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Stroke frequently results in communication impairments that negatively impact quality of life and overall recovery, yet the biological mechanisms underlying these changes are not well understood. Ultrasonic vocalizations (USVs) in rodent models of disease and aging have been used to improve our understanding of the biological mechanisms that underlie vocal deficits and their response to interventions. Changes in USVs after middle cerebral artery occlusion (MCAO) in mice have been reported, yet rat models have significant anatomical and behavioral advantages over mice, including the ability to vocally train rats with an established paradigm. We sought to determine whether a unilateral MCAO rat stroke model provides a biologically and behaviorally relevant way to study post stroke vocalization deficits. We hypothesized that left MCAO would be associated with changes in USVs. Six weeks after MCAO or sham-control surgery, USVs were recorded in rats using an established mating paradigm. Stroke was associated with differences in USV acoustics including more frequent use of simple calls characterized by shorter durations and restricted bandwidths. These parameters were also found to correlate with post stroke lingual weakness. This is the first study to describe changes to rat USVs using a stroke model. These results suggest the unilateral MCAO rat stroke model is a biologically and behaviorally relevant model to understand how stroke affects vocal behaviors.

Vocal communication impairment and anxiety are co-occurring and interacting signs of Parkinson Disease (PD) that are common, poorly understood, and under-treated. Both vocal communication and anxiety are influenced by the noradrenergic system. In light of this shared neural substrate and considering that noradrenergic dysfunction is a defining characteristic of PD, tandem investigation of vocal impairment and anxiety in PD relative to noradrenergic mechanisms is likely to yield insights into the underlying disease-specific causes of these impairments. In order to address this gap in knowledge, we assessed vocal impairment and anxiety behavior relative to brainstem noradrenergic markers in a genetic rat model of early-onset PD (Pink1-/-) and wild type controls (WT). We hypothesized that 1) brainstem noradrenergic markers would be disrupted in Pink1-/-, and 2) brainstem noradrenergic markers would be associated with vocal acoustic changes and anxiety level. Rats underwent testing of ultrasonic vocalization and anxiety (elevated plus maze) at 4, 8, and 12 months of age. At 12 months, brainstem norepinephrine markers were quantified with immunohistochemistry. Results demonstrated that vocal impairment and anxiety were increased in Pink1-/- rats, and increased anxiety was associated with greater vocal deficit in this model of PD. Further, brainstem noradrenergic markers including TH and α1 adrenoreceptor immunoreactivity in the locus coeruleus, and β1 adrenoreceptor immunoreactivity in vagal nuclei differed by genotype, and were associated with vocalization and anxiety behavior. These findings demonstrate statistically significant relationships among vocal impairment, anxiety, and brainstem norepinephrine in the Pink1-/- rat model of PD.

Voice and swallowing deficits can occur with aging. Tongue exercise paired with a swallow may be used to treat swallowing disorders, but may also benefit vocal function due to cross-system activation effects. It is unknown how exercise-based neuroplasticity contributes to behavior and maintenance following treatment. Eighty rats were used to examine behavioral parameters and changes in neurotrophins after tongue exercise paired with a swallow. Tongue forces and ultrasonic vocalizations were recorded before and after training/detraining in young and old rats. Tissue was analyzed for neurotrophin content. Results showed tongue exercise paired with a swallow was associated with increased tongue forces at all ages. Gains diminished after detraining in old rats. Age-related changes in vocalizations, neurotrophin 4 (NT4), and brain derived neurotrophic factor (BDNF) were found. Minimal cross-system activation effects were observed. Neuroplastic benefits were demonstrated with exercise in old rats through behavioral improvements and up-regulation of BDNF in the hypoglossal nucleus. Tongue exercise paired with a swallow should be developed, studied, and optimized in human clinical research to treat swallowing and voice disorders in elderly people.

Parkinson disease (PD) is devastating to sensorimotor function that includes cranial/oromotor and limb motor deficits. However, the onset, progression, and neural correlates of PD-related dysfunctions are poorly understood. To address this gap, we used a genetic rat model of PD, DJ1 -/-, and hypothesized that motor deficits would manifest early in the disease process, be progressive in nature, and be related to pathologies in brainstem structures associated with sensorimotor function. The present study compares homozygous DJ1 -/- male rats to age-matched wild type controls. Progressive cranial sensorimotor function (ultrasonic vocalizations and tongue motor performance) and limb motor function (tapered balance beam) was analyzed at 2, 4, 6, and 8 months of age. Additionally, tyrosine hydroxylase cell counts were performed in the locus coeruleus and correlated to behavioral measures. We found that compared to wild type controls, DJ1 -/- show deficits in ultrasonic vocalizations as well as oromotor (tongue) deficits that were progressive. Overtime, DJ1 -/- rats cross a tapered balance beam with significantly decreased speed of traversal. Additionally, in the DJ1 -/-, tyrosine hydroxylase positive cells in the locus coeruleus are significantly reduced and are negatively correlated to oromotor behaviors. Characterizing the DJ1 -/- model of PD provides important foundational work necessary to define behavioral and early-onset biomarkers that parallels early-stage PD pathology in humans.

Voice disorders manifest in the early stages of Parkinson disease (PD), suggesting the vulnerability of the laryngeal sensorimotor system to mild alterations in dopamine signaling. Previous research has demonstrated that manipulations of central dopamine result in acoustic changes in rat ultrasonic vocalization (USV) and selective manipulation of receptor subtypes results in dose dependent changes in call rate and complexity. However, no study has specifically focused on the influence of dopamine receptor subtypes on acoustic features of USV production. This study examined the influence of D1 and D2 receptor subtypes on voluntary laryngeal sensorimotor control (USV) and gross whole-body involvement. Rat USV acoustics and catalepsy descent time were analyzed following the administration of selective D1 and D2 receptor antagonists in isolation and in combination, and a vehicle control. Results support the hypothesis that degradations of the acoustic signal would be most severe following combined receptor antagonism (D1 + D2) compared with D1 or D2 receptor antagonism alone, and the vehicle (saline) condition. In addition, results indicate that selective D1 receptor antagonism alters acoustic parameters to a greater extent than D2 receptor antagonism. Thus, dopamine receptor subtypes appear to influence acoustic parameters to different degrees. Catalepsy descent time was longest following combined dopamine receptor antagonism but was also significantly increased with selective D1 or D2 antagonism. Together, these results support the potentially different contributions receptor subtypes play in cranial and limb sensorimotor control.

In Parkinson's disease both limb and cranial sensorimotor functions are impaired, leading to a profound diminished quality of life for many patients. Toxin and genetic animal models of Parkinson's disease are likely essential for understanding the pathology associated with these impairments as well as for the development and testing of potential therapeutics. Here we describe useful novel and established behavioral outcome measures for assessing limb and cranial sensorimotor functions in toxin and genetic models of parkinsonism in rats and mice.

The sensorimotor speech/voice deficits associated with Parkinson disease have been well documented in humans. They are largely resistant to pharmacological and surgical treatment, but respond to intensive speech therapy. The mechanisms underlying this phenomenon are not well understood and are difficult to systematically test in humans. Thus, we turn to the rat as a model. The purpose of this study is to compare the ultrasonic vocalization (USV) of rats in three conditions: control, haloperidol-induced transient dopamine depletion, and unilateral 6-hydroxydopamine (6-OHDA) induced moderately-severe degeneration of dopamine neurons. It was hypothesized that both dopamine-altered conditions would lead to a change in the features of the USV acoustic signal. Results demonstrated that bandwidth decreased in the dopamine-altered rats. This is the first study to document a degradation of the acoustic signal of frequency-modulated 50-kHz calls as a result of interfering with dopamine synaptic transmission in rats. The data suggest that mild transient dopamine depletion with haloperidol or even unilateral degeneration of dopamine neurons is associated with changes in the USV acoustic signal. Dopaminergic dysfunction influences USV quality without reducing the number of calls. This study provides a foundation to examine the role of dopamine in sensorimotor processes underlying USV production and potentially to explore treatments for dopamine deficiency-related impaired vocal outcome.

Unilateral lesions to the medial forebrain bundle with 6-hydroxydopamine (6- OHDA) lead to force and timing deficits during a complex licking task. We hypothesized that training targeting tongue force generation during licking would improve timing and force measures and also lead to striatal dopamine sparing. Nine month-old male Fisher344/Brown Norway rats were used in this experiment. Sixteen rats were in the control condition and received tongue exercise (n=8) or no exercise (n=8). Fourteen rats were in the 6-OHDA lesion condition and underwent tongue exercise (n=7) and or no exercise (n=7). Following 4 weeks of training and post-training measures, all animals underwent bilateral stimulation of the hypoglossal nerves to measure muscle contractile properties and were then transcardially perfused and brain tissues collected for immunohistochemistry to examine striatal dopamine content. Results demonstrated that exercise animals performed better for maximal force, average force, and press rate than their no-exercise counterparts, and the 6-OHDA animals that underwent exercise performed as well as the control no exercise group. Interestingly, there were no group differences for tetanic muscle force, despite behavioral recovery of forces. Additionally, behavioral and neurochemical analyses indicate that there were no differences in striatal dopamine. Thus, targeted exercise can improve tongue force and timing deficits related to 6-OHDA lesions and this exercise likely has a central, versus peripheral (muscle strength) mechanism. However, this mechanism is not related to sparing of striatal dopamine content.

Deficits in tongue function in conjunction with airway compromise can contribute to dysphagia associated with Parkinson disease (PD). However, it is unknown if these deficits are related to the primary disease pathology in PD, nigrostriatal dopamine depletion. To directly study the impact of striatal dopamine depletion on tongue function, we used unilateral infusion of the neurotoxin 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle and measured tongue force and timing parameters during a complex tongue protrusion task for a water reward. Maximal and average forces were significantly diminished and average press time was significantly longer after neurotoxin administration, reflecting aspects of bradykinesia and hypokinesia associated with PD. Our findings suggest that even unilateral deficits to the nigrostriatal dopamine system may be contributing to some of the lingual sensorimotor deficits seen in PD. Because previous research in rat models of PD has shown that targeted training of the limb can rescue behavioral deficits and spare striatal dopamine neurons, early intervention for cranial sensorimotor deficits may also be indicated.