Evidence for early and progressive ultrasonic vocalization and oromotor deficits in a PINK1 gene knockout rat model of Parkinson's disease

Abstract

Parkinson disease (PD) is a progressive neurodegenerative disease that leads to a wide range of motor and non-motor deficits. Specifically, voice and swallow deficits manifest early, are devastating to quality of life, and are difficult to treat with standard medical therapies. The pathological hallmarks of PD include accumulation of the presynaptic protein alpha-synuclein as well as degeneration of substantia nigra dopaminergic neurons. However, there is no clear understanding of how or when this pathology contributes to voice and swallow dysfunction in PD. In the present study, we evaluated the effect of loss of function of the PTEN-induced putative kinase 1 gene in rats (PINK1 −/−), a model of autosomal recessive PD in humans, on vocalization, oromotor and limb function, and neurodegenerative pathologies. Behavioral measures included ultrasonic vocalizations, tongue force, biting, and gross motor performance that were assayed at 2, 4, 6, and 8 months of age. Aggregated alpha-synuclein and tyrosine hydroxylase immunoreactivity were measured at 8 months. We show that compared to wildtype controls PINK1 −/− rats develop (1) early and progressive vocalization and oromotor deficits; (2) reduced tyrosine hydroxylase immunoreactivity in the locus coeruleus that correlates with vocal loudness and tongue force; and (3) alpha-synuclein neuropathology in brain regions important for cranial sensorimotor control. This novel approach of characterizing a PINK1 −/− genetic model of PD provides the foundational work necessary to define behavioral biomarkers for the development of disease-modifying therapeutics for PD patients.

Vocalization development in common marmosets for neurodegenerative translational modeling

“…Changes in vocalizations in animal models of PD have been demonstrated in several model species. Common findings in rodents with parkinsonism induced by neurotoxin or transgenesis are reduced number of calls, reduced intensity of calls, and reduced call-complexity [24, 41, 42], most of which are improved with behavioral therapy (vocal exercise) [25, 43] but not with levodopa [44]. Studies in common marmosets with neurotoxin-induced parkinsonism have only reported a reduced number of vocalizations, without performing any further acoustic analyses [45, 46, 47, 48, 49].…”

“…These voice and speech deficits are mostly refractory to standard of care medical treatment (levodopa) [20] or surgical treatment (deep brain stimulation) [21, 22]. Although voice and speech changes are not commonly reported by patients with PD until the later stages of the disease [23], there is recent evidence of preclinical communication changes, both in humans [3] and in animal models [24, 25]. Study of vocal changes early in neurodegenerative diseases can result in greater understanding of disease pathology, progression, and identification of behavioral biomarkers, that could improve diagnosis and treatment.…”

Automated acoustic analysis of 50-kHz ultrasonic vocalizations using template matching and contour analysis

“…Ultrasonic Vocalizations (USVs) are a useful tool for inferring affective states in the rat and have been incorporated in research paradigms modeling important human conditions such as drug abuse, [1][2][3] depression, fear, and anxiety disorders, 4 Parkinson disease, 5 and aging. 6 Moreover, USVs are a useful tool for examining the neurobiological substrates of reward.…”

“…For example, in models of Parkinson disease and neurodegeneration, it has been shown that dopamine depleting lesions and aging produce changes in the acoustic features of USVs, such as decreases in amplitude and reductions in fundamental frequency bandwidth. 5,[10][11][12] Notably, these changes affect the acoustic qualities of vocalizations rather than the quantity of observed USVs. Moreover, it has been convincingly shown that repeated training of USVs improves the vocal deficits induced by dopamine depleting lesions.…”

Decreased approach behavior and nucleus accumbens immediate early gene expression in response to Parkinsonian ultrasonic vocalizations in rats

“…Several pharmacological (dopamine receptor antagonists), neurotoxin (6-hydroxydopamine) and genetic rodent models (overexpression of human wild-type alpha synuclein under the Thy-1 promotor in the mouse and with AAV2/5 in the rat) of PD demonstrate degradation in acoustic features of USVs (Ciucci et al, 2009; Ciucci et al, 2007; Gombash et al, 2013; Grant et al, 2014; Ringel, Basken, Grant, & Ciucci, 2013; Wright, Dobosiewicz, & Clarke, 2013). Specifically, recent evidence from our laboratory indicates that in rats, the complete knockout (KO) of PTEN-induced putative kinase 1 ( PINK1 ), a gene associated with autosomal recessive, early onset PD in human populations (Bonifati et al, 2005; Kawajiri, Saiki, Sato, & Hattori, 2011; Tan et al, 2006; Valente et al, 2004), results in early and progressive reductions of USV bandwidth, peak frequency, and intensity as compared to wild-type (WT) controls (Grant, Pultorak, Kelm-Nelson, & Ciucci, 2013). The impact of these PINK1 KO deficits in USV production on social communication is unknown.…”