Molecular Genetics of Visual Circuit Assembly in the Developing Superior Colliculus

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My long-term goal is to understand how neural circuits underlying specific brain functions are formed, modified by experience, and altered in neurological conditions. The goal of this proposal is to examine mechanisms that regulate formation of the long-range neuronal connections between the superior colliculus (SC) and specific subcortical brain areas. We chose to focus on the connections between superficial layer of SC (sSC) and the thalamus. The SC is a midbrain center that plays an important role in sensory and motor processing. The sSC receives visual inputs from the retina and cortex, and sSC-thalamic connections are known to mediate defensive responses to threating visual stimuli. As most of traditional studies have investigated organization of sensory inputs to sSC, little is known about mechanisms regulating development of sSC output pathways. Moreover, no study has described developmental regulation of sSC-thalamic circuits underlying visually-driven behavioral responses. In a screen for the markers labeling subsets of sSC neurons, we have identified several genes that are likely to control development of sSC neurons. Now, we propose to investigate the role of those molecules in sSC output circuit assembly. We have already demonstrated that a transcriptional factor, retinoid-related orphan receptor β (Rorβ), regulates sSC neuronal projections to specific thalamic nuclei. Here, we plan to examine downstream mechanisms of Rorβ-dependent regulation by gain- and loss-of-function approaches. We will also investigate the role of another transcription factor, Brn3b, in the development of distinct sSC circuits and identify the downstream effectors of Brn3b. Given that sSC neurons, confined to specific sublayers, selectively project axons to distinct thalamic nuclei, and that Brn3b and Rorβ are expressed in different sublayers of sSC, we hypothesize that Brn3b regulates axonal projections via Rorβ-independent mechanisms. Manipulations of Rorβ and Brn3b expression produce different patterns of altered axonal projections to the thalamic nucleus, known to govern visual-cue triggered behaviors. Based on these findings, we will test if Rorβ- and Brn3b-dependent mechanisms of circuit assembly are required for appropriate behavioral responses to visual threat. The success of the proposed project will improve our understanding of the molecular basis for establishing the long-range connections between sSC and thalamic areas. It will also provide novel mechanistic insights into developmental assmebly of subcortical visual circuits regulating responses to the threatening stimuli.