Objective: Investigate an emerging anxiety-like phenotype at various timepoints in a novel bilateral rodent model of parkinsonian alpha-synuclein pathology.

Background: Parkinson’s Disease (PD) anxiety poses a significant economic and personal burden yet the underlying mechanisms driving anxiety are heterogeneous and complex. Emerging evidence from PD patients and rodent models supports the idea that proteinopathies alter synaptic proteins and thus, neurotransmission which serves as the catalyst for progressive neurodegeneration up to 20 years before motor symptom onset and clinical diagnosis. Anxiety has been postulated as one of the earliest disease manifestations, and its progression closely follows the Braak staging spread of alpha-synuclein (a-syn) and Lewy body formation. In healthy brains, a-syn is postulated to play crucial roles in cellular function and neurotransmission, but how perturbations of this protein contribute to PD anxiety remains enigmatic, leaving millions underdiagnosed and lacking treatment options. Unfortunately, many current models fail to recapitulate proteinaceous inclusions, lack face validity, or are typically attained unilaterally.

Method: Thus, to create a unique model of PD with improved face validity, taking non-motor symptoms into account, Sprague Dawley rats were injected bilaterally in the Substantia Nigra with the adeno-associated virus (AAV) expressing human α-syn (hα-SYN), or an AAV carrying an empty transgene cassette as control. After recovery, animals were placed through a battery of anxiety and motor assays including, successive alleys, open field, novelty-induced hypophagia, and rotarod testing at various timepoints to investigate when an anxiety-like phenotype may emerge.

Results: Initial results from this work suggest hα-SYN, but not control, animals at 6-weeks after injection show an emerging anxiety-like phenotype which becomes exacerbated at 14-weeks post-injection. Motor deficits were not yet present at the timepoints chosen. Postmortem analyses will include quantitative histological measures to validate vector transduction, formation of pathological α-syn, and nigral degeneration.

Conclusion: Results from our current study will serve as a guide to better characterize emerging dysfunction in the motor and non-motor neurocircuitry linked to PD and illuminate ways to slow or halt their progression.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/investigating-an-emerging-anxiety-like-phenotype-in-a-novel-bilateral-rodent-model-of-parkinsonian-alpha-synuclein-pathology/