Ph.D. (Neuroanatomy) 1977, University of Chicago
My laboratory has an interest in both developmental neuroscience and CNS plasticity and regeneration following spinal cord and brain injuries in the adult. Our developmental research focuses on identifying molecular interactions between cells which regulate neuronal sorting during compartment formation in the striatum and axonal guidance and target selection during the period of circuit formation and synaptogenesis in the basal ganglia. The mammalian striatum is critically important for integrating a variety of motor, sensory and cognitive functions. In addition to its involvement in neurodegenerative disorders, such as Parkinson’s disease and Huntington’s chorea, human functional imaging studies implicate the striatum and its basal ganglia connections in several developmental disorders, psychological diseases and addictions. These include: Tourette’s syndrome, schizophrenia, obsessive-compulsive disorders (OCD), attention-deficit/hyperactivity disorder (ADHD), and drug addiction. To identify the underlying anatomical substrates that contribute to these varied disorders, it is essential to develop a better understanding of molecular interactions that regulate striatal development and the formation of axonal interconnections within the basal ganglia. Thus, studies in my laboratory are designed to identify how a specific class of cell surface molecules, the ephrins and their associated Eph tyrosine kinase receptors, participate in the formation of neuronal compartments and topographic axonal projections within the basal ganglia. In vivo experiments indicate that specific members of this ligand/receptor family likely participate in the development of striosome/matrix compartments in the striatum and that Eph receptors are present on the axonal projections from these compartments to the substantia nigra. In my laboratory a combination of experimental approaches is utilized for our studies, including mice with deletions or mutations of specific Eph/ephrins, in utero transplantation of progenitor cells with mutations or deletion of selected Eph/ephrins into the developing striatum, and in utero electroporation of plasmids to misexpress mutant Eph/ephrins in the developing striatum. In conjunction with the animal studies, in vitro striatal slice cultures and cultures of dissociated primary cortical and striatal neurons are also used as preparations to evaluate how mutations in Eph receptors or ephrins alter the specificity of axonal projections in the basal ganglia and the physiological properties of synapse on striatal neurons. To identify the underlying anatomical substrates that contribute to these varied disorders, it is essential to develop a better understanding of molecular interactions that regulate striatal development and the formation of axonal interconnections within the basal ganglia.
A second area of my research focuses on determining whether ephrins and Eph receptors act as inhibitory signals that limit the extent of axonal regeneration and synaptic plasticity after CNS trauma. Spinal cord injury is the primary model system used in my laboratory to evaluate whether the Eph receptors and ephrins, which participate in the formation of spinal cord neural circuits during development, are re-expressed following spinal cord injury in the adult. Information gained from these studies will be used to obtain insights into whether molecular signals acting during the development of axonal connections in the spinal cord are recapitulated in response to spinal cord injury. A major focus of these experiments is to evaluate how Eph/ephrins regulate glial scar development and the reformation of the blood brain barrier following CNS lesions in the adult. A second emphasis of this research is to determine whether the up-regulation of Eph/ephrins that occurs at the glial scar provides inhibitory signals to injured axons that prevent axonal regeneration. Thus, the ultimate goal of the studies on spinal cord lesions is to identify whether altering the activity of specific Eph receptor tyrosine kinases results in enhanced axonal regeneration and functional recovery after spinal cord injuries. As the role of specific Eph/ephrins is identified after spinal cord lesions, siRNA experiments will be performed to determine whether this approach might be a feasible treatment to promote axonal regeneration and the recovery of spinal cord functions after spinal cord injury in adults.