Genome sequencing has uncovered thousands of genes. Of these, an estimated 80% are expressed in the brain.* Now we face the exciting challenge of discovering what these genes do, because relatively few have been studied in detail. As a neuroscientist, my interest is in identifying roles for genes whose function is not yet known, and uncovering new and surprising functions of already-discovered genes, with an eye toward their functions in neurons. As a psychiatrist, I am interested in studying genes which play a role in neuropsychiatric diseases and in coping with environmental stresses, especially those inflicted by drugs of abuse. Some of these genes may also influence how neurons age.

Toward these ends, I utilize the nematode worm C. elegans, an organism with a relatively simple nervous system, yet which employs many of the genes found in mammalian neurons. I use genetics, molecular biology, pharmacology, and microscopy (fluorescence, confocal, and conventional wide-field) to study the effects of altering worm genes on neuronal function and behavior. Genes are selected in two ways. “Forward” genetic screens allow us to look for very rare alterations of protein function without any preconceptions about what genes may be involved. “Reverse” genetics permits the study of the effects of specific genes of interest. I am particularly excited about using this technique to study targets identified in human genetic research as candidates for susceptibility to neuropsychiatric disease. We can rapidly establish genetic models in worms, both for their own study and to help guide future work in mammals. For this reason I am especially open to collaboration with colleagues developing mammalian models.

I am actively pursuing three projects. First, in keeping with the mission of the Ernest Gallo Clinic & Research Center, I am studying the destructive impact of abused substances at the cellular level. In particular, I have been using C. elegans to investigate the mechanism of the neurotoxic effects of amphetamines. Second, I am developing a model of neuronal degeneration that may shed light on what makes neurons vulnerable in neuropsychiatric diseases, including schizophrenia and Parkinson’s disease. It is possible that some of these genes may also play a role in the adverse consequences of amphetamine exposure. Finally, I am studying the toxic effects of the neurotransmitter dopamine using a toxicological assay. Several mutants that show enhanced survival in the presence of toxic dopamine concentrations have been isolated and are being characterized. These may lead to identification of novel targets that are affected by excess dopamine, as may occur in the pathobiology of Parkinson’s disease.

*As determined at the Allen Institute for Brain Science; Lein et al. (2007) Nature 445: 168.