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: 10487711
• 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/10487711
• 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; 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：使用工程电气突触的神经回路精确编辑 开创性方法，包括光遗传学和设计器受体专门激活 设计师药物（Dreadds）可以直接调节个体的活性。 定义的单元格类型。然而，选择性规范的 神经回路的标志性特征：两个特定脑细胞之间的界面。解决这个问题 挑战，我们已经创建了一种新的方法，即使用连接素的电路的长期整合 （Lincx），使用一对新型工程连接蛋白半通道直接调节 基因定义的神经回路。当半通道对的每个成员在 两个不同的电池类型组成电路，它们参与异型对接 （彼此对接）和电气突触构成两个细胞之间。这些 一对半通道正在设计1）以防止它们进行同型对接 （与自己形成电气突触），以及2）破坏它们与其他对接 连接蛋白半通道在哺乳动物大脑中内源表达。最后，3） 半通道对表现出矫正。这三个属性一起将Lincx与 前所未有的空间，时间和上下文精度，使神经的精确编辑 电路。 我们建议在模型生物体中部署lincx。我们将确定Lincx的影响 神经调节对神经回路生理和情感行为。我们还将测试是否 Lincx调制足以恢复精神病动物模型中的正常行为 疾病。这些高风险实验的成功完成将产生一种新方法 长期电路编辑以调节临床前模型中的情绪状态。将来，Lincx 可以与新兴的病毒工具集成，以实现遗传编码的系统性输送 特定脑细胞类型的蛋白质。因此，林克斯也有通往人类的可达到的途径 改善毁灭性精神病的翻译。