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.