Inflammation as a Contributor to Ingestive and Vocal Dysfunction in a PINK1 Knockout Rat Model of Parkinson Disease
Authors: Yang Katie M , Mulholland Haleigh N , Kurup Meghna P , Ciucci Michelle R 
Published: November 2023

Objective

To determine if activated microgliosis occurs in regions known to accumulate α‐synuclein (α‐syn) aggregates in a PINK1 −/− rat model of Parkinson Disease. Deficits in voice and ingestive behaviors, including those in functional swallowing that contribute to aspiration pneumonia, occur in the early stages of Parkinson Disease (PD) and have a complex underlying neuropathology that occurs outside of the classical central dopamine loss framework. Late‐stage PD patient brain tissue shows that vagal nuclei that provide afferent and efferent projections to structures of ingestion and vocalization have degeneration of neurons that may result from pathological aggregation of abnormal α‐syn. Additionally, α‐syn aggregates have been shown to activate resident microglia, leading to a significant increase in neuroinflammation including the release of pro‐inflammatory cytokines. Thus, we hypothesized that abnormal a‐syn aggregation will be present in vagal nuclei controlling swallowing and digestion, including the dorsal motor nucleus of the vagus, the nucleus ambiguus, and the nucleus of the solitary tract as well as the hypoglossal nucleus. We also hypothesized that these aggregates would be associated with increased levels of microgliosis and pro‐inflammatory molecule secretion. To test these predictions, we used a genetic animal model of PD, the PINK1 knockout (−/−) rat, which shows early and progressive deficits in oropharyngeal swallowing, defecation, and acoustic parameters of their ultrasonic vocalizations as well as aggregation of α‐syn within muscles innervated by various branches of the vagus nerve. We performed immunohistochemistry for proteinase K‐resistant α‐syn aggregates and activated microglia marker OX‐42 within these nuclei in 14 10‐month‐old PINK1 −/− and 10 age‐matched wild‐type controls. Three bilateral serial sections where the central canal was present were analyzed using custom‐designed software in ImageJ to quantify total mean optical density of the OX‐42 immunolabelling in each section. Qualitative analysis determined that α‐syn aggregates were present within all of the regions of interest within the PINK1 −/− animals but not the wild‐type animals. Surprisingly, the mean optical density of OX‐42 immunolabelling was significantly decreased in these regions of interest within the PINK1 −/− animals compared to age‐matched wild‐type controls and was positively correlated with acoustic parameters of PINK1 −/− animals ultrasonic vocalizations, suggesting a relationship between inflammation and behavioral outcomes. We conclude that α‐syn aggregation is associated with a decrease in microglial activation in brainstem regions of the PINK1 −/− model in the early stages of pathology. These findings contribute to our understanding of how protein aggregation and deficits in central inflammation contribute to ingestive and vocal deficits in the PINK1 −/− rat model of PD.

Support or Funding Information

Support: Howard Hughes Medical Institute Gilliam Fellowship (Yang); University of Wisconsin‐Madison Department of Surgery‐Otolaryngology (Mulholland, Kurup, Ciucci)