Synaptic Targeting in Hard-Wired Neural Circuits

****** 神经突触的精确连接是由什么样的分子指令来实现的？ 只有对生存最关键的行为才与基因组紧密相连。 像呼吸和原始反射这样的行为是无法习得的，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。 我的研究目标是找出每一个必要的分子，并充分连接一个硬连线的神经回路。 我的总体假设是，一组特定的细胞表面分子需要产生一个独特的硬连线突触连接。 我的实验方法将使用已识别神经元的单细胞RNA测序，同时对所有细胞表面受体进行系统表征，以了解它们如何创建神经元的精确布线模式。 然后，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。 这项研究将是第一次展示精确的遗传指令，可以完全硬连线和错误连线神经回路。 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。

****** 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. The goal of my research is to identify every molecule necessary and sufficient to wire up a hard-wired neural circuit. My overall hypothesis is that a specific set of cell-surface molecules are required to generate a distinct hard-wired synaptic connectivity. My experimental approach will use single cell RNA sequencing of identified neurons in concert with a systematic characterization of all cell-surface receptors to understand how they can create the neuron's precise wiring pattern. We will then express these molecules in another neuron to re-wire its synaptic connections, alter its function, and thus alter the animal's perception and behavior. 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.