Striatal Neuroplasticity Mechanisms that Preserve Motor Behavior in a model of Parkinsonâs Disease

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Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder in which loss of dopamine (DA) leads to cognitive and motor impairments. Motor symptoms include resting tremor, rigidity, altered gait, and bradykinesia. The DA precursor L-dopamine (L- 3, 4-dihydroxyphenyalanine) is the gold standard therapy, but it can lose efficacy and produce dyskinesias. The work proposed in this grant application will focus on identifying and characterizing synaptic and network level changes in the striatum that preserve motor function in models of PD. Our preliminary data indicate that a transient elevation of nigrostriatal DA triggers mechanisms of long-term plasticity that prevent the development of motor impairments after induction of a dorsal striatal 6-hydroxydopamine model of PD. To gain mechanistic insight into this form of plasticity, in Aim 1 we will perform a number of experiments that address its induction and maintenance, including determining how long the normalized motor behavior persists, whether DA receptor agonists (rather than endogenous DA) are able to induce the neuroplasticity to normalize motor behavior, and whether the plasticity occurs in other common and, in some cases, more complete models of PD. Since motor behavior is strongly influenced by the balance of activity in striatal direct and indirect pathway output neurons, the other two Aims of this grant application will determine synaptic and circuit level changes in the striatal output neurons. In Aim2, we will use electrophysiology to measure changes in the excitability of the striatal output neurons and their connections to cortico- and thalamostriatal inputs, the major drivers of striatal activity. In Aim 3, we will use in vivo calcium imaging to measure the activity patterns of these two neuronal populations while monitoring motor behavior after induction of the novel plasticity mechanism in the striatal PD model. Work described in this proposal provides a rare and exciting opportunity to gain insight into how striatal DA signaling and plasticity affect movement normally and in PD, and set the stage to identify improved therapeutic approaches. Additionally, the work will lay the foundation for investigation into similar dopamine-mediated neuroplasticity mechanisms that may exist in other regions of the brain and affect the cognitive and emotional aspects of the disease.