Objective: Test the hypothesis that unilateral chemogenetic inhibition of the nigrovagal pathway in the subthreshold Paraquat (P) + dietary lectin (L) exposure rat model of parkinsonism will provide contralateral protection and cause ipsilateral hemiparkinsonism.

Background: We recently demonstrated that there is a direct monosynaptic nigrovagal dopaminergic pathway in the rat and that oral exposure of subthreshold doses of P+L causes bilateral levodopa responsive parkinsonism accompanied by substantia nigra pars compacta (SNpc) neuronal degeneration (Anselmi, et. al., npj Parkinson’s disease 4:30, 2018). In this model misfolded alpha-synuclein ascends from the stomach via the vagus nerve to reach the dorsal motor nucleus of the vagus (DMV) and then into the SNpc causing neuronal degeneration and maladaptive hyperactivity in the nigrovagal pathway. We predicted that silencing this maladaptive hyperactivity will prevent parkinsonism.

Method: Adult Sprague Dawley rats were stereotactically injected with AAV2- Ef1a-eYFP-IRES-WGA-Cre into the DMV and AAV8-hSyn-DIO-hM4Di-mCherry into the SNpc on the left side. This allowed specific chemogenetic inhibition of the left nigrovagal pathway when P+L was given orally along with the chemogenetic activator CNO in the water supply for 1 week. Control animals received inactive vectors. Behavioral assessments at 2, 4, 8, 12, 16 and 20 weeks; and terminal electrophysiology and histology.

Results: All test animals developed stable left hemiparkinsonism and control animals developed bilateral parkinsonism as determined on the stepping, vibrissae evoked forelimb placement and cylinder tests. Electrophysiological recordings from the subthalamic nucleus showed expected increased firing rate and burstiness on the unprotected side and no changes in the protected side. Histology showed unilateral expression of hM4Di and mCherry exclusively in the nigrovagal pathway and ipsilateral SNpc neuronal preservation. Contralateral SNpc demonstrated >50% neuronal degeneration with lewy body-like inclusions that were positive for misfolded alpha-synuclein.

Conclusion: We show that maladaptive nigrovagal neuronal hyperactivity plays a critical role in accelerating synucleinopathy and SNpc neurodegeneration providing proof of concept the nigrovagal pathway is a novel therapeutic target to prevent disease progression in Parkinson’s disease

References: 1. Anselmi L, Bove C, Coleman FH, Le K, Subramanian MP, Venkiteswaran K, Subramanian T, Travagli RA. Ingestion of subthreshold doses of environmental toxins induces ascending Parkinsonism in the rat. npj Parkinson’s Disease. 2018;4(1):30. doi: 10.1038/s41531-018-0066-0 2. Anselmi L, Toti L, Bove C, Hampton J, Travagli RA. A Nigro-Vagal Pathway Controls Gastric Motility and Is Affected in a Rat Model of Parkinsonism. Gastroenterology. 2017;153(6):1581-93. doi: 10.1053/j.gastro.2017.08.069.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/maladaptive-nigrovagal-neuronal-plasticity-causes-ascending-alpha-synucleinopathy-in-a-novel-environmental-toxin-based-rat-model-of-parkinsonism/