Deciphering the genetic code of neuronal type connectivity through bilinear modeling

Understanding how different neuronal types connect and communicate is critical to interpreting brain function and behavior. However, it has remained a formidable challenge to decipher the genetic underpinnings that dictate the specific connections formed between neuronal types. To address this, we propose a novel bilinear modeling approach that leverages the architecture similar to that of recommendation systems. Our model transforms the gene expressions of presynaptic and postsynaptic neuronal types, obtained from single-cell transcriptomics, into a covariance matrix. The objective is to construct this covariance matrix that closely mirrors a connectivity matrix, derived from connectomic data, reflecting the known anatomical connections between these neuronal types. When tested on a dataset of Caenorhabditis elegans, our model achieved a performance comparable to, if slightly better than, the previously proposed spatial connectome model (SCM) in reconstructing electrical synaptic connectivity based on gene expressions. Through a comparative analysis, our model not only captured all genetic interactions identified by the SCM but also inferred additional ones. Applied to a mouse retinal neuronal dataset, the bilinear model successfully recapitulated recognized connectivity motifs between bipolar cells and retinal ganglion cells, and provided interpretable insights into genetic interactions shaping the connectivity. Specifically, it identified unique genetic signatures associated with different connectivity motifs, including genes important to cell-cell adhesion and synapse formation, highlighting their role in orchestrating specific synaptic connections between these neurons. Our work establishes an innovative computational strategy for decoding the genetic programming of neuronal type connectivity. It not only sets a new benchmark for single-cell transcriptomic analysis of synaptic connections but also paves the way for mechanistic studies of neural circuit assembly and genetic manipulation of circuit wiring.