Individuals with Parkinson disease (PD) experience vocal communication deficits that negatively impact health and quality of life. PD pathology is widespread, including alpha-synuclein aggregation and decreases in neurotransmission within brainstem regions. However, very little is known about how these PD-associated pathologies contribute to vocal communication deficits and thus, current treatments are ineffective. To develop treatments tailored to vocal dysfunction, it is paramount to understand pathology at gene and protein levels. The proposed research will address these unknowns by profiling differentially expressed transcripts using RNA sequencing in brainstem regions linked to vocal production in health and PD. We will use a validated rat model of PD, Pink1-/-, and compare data to aged-matched wildtype (WT) controls. Pink1-/- rats show early, progressive vocal communication deficits that recapitulate communication deficits in human PD. Pink1 -/- and WT rats will be studied at two timepoints, 2 months (prior to deficits) and 8 months (early-stage pathology). Because there are known sex differences with human PD, we will characterize female vocalizations and correlative pathology. The proposed work is a series of studies that are an exploratory, descriptive, and hypothesis-driven to demonstrate associations between vocal behavior, gene expression networks, and consequences on protein regulation.
Specific aims for this proposal are 1A) to identify and compare large-scale gene expression variations in brainstem regions that regulate vocal communication in Pink1 -/- and WT male and female rats and 1B) biologically validate vocalization-related modules correlated to individual gene, protein, and vocal data in Pink1 -/- and WT male and female rats. We hypothesize that male and female Pink1 -/- rats will show functional vocal deficits compared to WT (Experiment (Exp) 1) and we expect behavioral differences between male and female rats within both genotypes and between genotypes (Exp 2). We expect vocal parameters to differ between 2 and 8 months of age for all groups. Further, we expect that Pink1 -/- rats will demonstrate differential expression of genes involved in neurotransmitter, receptor, and enzyme expression, homeostatic function, growth factors, synaptic plasticity and transcription factors, as well as key genes associated with PD pathology in the periaqueductal gray and nucleus ambiguus, but not the non-vocal motor red nucleus, compared to WT (Exp 3). WCGNA bioinformatics analysis will identify differentially expressed genes that can be categorized into network modules based on function in Pink1 -/- rats compared to WT (Exp 4). Finally, we expect that the individual relative mRNA expression (Exp 5) and protein concentrations (Exp 6) will correlate with the extent of vocal dysfunction. These data will provide insight into novel targets that represent a direct mechanistic link to vocal deficits in PD. This translational research combines techniques and theory from behavioral, molecular, and physiological sciences and will provide in-depth knowledge of biomarkers related to PD vocalization deficits.
Parkinson disease is devastating to vocal communication and significantly impacts quality of life. Treatment is ineffective because the underlying neural mechanisms for these deficits are unknown. This research uses translational rat model of Parkinson disease to study genetic and protein targets and pathways associated with deficits in vocal communication. This information is crucial for identifying biomarkers for improved patient treatment plans.
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