ENSEMBLE RECORDINGS IN MODELS OF NEURODEGENERATIVE DISEASE

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The experiments proposed have as their goal combining gene-based and neurobiology-based methods to advance understanding of the fundamental neurobiology of the nigrostriatal system and its particular disruption in Parkinson's disease. Our proposed approach is to develop and implement studies of striatal ensemble activity in the mouse, with the immediate aim of studying transgenic mice generated by our colleagues in the Center, and with the long-term goal of taking advantage of the extraordinary opportunities to examine the fundamental molecular and neurologic bases of parkinsonian disorders by studying mice reengineered to over or under express genes implicated in parkinson's disease. We propose to use two methods to record ensemble activity in the mouse striatum, both based on our ongoing work in the rat. First, we propose to use multiple tetrode assemblies to record simultaneously from striatal neurons as mice undergo training on procedural learning tasks. Second, we propose to monitor the striatal induction of immediate-early genes (IEGs) by local cortical microstimulation and by dopamine receptor agonist treatments, and by combinations of these treatments. For each of these two methods of ensemble activity recording, we then propose to study the effects on the activity of localized striatal dopamine depletion. Based on work from our own and other laboratories, we hypothesize that such dopamine deletion will produce disruption of neuronal coding of procedural tasks by striatal neurons, and disruption of corticostriatal transmission. Finally, we propose to use these functional assays to test transgenic mice produced by members of the Center to examine the neurobiologic consequences of expressing human alpha-synuclein in the mouse (Hyman), and of deletion or mutation of the torsin A gene in transgenic mice (Breakefield). These experiments should significantly advance understanding of the neurobiology of nigrostriatal function and specific gene-based changes in this function in murine models designed to discover the pathogenesis of Parkinson's disease.