Novelty and valence encoding in the zona incerta in parkinsonian monkeys - PROJECT SUMMARY/ABSTRACT The loss of midbrain dopamine cells that occurs in Parkinson’s disease (PD) results in pathological changes to neural activity throughout the basal ganglia that justify circuitry models which explain motor deficits. Parkinsonian animal models have revealed that the activity of the zona incerta (ZI) may also be abnormal in the parkinsonian state. The ZI is an understudied brain region that has recently received attention in animal studies for its role in shifting attention by modulating oculomotor and locomotor responses to engage with positively valued or novel stimuli. This is demonstrated in healthy animals where subpopulations of ZI neurons exhibit changes in neural activity to presentation of positive or novel stimuli. The ZI serves as a global modulator, receiving most of its inputs from cortex, and sending inhibitory outputs to the thalamus and brainstem. I propose that the ZI could have an important role in deficient processing of novelty and valence in parkinsonism, which could contribute to lack of motivation characteristic of PD. In parkinsonian rodents, ZI neurons show increased spontaneous activity, while in parkinsonian monkeys, activity related mRNA expression is increased compared to healthy animals. Driven by this evidence, in Aim 1 I will conduct electrophysiological recordings of the ZI in healthy monkeys to determine spontaneous activity and response to stimuli signaling positive/negative valence and novelty during a visuomotor task. These recordings will then be repeated following the development of parkinsonism in these animals by administration of the neurotoxin MPTP. I hypothesize that the spontaneous activity of ZI neurons will be increased in the parkinsonian state when compared to healthy animals, but neural responses to novelty and positive valence during the task will instead be reduced. Previous studies that examined cortical regions in parkinsonian animal models reveal both reductions in terminal innervation to subcortical structures and changes at the synaptic level in remaining terminals. In Aim 2, I will use immunohistochemistry and confocal and electron microscopy to compare the density and synaptic structure of cortical inputs to the ZI between healthy and parkinsonian monkeys. I hypothesize that cortical-ZI inputs in parkinsonian monkeys will be reduced, and the remaining cortical terminals will have abnormal synaptic structure, perhaps underlying the functional alterations I predict. These studies will be conducted in a laboratory at the Emory National Primate Research Center that has the resources and expertise to support my studies. The experiments proposed fit my training goals of mastering neuroscience techniques and concepts, specifically training in in vivo electrophysiology, surgical skills, immunohistochemistry, modeling parkinsonism, and behavioral assessment of monkeys. The studies I propose will offer a comprehensive view of the effects of parkinsonism on the ZI’s activity and on cortical-ZI innervation in monkeys, and may serve as a basis to develop circuitry models and therapeutic targets aimed at ameliorating some of the neuropsychiatric symptoms of PD.
