Synaptic Targeting in Hard-Wired Neural Circuits

点击翻译按钮获取中文摘要

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 (< 50) of different cell-surface molecules are required to generate a distinct hard-wired synaptic targeting pattern.   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.