The role of axonal guidance genes in the regulation of dopamine-mediated behaviors and synaptic connectivity

项目总结/文摘:

Project Summary/Abstract: Netrin-1 signaling through the netrin receptor deleted in colorectal cancer (Dcc) serves a critical role in neural circuit development by promoting growth cone motility, axonal branching, and synaptogenesis. Emerging evidence now suggests secreted netrins play an additional role in maintaining excitatory synaptic connections in the adult brain. While netrin-1 is highly expressed during neurodevelopment, this expression decreases globally after central nervous system (CNS) formation. Interestingly, neurons of the ventral tegmental area (VTA) maintain high expression of both Netrin-1 and Dcc in adult mice. To date, the function of netrin-1 and netrin receptors in VTA neurons of the adult CNS remains unknown. I hypothesize that Netrin-1 plays a fundamental role in regulating synaptic connectivity in the adult VTA, and alterations in the expression levels of the Ntn1 gene will result in disease relevant dysregulation of dopaminergic neuron connectivity and measurable changes in dopamine-mediated behaviors. To test this, I propose to 1) assess synaptic contribution of Netrin-1 in the VTA and 2) the behavioral impact of cell-type specific genetic disruption of Ntn1. Determining the function of Netrin- 1 in adult neurons will not only shed light on the molecular mechanisms responsible for regulating excitatory and inhibitory synaptic connectivity in the midbrain dopamine system, and will contribute to our understanding of how alterations in dopamine circuitry may contribute to psychiatric dysfunction.