ABSTRACT/PROJECT SUMMARY Vocal deficits are highly prevalent and debilitating in Parkinson disease (PD). These deficits, like many others mediated by the vagus nerve (swallowing, gastrointestinal (GI) function) appear prior to diagnosis, negatively impact quality of life, and do not respond to current treatments that target dopamine modulation/motor signs. The pathologic mechanisms underlying vocal deficits are poorly understood, especially in females. To address these gaps in knowledge I will use a translational genetic model of PD, rats with a homozygous knockout of Pink1 (Pink1-/-). PINK1 is implicated in early-onset autosomal recessive PD (PARK6), where mutations cause mitochondrial dysfunction and early-stage clinical signs identical to sporadic PD. Loss of PINK1 results in phosphorylation/aggregation of α-synuclein (α-syn) throughout the nervous system and I expect this occurs in lower vagal brainstem regions during the prodrome. My preliminary data revealed vagal dysfunction in swallowing and GI dysfunction, analogous to human PD, demonstrating feasibility and translational relevance of this model. However, pathology and its relationship with vocal/other vagal dysfunction in the prodromal stage, especially in females, is unknown. The central hypotheses of this work are (1) vocal behaviors/those controlled by the vagus nerve decline during the prodromal stage of PD compared to age-matched controls, (2) vocal/other vagal brainstem regions are susceptible to early-stage α-syn pathology, (3) there are sex-based differences in brain and behavior manifestation. Based on the scientific premises that caudal brainstem regions show α-syn pathology prior to rostral regions and nigrostriatal dopamine depletion, and that manifestation of PD is influenced by sex, I propose to use male and female WT and Pink1-/- rats to study behavioral and pathologic changes in vagal and non-vagal systems in the prodrome (4 mo). Aim 1 will evaluate differences in vocal, other vagal (swallowing, GI), and non-vagal (limb motor) behaviors based on genetic (Pink1) and sex conditions. I hypothesize measures of vocal/vagally mediated behaviors will be decreased in (a) Pink1-/- rats compared to WTs and (b) Pink1-/- male rats compared to females. Aim 2 will assess pathologic α-syn in vagal (nucleus ambiguus, nucleus tractus solitarius, dorsal motor nucleus of vagus) and non-vagal (substantia nigra) brainstem nuclei. I hypothesize that pathologic α-syn in vagal nuclei will be increased in (a) Pink1-/- rats compared to WTs and (b) Pink1-/- male rats compared to females. Aim 3 will identify relationship patterns between vocal/other vagal behavior and pathological abnormalities in the lower brainstem. I hypothesize that in Pink1-/- rats, pathologic α-syn in vagal nuclei will be inversely correlated with measures of voice, swallow, and GI physiology. This work is innovative in revealing how vocal (dys)function (behaviorally and in CNS) compares to that of vagal and non-vagal, and si...