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Collaborative Research: Molecular Mechanisms of Astrocyte Neuron Interactions in the Development of Synchronous Activity in Neuronal Networks

合作研究：星形胶质细胞神经元相互作用在神经网络同步活动发展中的分子机制

基本信息

批准号：
1755033
负责人：
Rhonda Dzakpasu
金额：
$ 10.72万
依托单位：
Georgetown University
依托单位国家：
美国
项目类别：
Continuing Grant
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1755033&HistoricalAwards=false
关键词：
Collaborative Research Molecular Mechanisms Astrocyte

项目摘要

Brain cells are of two types. Neurons are the most well-known; they communicate with each other by generating spikes of electrical activity. The second cell type, glial cells, play a variety of roles that are less well understood. In the awake adult brain, the overall spiking activity of neurons appears random. However, in deep sleep or under anesthesia, the spiking activity pattern becomes synchronized within and between various brain regions. During brain development, this type of synchronous spiking is thought to be necessary for the circuit maturation, and the establishment and maintenance of the functional organization of the brain. The focus of this research is to understand the role of one type of glial cell (astrocytes) in the emergence of synchronous spiking activity patterns in the developing brain. The main hypothesis is that astrocytes play a decisive role in the synchronization of neuronal activity in the brain. Preliminary data has demonstrated that astrocytes are necessary for synchronization of spiking activity; the proposed research will elucidate the molecular pathways within astrocytes that control the synchronization of spiking in surrounding neurons. The results of this research will identify fundamental mechanisms of astrocyte-neuron interactions that shape synchronous activity during brain development. This project is conducted at a Historically Black University, and will immerse minority students in cutting edge neuroscience research, and foster peer-mentoring based on interactions between undergraduate and graduate researchers.Preliminary data using mixed neuron and astrocyte cultures on multi-electrode arrays (MEAs) showed random spiking activity which synchronized over time, in comparison to astrocyte-free neuronal cultures, which only show random activity without synchronization. The main hypothesis of this research is that astrocytic release of glutamate mediated by the mGluR1 G-protein-coupled-receptor (GPCR) pathway mediates the effects of astrocytes on the development of neuronal synchronous activity. A model for the mechanism by which the astrocyte mGluR1 pathway mediates neuronal synchronization will be tested using several different dominant negative constructs. A dominant-negative mGluR1 receptor that blocks downstream signaling will be used to understand this signaling pathway's role in both population synchrony, and in the temporal relationship between calcium oscillations within astrocytes and the development of neuronal synchronous bursts. A dominant-negative SNARE protein Vamp2/Syb2 will be used to block glutamate release from astrocytes. The role of the mGluR1 pathway and mGluR1 mediated glutamate release in the development of synchrony will also be examined in vivo. The strength of this project is the combination of multi-electrode electrophysiology, molecular dissection of the mGluR1 pathway in astrocytes, and computational analyses.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.

脑细胞有两种类型。神经元是最著名的;它们通过产生电活动的尖峰来相互交流。第二种细胞类型，神经胶质细胞，发挥着各种各样的作用，这些作用还不太清楚。在清醒的成年人大脑中，神经元的整体尖峰活动似乎是随机的。然而，在深度睡眠或麻醉下，尖峰活动模式在不同的大脑区域内和之间变得同步。在大脑发育期间，这种类型的同步尖峰被认为是回路成熟以及大脑功能组织的建立和维持所必需的。这项研究的重点是了解一种类型的神经胶质细胞（星形胶质细胞）在发育中的大脑中出现同步尖峰活动模式中的作用。主要假设是星形胶质细胞在大脑神经元活动的同步中起决定性作用。初步数据表明，星形胶质细胞是必要的同步尖峰活动;拟议的研究将阐明星形胶质细胞内的分子通路，控制周围神经元的尖峰同步。这项研究的结果将确定星形胶质细胞-神经元相互作用的基本机制，这些机制塑造了大脑发育期间的同步活动。该项目在一所历史悠久的黑人大学进行，将使少数民族学生沉浸在前沿神经科学研究中，并在本科生和研究生研究人员之间的互动基础上促进同行指导。在多电极阵列（MEA）上使用混合神经元和星形胶质细胞培养物的初步数据显示，与无星形胶质细胞的神经元培养物相比，随机尖峰活动随时间同步，其仅显示随机活动而没有同步。本研究的主要假设是mGluR 1 G蛋白偶联受体（GPCR）途径介导的星形胶质细胞释放谷氨酸介导星形胶质细胞对神经元同步活动发展的影响。星形胶质细胞mGluR 1途径介导神经元同步化的机制模型将使用几种不同的显性负性结构进行测试。阻断下游信号传导的显性负性mGluR 1受体将用于了解该信号传导途径在群体同步性以及星形胶质细胞内钙振荡与神经元同步爆发发展之间的时间关系中的作用。显性负性SNARE蛋白Vamp 2/Syb 2将用于阻断星形胶质细胞的谷氨酸释放。还将在体内检查mGluR 1通路和mGluR 1介导的谷氨酸释放在同步性发展中的作用。该项目的优势在于结合了多电极电生理学、星形胶质细胞中mGluR 1通路的分子解剖和计算分析。该奖项反映了NSF的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。