University of Virginia Health System

Wiring the Brain Our lab is interested in how connections are formed in the developing brain. Our approach is to follow the life history of one neuronal type, serotonergic neurons in the fruit fly ventral nerve cord, and examine its development from cellular differentiation to synapse formation. Introduction The overall objective of my research is to understand the basic mechanisms by which the central nervous system (CNS) is patterned during development. In particular, I am very interested in serotonergic neurons, both in how they develop and how alterations in serotonin release may influence other parts of the CNS. My approach is to concentrate these studies on the life of a single identified insect serotonergic neuron from birth to synapse formation. These studies are carried out in both grasshopper and fruit fly embryos using the complementary cellular and genetic experimental advantages of each animal. Eventually I wish to carry some of these studies over into the Zebrafish. As many of the mechanisms of neural development are conserved across species, these studies should shed light on the general rules of CNS development and that of serotonergic neurons in particular. As serotonergic neurons are likely to play central roles in many human diseases, these studies are likely to be very important. The two main questions being asked currently are how serotonergic neurons acquire specific identities and how they form terminal arbors in the target neuropil. Much of the current work focuses on the cocaine/Prozac sensitive serotonin re-uptake transporter (SERT): regulation of SERT expression during development and the role SERT plays in the formation of CNS connections. Growth cone guidance In the fly and grasshopper, the two serotonergic neuron, s1 and s2, send growth cones across the midline before innervating their targets on contralateral CNS. The current lab objectives are to examine the changes that occur in these cells upon crossing the midline. In both systems, SERT, or serotonin uptake activity is initiated in these cells immediately after the growth cones cross the midline. Using cellular and biochemical approaches in the grasshopper, we have identified an FGF-like midline factor which regulates SERT. Using genetic techniques, we have confirmed the role of FGF signalling as an instructive regulatory step in serotonergic development. We are now undertaking a directed and non-directed genetic screen for molecules that control these early steps in serotonergic development. In addition, we are examining the physiological effects of blocking the early regulation of serotonin uptake. In mice, flies and grasshoppers, serotonin uptake activity is detected in serotonergic neurons well before serotonin synthesis. In the fly, blocking this early onset of serotonin uptake results in behavioral phenotypes for which we are now searching for an anatomical basis. Terminal arbor formation We have performed a number of experiments to examine how changes in the serotonergic growth cone guidance occur. To test of various changes, serotonergic neurons have been ectopically transplanted before and after their growth cones have crossed the midline. These transplanted cells extend growth cones to either the midline or the ipsilateral neuropil (their eventual target) depending on their age at transplantation. While this experiment has revealed much about the changes that occur in growth cone guidance in crossing the midline, they have also revealed much about terminal arbor formation in the complex neuropil. Serotonergic neurons normally form very characteristic branches in the neuropil. By examining the geometry of branches that form from ectopically placed cells, we have learned much about the rules that govern these patterns. We have now begun a combination of both in vivo experimentation and computational modeling to examine terminal arbor formation.

Other Websites for this mentor:
http://faculty.virginia.edu/condron_lab/