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

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PROJECT SUMMARY/ABSTRACT Greater than 90% of individuals with Parkinson disease (PD) experience significant vocal communication deficits that appear early in the manifestation of the disease, negatively impact quality of life, and are refractory to current therapeutic approaches. PD pathology occurs in both the central and peripheral nervous systems and differs according to sex, but how this affects vocal communication is unknown and presents a critical gap in knowledge, limiting current patient treatments. This research will elucidate how vocal dysfunction manifests at a biological and functional level. The long-term goal and primary objective of this work is to understand, prevent, and/or reverse vocal communication deficits in individuals with PD. To accomplish this, a validated rat model of PD, Pink1-/-, will be used. Male and female Pink1-/- rats show early, progressive vocal deficits with brainstem and laryngeal pathology that recapitulate the communication deficits observed in human PD. Based on preliminary data, this research will address the hypothesis that the neuroanatomical biochemistry of vocalization pathways in Pink1-/- rats is significantly different compared to wildtype control rats (Specific Aim 1). The rationale for this study is the need for basic, mechanistic information on sex-specific vocal pathways and respective connections that will be key targets to improve and/or modulate vocal behavior over time. By applying retrograde tracers into the vocal fold, the peripheral (larynx) to central (brainstem) connections will be assessed in Pink1-/- and control rats. Using 3D modeling, differences in the distribution and density of neurons within central nervous system vocalization pathways will be quantified. Because current treatments for PD voice deficits are insufficient, the second goal of this proposal is to address the hypothesis that currently approved therapeutics will be identified and validated for the treatment and modulation of PD vocal communication deficits (Specific Aim 2). The rationale for this work is the need for drugs that effectively modulate vocal production for future human PD clinical trials. Using gene targets from Pink1-/- larynx and brainstem datasets, a list of biologically relevant drugs will be generated using drug-repurposing catalogs. The application of selected drugs to in vitro Pink1-/- larynx as well as brainstem cell cultures will generate significant alterations in the gene transcript as quantified with single cell RNA-sequencing. To confirm efficacy, these therapeutics will be administered to Pink1-/- rats to measure in vivo vocalization improvements. The simultaneous administration of new drugs to both biological (cellular) and functional (animal) platforms provides distinct yet integrated information that is unable to be obtained from the human patient population. This approach is innovative because it incorporates new techniques and theory from molecular, physiological, and communication sciences and will provide in-depth knowledge of sex-specific PD vocalization deficits. This proposal is significant because it targets a voice research platform that addresses a clinically relevant, undertreated question and will directly impact the treatment of PD voice dysfunction.