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Functional Analysis of Nonmotor Symptoms from Regions Innervating the Locus Coeruleus in a Mouse Gut-Brain Alpha-Synuclein PFF Model

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[Technical Report, Annual Report]

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Johns Hopkins University

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The non-motor symptoms associated with Parkinsons disease have been largely overlooked, gaining only small recognition in the last decade. These NMS vary, encompassing both the psychiatric and the cognitive. The loss of noradrenergic neurons in the locus coeruleus precedes the loss of dopamine neurons in the SNc and to a greater extent. Like the SNc, the loss of LC neurons may result from the accumulation of alpha-synuclein, which is the main component in Lewy bodies and has been postulated to behave like a prion leading to the Braaks hypothesis. The Braak hypothesis has been expanded based on the concept that pathologic a-syn may initiate in thegastrointestinal tract and spread in a retrograde manner from the enteric nervous system ENS up the vagus to the dorsal motor nucleus of the vagus. Since there was no appropriate animal model of a-syn transmission from the ENS to the CNS, we developed a clinically relevant gut-brain a-syn preformed fibril PFF transmission mouse model that recapitulates the spread of a-syn according to Braaks model. Following our SoW, made the PFF and rabies virus during the first quarter and injected PFF into the mouse gut during the second. We were able to harvest some of the early injected mice before the university shutdown due to the COVID-19 pandemic. These mice showed phospho-syn staining the duodenum and pylorus of the mice but we saw little to no labeling in the brain, and thus we were unable to reproduce the transmission previously reported. Due to the shutdown, we were forced to euthanize the remaining gut-injected mice and keep only breeding pairs. After further investigation, we discovered that the reported dose of PFF had been incorrectly calculated resulting in only 20 of the reported PFF being injected. Secondly, the surgical anesthetic published Isoflurane was not the anesthetic used Ketamine. Ketamine has been shown to have anti-inflammation properties, and it is believed that this reduction in inflammation and

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  • Medicine and Medical Research

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[A, Approved For Public Release]