- 2004 Vern Chapman Lecture, 18th International Mouse Genome Meeting
- 2004 Recipient of Julius Axelrod Medal
- 1999 Tyner Eminent Scholar, Florida State University, Tallahassee, FL
- 1999 Wallace Rowe Lecture, American Association of Laboratory Animal Sciences 50th Annual Meeting
- 1998 Fourteenth von Euler Lecture, Karolinska Institute, Stockholm, Sweden
- 1998 Second International Fellow of the Garvan Institute, Sydney, Australia
- 1994 Charles-Leopold Mayer Award, French Academy of Sciences (shared with Dr. R. Brinster)
- 1989 Distinguished Service Award of US Department of Agriculture.
- 1988 Elected to National Academy of Sciences
- 1988 Elected to American Academy of Arts and Sciences
- 1987 Elected Fellow of American Association for the Advancement of Science
- 1983 New York Academy of Sciences Award in Biological and Medical Sciences
- 1982 George Thorn Award, Howard Hughes Medical Institute
- 1988-1991 Co-Chairman of Four Mouse Molecular Genetics Meetings, Cold Spring Harbor & Heidelberg
Our group uses genetic techniques to study the role of neuromodulators in the development and function of the mammalian nervous system. Most neuromodulators are polypeptides or amino acid derivatives. They are packaged in synaptic vesicles and released into the synaptic cleft upon neuronal stimulation where they modulate the activity of neurons by binding to membrane receptors coupled to G-protein-linked signaling pathways. Our group has been studying the role of the catecholamines, norepinephrine and dopamine, by making mice in which enzymes required for their biosynthesis have been inactivated.Mice that cannot synthesize dopamine develop normally but they become hypoactive and die of starvation a few weeks after birth. Treatment with L-dopa restores dopamine and restores locomotion and feeding and most other behaviors for about 8 hours. Thus, it is possible to study the same mice in either a dopamine replete and dopamine depleted state. Using this model, we have been examining the roles of dopamine in motivation, reward and learning. We also use viral gene therapy strategies to restore dopamine signaling to particular brain regions to ask where dopamine is needed for particular behaviors. We have begun using genetic techniques to manipulate the activity of dopamine neurons. For example, we have removed NMDA receptors from dopamine neurons to reduce excitatory glutamatergic input and discovered that those mice cannot remember where pleasurable events occur. Next, we will be expressing genes into dopamine neurons that will allow pharmacological activation or inactivation of dopamine neuron activity to allow us more directly assess the role of dopamine neurons in various behaviors.
Another area of interest involves the role of hypothalamic neurons that express a neuropeptide called agouti-related protein (AgRP). This small population of neurons is involved in the regulation of appetite and metabolism. We devised a method to selectively kill these neurons and discovered that mice die of starvation. A few days after killing AgRP neurons, the mice neither initiate feeding voluntarily nor swallow much liquid diet even if it is introduced directly into their mouth. Thus, we believe sudden loss of these AgRP neurons disrupts the normal motivational and consummatory systems that control feeding behavior. In addition to AgRP, these neurons make neuropeptide Y and gamma-amino butyric acid (GABA). We have eliminated AgRP and NPY as being critical players in the starvation phenotype and are currently concentrating on the role of GABA.