Decoding the Mechanisms for Selective Retinotectal Circuit Wiring

PROJECT SUMMARY The precise assembly of neural circuits is crucial for understanding the functioning of the nervous system. While studies have shed light on the molecular and cellular mechanisms behind various aspects of neural development, such as neurite outgrowth and synaptogenesis, the mechanisms governing synaptic specificity in the mammalian central nervous system are not fully understood. The early visual processing pathways provide an excellent model to understand these questions in vivo. The eyes convert visual features into electrical signals and inform the rest of the brain through diverse but precise wiring. The connections from the retina to brain targets provide the structural basis for the circuit processing of different visual features. Our research focuses on understanding how retinal neurons select their synaptic partners in the brain, using the mouse retinotectal synapses as a model. By investigating the wiring of the retinotectal circuit, we aim to gain insights into how specific visual features are regulated from the retina to the superior colliculus. We hypothesize that each neuronal subtype has a unique repertoire of cell-recognition proteins, which determine compatibility with circuit partners and establish synaptic contacts at specific subcellular locations. Our recent work with transsynaptic tracing and single-cell RNA-Seq revealed selective neuronal outputs, indicating the involvement of specific cell adhesion molecules in synaptic specificity. We have developed tools for genetic and viral tracing and established electrophysiology-based circuit mapping assays to further our research. Our proposed aims include determining the mechanisms by which specific cell adhesion molecules instruct synaptic choice and wire up connections in the retinotectal circuit. First, we will focus on investigating the mechanisms regulating convergent pathways from the retina onto Wide Field Neurons based on our past publications. We aim to understand Npnt and Cdh13’s distinct function in vivo by linking neuroanatomy to retinotectal circuit functions. Second, we will focus on Cdh7, a specific Type II Cdh in wiring up the retinotectal circuits from ON-OFF Direction-Selective Ganglion Cells to Stellate Neurons in the superior colliculus, which may reveal the role of Type II Cdhs in the retinotectal circuit assembly. Methods established here may be applied to other parallel retinotectal circuits. These studies will be a major step forward in understanding how multiple genes interact to specify the wiring of complex neural circuits. This research has the potential to advance our understanding of neural circuit assembly and may have implications for understanding other circuits in the mammalian central nervous system. This project will lay the groundwork for understanding how cell-cell recognition regulates retinotectal circuit wiring, with insights into treatment for ophthalmological and neurological disorders.