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.

题目：利用工程电突触对神经回路进行精确编辑