Plasticity; Induced

Our nervous system is composed of billions of intricately connected neurons that can actively modify their activity patterns and their influence on the circuit partners they communicate with. Each neuron can receive and process information from thousands of other neurons through discrete connections, called synapses. It is currently not known whether changes made at one synapse between two neurons can influence the development and/or activity of neighboring synapses that the target cell makes with other synaptic partners. For example, it might be the case that a decrease in communication at one synapse triggers increases in communication at other synapses in a brain circuit. The goal of this study is to document the existence of such compensatory programs, and to elucidate their underlying mechanisms. This project is conducted using individual cells in the neuromuscular circuitry of the fruitfly Drosophila melanogaster because of the advantages this preparation presents for studying and manipulating synaptic function, and because of striking functional similarity these cells share with mammalian excitatory brain synapses. The project includes a joint University of Chicago - University of Puerto Rico summer program for undergraduate students, which will integrate underrepresented citizens into cutting edge research labs to facilitate their development as independent researchers. It will additionally strengthen ties with predominantly Hispanic and Black schools on the south side of Chicago through outreach programs that allow high school students and teachers to conduct project-relevant lab experiments and disseminate the work in their respective classrooms. A joint quarter-long laboratory course for undergraduate juniors and seniors at the Woods Hole Biological Laboratories will enable students to gain high levels of competence in advanced neuroscience experimental techniques. This project will advance our understanding of neural circuit function and adaptation, as well as enhance education and participation of underrepresented groups in STEM.Neural circuits have highly complex connectivity patterns in which many inputs congregate on single targets. The number and strength of the synapses provided by each input can vary greatly, but how these synapses respond to perturbations – a process known as synaptic plasticity – is not completely understood. Unlike the densely packed synapses of the brain, motor neuron-muscle connections are easily visualized and differentiated from each other, facilitating examination of all synapses from each input. The central hypothesis of this project is that co-innervation in early circuit development creates an environment in which subsequent functional defects trigger synaptic plasticity in the remaining connections. Rigorous analyses of several co-innervating motor neuron pairs will characterize the contribution of each input to the total muscle activity and examine how perturbations in one input induce structural and functional plasticity phenotypes in the adjacent input(s), a process we refer to as inter-input synaptic plasticity (IISP). Genetic manipulations combined with calcium imaging and electrophysiological recordings will examine IISP in the neuromuscular circuit and help delineate molecular pathways that enable IISP. The results of this project will fundamentally advance understanding of how synaptic inputs develop and interact in a complex nervous system. The educational module expands student research experiences, while the outreach plan combines mentoring and research to train underrepresented high school, undergraduate, and graduate students and expand access to neuroscience.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

我们的神经系统由数十亿个错综复杂的神经元组成，这些神经元可以主动改变它们的活动模式，以及它们对与之通信的电路伙伴的影响。每个神经元可以通过称为突触的离散连接接收和处理来自数千个其他神经元的信息。目前尚不清楚在两个神经元之间的一个突触上所做的改变是否会影响目标细胞与其他突触伙伴进行的相邻突触的发育和/或活动。例如，可能的情况是，一个突触的通讯减少会触发大脑回路中其他突触的通讯增加。这项研究的目的是证明这种补偿计划的存在，并阐明其潜在的机制。这个项目使用果蝇神经肌肉回路中的单个细胞进行，因为这种准备为研究和操纵突触功能提供了优势，并且由于这些细胞与哺乳动物兴奋性脑突触具有惊人的功能相似性。该项目包括芝加哥大学和波多黎各大学针对本科生的联合暑期项目，该项目将把代表性不足的公民纳入尖端研究实验室，以促进他们作为独立研究人员的发展。它还将通过外展计划加强与芝加哥南侧以西班牙裔和黑人为主的学校的联系，这些计划允许高中生和教师进行与项目相关的实验室实验，并在各自的教室中传播工作。伍兹霍尔生物实验室为本科生、大三和大四学生开设的为期四分之一的联合实验室课程将使学生在高级神经科学实验技术方面获得高水平的能力。这个项目将增进我们对神经回路功能和适应的理解，并加强STEM中代表不足的群体的教育和参与。神经回路具有高度复杂的连接模式，其中许多输入聚集在单个目标上。每种输入提供的突触的数量和强度可能有很大的不同，但这些突触如何对扰动做出反应--这一过程被称为突触可塑性--还没有完全了解。与大脑密集排列的突触不同，运动神经元-肌肉连接很容易被可视化和相互区分，便于检查每一次输入的所有突触。该项目的中心假设是，早期电路发育中的共同神经支配创造了一种环境，在这种环境中，随后的功能缺陷触发了剩余连接中的突触可塑性。对几个共同支配运动神经元的严格分析将表征每个输入对总肌肉活动的贡献，并研究一个输入的扰动如何诱导相邻输入的结构和功能可塑性表型(S)，我们称之为输入间突触可塑性(Iisp)。结合钙成像和电生理记录的基因操作将检查神经肌肉回路中的IISP，并帮助描绘使IISP成为可能的分子途径。该项目的结果将从根本上促进对突触输入如何在复杂神经系统中发展和相互作用的理解。教育模块扩展了学生的研究经验，而外展计划结合了指导和研究，以培训未被充分代表的高中生、本科生和研究生，并扩大获得神经科学的机会。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

项目成果

Structural and Functional Synaptic Plasticity Induced by Convergent Synapse Loss in the Drosophila Neuromuscular Circuit

• DOI: 10.1523/jneurosci.1492-20.2020
• 发表时间: 2021-02-17
• 期刊: JOURNAL OF NEUROSCIENCE
• 影响因子: 5.3
• 作者: Wang，Yupu;Lobb-Rabe，Meike;Carrillo，Robert A.
• 通讯作者: Carrillo，Robert A.

Systematic expression profiling of Dpr and DIP genes reveals cell surface codes in Drosophila larval motor and sensory neurons.

Dpr 和 DIP 基因的系统表达谱揭示了果蝇幼虫运动和感觉神经元的细胞表面密码。

• DOI: 10.1242/dev.200355
• 发表时间: 2022
• 期刊: Development (Cambridge, England)
• 作者: Wang,Yupu;Lobb-Rabe,Meike;Ashley,James;Chatterjee,Purujit;Anand,Veera;Bellen,HugoJ;Kanca,Oguz;Carrillo,RobertA
• 通讯作者: Carrillo,RobertA