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 a-synuclein (a-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 a-syn pathology, (3) there are sex-based
differences in brain and behavior manifestation. Based on the scientific premises that caudal brainstem regions
show a-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 a-syn in vagal
(nucleus ambiguus, nucleus tractus solitarius, dorsal motor nucleus of vagus) and non-vagal (substantia nigra)
brainstem nuclei. I hypothesize that pathologic a-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 a-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 significant as I will address clinically relevant gaps in knowledge
in the prodrome, impossible to do in humans, to guide identification and treatment of voice. This work is central
to the fellowship training to prepare the PI for a tenured faculty position with an independent line of research.