Cell Type-specific Anterograde Circuit Mapping and Functional Control by Optimizing YFV-17D Transneuronal Systems

通过优化 YFV-17D 跨神经元系统进行细胞类型特异性顺行电路映射和功能控制

基本信息

批准号：
10505702
负责人：
Wei Xu
金额：
$ 156.63万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2025-07-31
项目状态：
未结题

项目摘要

Cell Type-specific Anterograde Circuit Mapping and Functional Control by Optimizing YFV-17D Transneuronal Systems Summary To elucidate the functional organization of brain circuitry we need to delineate neuronal connectivity and control the activity of neurons with specific connectivity. Both tasks have increasingly relied on transneuronal viral vectors. Anterograde transneuronal viral vectors, which spread from presynaptic neurons to the postsynaptic neurons, can reveal the neuronal projections and selectively target postsynaptic neurons. Due to the lack of ideal anterograde transneuronal viral vectors, we have spent the last few years developing a new anterograde system based on yellow fever vaccine—YFV-17D. We have successfully constructed two major anterograde tools: the packaging defective YFV∆CME for mapping neuronal projectomes, and the replication defective YFV∆NS1 (or YFV∆CMENS1) for transneuronal control of gene expression in postsynaptic neurons, which can be used for functional observation or manipulation. Neuronal toxicity can be avoided in the case of YFV∆NS1 and YFV∆CMENS1, but not in YFV∆CME. These new systems provide benefits of transneuronal efficacy, diverse applications, and ease of engineering, but they still have limitations for many experimental scenarios. Here we propose to further improve these viral systems to make them broadly applicable, powerful and safe tools for functional dissection of the brain circuits. Firstly, we will construct self- constrained YFV-17D to further minimize neuronal toxicity incurred by viral replication in neurons, which will make these vectors more useful for both research and potential clinical applications. Secondly, we will test multiple strategies to target this system to specific neurons for cell-type specific tracing or functional control in both local circuits and long-range projections. Some of the cell type specific tools will not rely on the availability of genetically modified mouse lines and can be applied to broad species. Thirdly, we will incorporate commonly used tags, sensors or effectors in the optimized transneuronal viral vectors for versatile applications. We will also apply the improved versions to delineate a selected neuronal circuit that is of great interest to neuroscientists. Therefore, this project will yield a set of highly powerful tools widely applicable to neuroscience research, and will reveal the projectomes of multiple classical neuronal types.

细胞类型特定的顺行电路映射和功能控制优化 YFV-17D 跨神经元系统概括为了阐明大脑回路的功能组织，我们需要描绘神经元连接性和控制具有特定连接性的神经元的活动这两项任务都具有。越来越依赖于顺行跨神经病毒载体。从突触前神经元传播到突触后神经元，可以揭示神经元投射由于缺乏理想的顺行跨神经元，选择性地靶向突触后神经元。病毒载体，我们在过去几年里开发了一种基于病毒载体的新顺行系统黄热病疫苗——YFV-17D，我们已经成功构建了两大顺行工具：用于映射神经投影组的包装缺陷 YFVΔCME 和复制缺陷 YFVΔNS1（或 YFVΔCMENS1）用于突触后神经元基因表达的跨神经元控制，可用于功能观察或操作，避免神经元毒性。对于 YFVΔNS1 和 YFVΔCMENS1，但在 YFVΔCME 中则不然。这些新系统提供了优势。跨神经元功效、多样化的应用和易于工程设计，但它们仍然具有许多实验场景的局限性。在这里我们建议进一步改进这些病毒系统，使其广泛适用，首先，我们将构建自我的大脑回路功能解剖工具。限制YFV-17D进一步最小化由病毒在神经元中复制引起的神经元毒性，这将使这些载体对于研究和潜在的临床应用更加有用。其次，我们将测试多种策略，将该系统针对细胞类型的特定神经元局部电路和远程投影中的特定跟踪或功能控制。细胞类型特异性工具不会依赖于转基因小鼠系的可用性，并且可以第三，我们将整合常用的标签、传感器或效应器。我们还将应用在优化的跨神经元病毒载体中以实现多种应用。改进版本来描绘人们非常感兴趣的选定神经回路因此，该项目将产生一套广泛适用于神经科学家的强大工具。神经科学研究，并将揭示多种经典神经类型的投射组。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Brain-wide circuit-specific targeting of astrocytes.

星形胶质细胞的全脑回路特异性靶向。

DOI：
发表时间：
2023-12-18
期刊：
影响因子：
0
作者：
Thompson, Alyssa;Arano, Rachel;Saleem, Uzair;Preciado, Rebecca;Munoz, Lizbeth;Nelson, Ian;Ramos, Katarina;Kim, Yerim;Li, Ying;Xu, Wei
通讯作者：
Xu, Wei