Synaptic Targeting in Hard-Wired Neural Circuits

硬连线神经回路中的突触靶向

• 批准号: RGPIN-2020-04902
• 负责人: Chen, Brian
• 金额: $ 3.64万
• 依托单位: McGill University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2020
• 资助国家: 加拿大
• 起止时间: 2020-01-01 至 2021-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=717454
• 关键词: Synaptic; Targeting; Hard; Wired; Neural

What are the molecular instructions to hard-wire precise synaptic connections? Only the most critical behaviours for survival are hard-wired into the genome. Behaviours such as breathing and primitive reflexes are not learned, and so the neural circuitry that controls them must be pre-specified using precise molecular instructions. Currently, we know very little about how hard-wired neural circuits are formed. My long term goal is to identify every molecule necessary and sufficient to wire up a hard-wired neural circuit. My overall hypothesis is that only a small number (. My experimental approach will use transcriptome sequencing of single identified neurons in concert with a systematic characterization of cell-surface receptors involved in synaptic targeting. Specifically, we will isolate single identified neurons with stereotyped hard-wired synaptic connectivities and sequence their RNA gene products. By comparing the gene expression patterns between pairs of differentially-connected neurons from the same animal, we will identify the molecules that pre-determine their synaptic connectivities. To understand how these molecules are used by these neurons, we will functionally characterize all cell-surface receptors required to create the neuron's precise wiring pattern. Finally, we will express these molecules in another neuron to re-wire its synaptic connections, alter its function, and thus alter the animal's perception and behaviour. This research will be the first demonstration of the exact genetic instructions that can completely hardwire and mis-wire a neural circuit. By understanding how key molecules at the cell surface can produce erroneous synaptic connections, we can investigate ways to correct it. Our proposed work is an important first step towards understanding the molecular instructions underlying innate behaviours.

硬连线精确突触连接的分子指令是什么？ 只有对生存最关键的行为才被硬连接到基因组中。 呼吸和原始反射等行为是无法习得的，因此控制它们的神经回路必须使用精确的分子指令预先指定。 目前，我们对硬连线神经回路是如何形成的知之甚少。 我的长期目标是识别连接硬连线神经回路所必需且充分的每一个分子。我的总体假设是，只有一小部分（。我的实验方法将使用单个已识别神经元的转录组测序，并结合参与突触靶向的细胞表面受体的系统表征。 具体来说，我们将分离出具有定型硬连线突触连接的单个已识别神经元，并对它们的 RNA 基因产物进行测序。 通过比较来自同一动物的成对差异连接神经元之间的基因表达模式，我们将识别预先确定其突触连接的分子。 为了了解这些神经元如何使用这些分子，我们将从功能上表征创建神经元精确布线模式所需的所有细胞表面受体。 最后，我们将在另一个神经元中表达这些分子，以重新连接其突触连接，改变其功能，从而改变动物的感知和行为。 这项研究将首次展示可以完全硬连线和错误连线神经回路的精确遗传指令。 通过了解细胞表面的关键分子如何产生错误的突触连接，我们可以研究纠正它的方法。 我们提出的工作是理解先天行为背后的分子指令的重要的第一步。