DESCRIPTION (provided by applicant): The basal ganglia are a highly conserved neural system that play a role in movement, learning, and cognition. The output of the basal ganglia is controlled by two neural pathways that either facilitate movement (direct pathway) or inhibit movement (indirect pathway). Dissruption in the balance of these two pathways underlies motor defecits observed in neurological diseases such as dystonia, Parkinson's disease, Tourette's syndrome, and Huntington's disease. Understanding how direct- and indirect-pathway circuits are coordinated at the cellular level is therefore of great importance and potential therapeutic value. Over the past decade, studies investigating the cellular organization of network function have converged upon classes of highly specialized neurons called inhibitory interneurons. The importance of these neurons in basal ganglia function is demonstrated by the fact that their loss in the striatum, the input nucleus of the basal ganglia, severely impairs motor function. Despite their importance, the basic role of interneurons in striatal processing remains poorly understood because they have been historically difficult to target for electrophysiological study. This proposal describes our use of a novel approach to study the role of inhibitory interneurons in the striatum, by using transgenic mouse lines to fluorescently label distinct cell types in the striatal circuit. This new technology enables direct testing of how inhibitory signaling affects neurons in the direct and indirect basal ganglia pathways for the first time. Using this approach, we will tests three hypotheses about inhibitory interneuron function in the striatum: (1) That different classes of interneurons play distinct roles in striatal processing (2) that striatal interneurons receive an important feedback signal that tunes striatal output and (3) that interneurons contribute to imbalances in striatal output (hyperactivation of the indirect-pathway) observed during Parkinson's disease. The experiments to test these hypotheses will utilize whole-cell recording techniques to study excitability and synaptic signaling of interneurons in acute brain slices. The slices will be made from transgenic mice where distinct cell types in the striatal circuit are fluorescently labeled, enabling discoveries about synaptic properties and connectivity to be placed in a systems-level context of circuit function. These results will yield insights into how synaptic plasticity or reorganization changes striatal output in PD and how this might contribute to circuit dysfunction in PD and other diseases of the basal ganglia.

PROJECT NARRATIVE Parkinson's Disease is a devestating neurological disorder that affects 1% of people over 65. Its well-known motor symptoms, including loss of voluntary movement and limb tremors, result from widespread dysfunction of the brain's motor control center, the basal ganglia. In this grant, I will test hypotheses that local inhibition of activity by specialized brain cells in the input nucleus to the basal ganglia, play a critical role in controling motor function in both health and disease. This research will advance our understanding of the neural circuitry that underlies motor control and potentially identify new targets for disease therapy.