Developmental Mechanisms of Fine-scale Cortico-cortical Circuit Formation

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Project Summary Cortico-cortical projection neurons (CCPNs) connect cortical areas with each other to facilitate sensory processing and execute appropriate motor actions. Defects in intra-cortical connectivity are associated with a variety of neural circuit disorders such as dyslexia, autism, and schizophrenia. Because these diseases have genetic components and potentially arise from altered brain development, it is important to understand how CCPNs know which area to target and which synaptic inputs to receive. The long-term goal of my research program is to gain mechanistic insights into cortical circuit assembly at the single cell level in an effort to understand underpinnings of neurodevelopmental disorders and develop new therapies. In doing so, we will be able to identify molecular and genetic mechanisms that link gene expression and neural activity to neuronal connectivity. The objective of this proposal is to identify mechanisms by which long-range cortico-cortical neuronal connectivity is established in the mammalian cortex using the mouse visual system as a model. Our central hypothesis is that V1 neurons, projecting to the AL (anterolateral: V1→AL) or the PM (posteromedial: V1→PM) higher visual areas, differ in timing and molecular regulation of their axonal projection development, and their input versus output connectivity is specified by two distinct rules: early specification and synaptic pruning mechanism, respectively. We will test this hypothesis with the following aims: 1) we will determine the patterns and timing of cortico-cortical neuronal projection development in the mouse visual cortex. 2) we will determine the roles of Teneurins, cell-adhesion molecules, in specifying the projection identities of V1→AL and V1→PM neurons. 3) we will determine developmental principles of ‘like-to-like’ cortico-cortical feedback circuit formation. This research is significant because elucidating the developmental mechanisms of neural circuit assembly will provide cell-type or circuit-specific therapeutic interventions for specific aspects of neurodevelopmental and psychiatric disorder phenotypes. The proposed research is innovative because we are using and developing the technical solutions to allow us to target gene expression and capture the rapid developmental connectivity dynamics of layer- and projection-specific cortical neurons. Results will provide a comprehensive understanding of how a long-range connectivity network arises at the cellular level. This new knowledge will have a positive impact on the neuroscience field as it will establish a solid foundation to provide connectivity-based therapeutic interventions for neurodevelopmental disorders.