Pathways, mechanisms, and treatments of vocal communication deficits in a Parkinson rat model

University Of Wisconsin-Madison, Madison WI

Investigators

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Abstract

PROJECT SUMMARY/ABSTRACT At least 90% of individuals with Parkinson disease (PD) experience significant vocal communication deficits that appear preclinically, negatively impact quality of life, and are refractory to current therapeutic approaches. Management of PD voice deficits is restricted by a limited scientific understanding of the preclinical disease framework resulting in a critical gap in knowledge. This research proposal directly aims to improve the understanding of preclinical PD biology to ultimately reduce disease progression and vocal symptom burden. Neuroinflammation plays an important role in the initial insult, spread, and severity of neurodegenerative disease and epidemiological studies suggest that anti-inflammatory drugs may be therapeutic and reduce the incidence of PD. Results of our current award, using the Pink1-/- rat model of preclinical PD, so far demonstrate that NF-κB and MAPK signaling result in upregulated inflammation in the brainstem vocal pathway. This continuing proposal is grounded in the new central hypothesis that inflammation within vocal motor brainstem nuclei, particularly the reciprocal modulation between microglia and astrocytes, contributes to neuronal dysfunction and death. Further, we hypothesize that this mechanistic action within vocal nuclei results in the preclinical onset and progression of PD voice deficits, and that anti-inflammatory drugs targeting these mechanisms will prevent progression PD vocal deficits. To accomplish this, Specific Aim 1 will use Pink1-/- and wildtype control co-cultures (astrocyte, microglia, and neurons) and a series of cross-talk experiments to quantify gene and protein changes in the NF-κB and MAPK inflammation pathways as well as evaluate their responses to anti-inflammatory drugs. We expect that, compared to wildtype controls, Pink1-/- co-cultures and media will demonstrate high levels of cytotoxic and apoptotic markers that will be decreased with anti- inflammatory drugs. Specific Aim 2 will use spatial transcriptomics within the brainstem descending vocal motor pathway to evaluate cell type and gene expression changes with age and sex between Pink1-/- and wildtype rats. We expect to see significant upregulation and clustering of immune cell numbers with age in the Pink1-/- rat compared to controls. Then, Pink1-/- rats will be given site-specific administration of anti- inflammatory drugs into the vocal pathway, tested for vocalization behavior, and inflammatory gene expression will be re-analyzed. We expect that vocalization acoustic parameters will increase with anti-inflammatory drugs (to control-like levels) and correlate with reductions in the production of proinflammatory cytokines. This proposal is the first to adopt an innovative approach combining both in vivo and in vitro methods for studying preclinical CNS inflammation in PD and vocalization. This work is significant because these data will initiate long-term advancements to the field by identifying the early inflammatory pathophysiology of voice deficits as well as anti-inflammatory treatments that target these mechanisms.