Our laboratory uses molecular genetic techniques in the mouse to alter genes involved in neuronal signaling and then we assess the behavioral consequences. The focus has been on dopamine neurons. We have generated mice that lack the ability to make dopamine and shown that they have severe deficits in motivation, locomotor activity cognitive activity. We then use viral techniques to restore dopamine signaling to specific brain regions and determine what behaviors are rescued. We are also beginning to modulate the firing properties of dopamine neurons by manipulating glutamate and GABA receptors selectively in dopamine neurons. For example, removal of NMDA receptors from dopamine neurons prevents burst firing and attenuates cue-dependent learning. We also are making a set of mice that will allow selective activation of G-protein cascades that are either excitatory or inhibitory. Dopamine signaling in the striatum is primarily directed onto medium spiny neurons, which are GABAergic projection neurons. We are beginning to manipulate GABA signaling by these neurons. Another area of interest involves the control of feeding and metabolism by neurons in the arcuate region of the hypothalamus that make agouti-related protein (AgRP), neuropeptide Y (NPY) and GABA. We have learned that GABA signaling by these neurons is essential to maintain feeding behavior and are in the process of dissecting the mechanisms involved.
