Precision editing of neural circuits using engineered electrical synapses

使用工程电突触精确编辑神经回路

• 批准号: 10700919
• 负责人: Kafui Dzirasa
• 金额: $ 112.7万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-08 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10700919
• 关键词: Address; Animal Model; Anxiety; Behavior; Brain; Cells; Connexins; Docking; Electrical Engineering; Electrical Synapse; Emotional; Emotions; Engineering; Exhibits; Future; Individual; Mental Depression; Mental disorders; Methods; Physiology; Pre-Clinical Model; Property; Proteins; Research; Synapses; Testing; Viral; addiction; brain cell; cell type; designer receptors exclusively activated by designer drugs; emotional behavior; experimental study; high risk; member; model organism; neural circuit; neuroregulation; novel; novel strategies; novel therapeutic intervention; optogenetics; prevent; tool; translation to humans

Title: Precision editing of neural circuits using engineered electrical synapses Pioneering approaches including optogenetics and designer receptors exclusively activated by designer drugs (DREADDs) enable the direct modulation of the activity of individual genetically defined cell types. Nevertheless, it remains a fundamental challenge to selectively regulate the hallmark feature of neural circuits: the interface between two specific brain cells. To address this challenge, we have created a new approach, Long-term integration of circuits using Connexins (LinCx), that employs a novel pair of engineered connexin hemichannels to directly modulate genetically defined neural circuits. When each member of the hemichannel pair is expressed in two different cell(s)/cell-types that compose a circuit, they engage in heterotypic docking (docking with each other) and an electrical synapse is constituted between the two cells. These pair of hemichannels is engineered 1) to prevent them from engaging in homotypic docking (forming electrical synapses with themselves), and 2) to disrupt them from docking with other connexin hemichannels endogenously expressed in the mammalian brain. Finally, 3) the hemichannel pair exhibits rectification. Together, these three properties confer LinCx with unprecedented spatial-, temporal-, and context precision, enabling the precise editing of neural circuits. We propose to deploy LinCx across model organisms. We will determine the impact of LinCx neuromodulation on neural circuit physiology and emotional behavior. We will also test whether LinCx modulation is sufficient to restore normal behavior in animal models of psychiatric disorders. Successful completion of these high-risk experiments will yield a new method for long-term circuit editing to regulate emotional states in preclinical models. In the future, LinCx can be integrated with emerging viral tools that enable systemic delivery of genetically encoded proteins to specific brain cell-types. Thus, LinCx also has an attainable path to human translation for ameliorating devastating psychiatric disorders.

标题：使用工程电突触精确编辑神经电路 开创性的方法，包括光遗传学和设计师受体专门激活 设计药物（DREADDs）能够直接调节个体遗传活性， 定义的细胞类型。尽管如此，有选择地监管这些机构仍然是一个根本性的挑战。 神经回路的标志性特征：两个特定脑细胞之间的界面。为了解决这个 挑战，我们创造了一种新的方法，使用连接蛋白的电路长期集成 （LinCx），其采用一对新的工程化连接蛋白半通道来直接调节 基因定义的神经回路当半通道对的每个成员被表达为 两种不同的细胞/细胞类型组成一个回路，它们参与异型对接 （彼此对接）并且在两个细胞之间构成电突触。这些 一对半通道被工程化1）以防止它们参与同型对接 （与自身形成电突触），以及2）破坏它们与其他 连接蛋白半通道在哺乳动物脑中内源性表达。（3）The 半通道对呈现整流。这三个属性共同赋予LinCx 前所未有的空间，时间和上下文精度，使神经网络的精确编辑 电路. 我们建议跨模式生物部署LinCx。我们将确定LinCx的影响 神经回路生理学和情绪行为的神经调节。我们还将测试 LinCx调节足以恢复精神疾病动物模型中的正常行为 紊乱这些高风险实验的成功完成将产生一种新的方法， 长期的电路编辑，以调节临床前模型中的情绪状态。在未来，LinCx 可以与新兴的病毒工具相结合， 特定脑细胞类型的蛋白质。因此，LinCx也有一条通往人类的可实现之路。 翻译来改善毁灭性的精神疾病。