Behavioral and neurophysiological correlates of striatal dopamine depletion: A rodent model of Parkinson's disease

Abstract

Both limb and cranial motor functions are adversely impacted by Parkinson's disease (PD). While current pharmacological and surgical interventions are effective in alleviating general limb motor symptoms of PD, they have failed to provide significant benefit for cranial motor functions. This suggests that the neuropathologies mediating limb and cranial motor impairments in PD may differ. Animal models provide a mechanism by which the potential neural dysfunctions underlying these different motor impairments may be characterized. Central goals to our laboratory have been to (a) determine the differential responses of cranial motor and limb motor function to striatal dopamine depletion and (b) determine the differential effects of striatal dopamine depletion on the integrity of cranial motor and limb motor neural circuits. This paper details the use of a comprehensive battery of limb and cranial motor behavioral tasks and the application of intracortical microstimulation to assess corticospinal and corticobulbar circuits in a rodent model of PD. Our work suggests that striatal dopamine depletion does differentially affect cranial and limb motor function and corticospinal and corticobulbar circuits. Further, we propose that cranial motor impairments in PD may be mediated by pathology both within and outside nigrostriatal dopamine system. Learning outcomes Readers will be able to (a) describe a set of motor tests used to assess limb motor and cranial motor function in an animal model of Parkinson's disease, (b) understand the application of intracortical microstimulation to assess corticospinal and corticobulbar circuits, (c) describe the differential effects of dopamine depletion on limb motor and cranial motor function in a rodent model of PD, and (d) understand the potential role of dysfunction outside the nigrostriatal system mediating cranial motor impairments in Parkinson's disease.

Tongue force and tongue motility are differently affected by unilateral vs bilateral nigrostriatal dopamine depletion in rats

“…Our finding of decreased tongue force following 6-OHDA is consistent with previous findings using this model and similar methods [13,36,41]. It is interesting to note, however, that in preclinical studies measuring maximal force output, nigrostriatal DA depletion tends to affect tongue force production to a greater extent than forelimb force production in young adult animals [6,13,28,36].…”

“…It is interesting to note, however, that in preclinical studies measuring maximal force output, nigrostriatal DA depletion tends to affect tongue force production to a greater extent than forelimb force production in young adult animals [6,13,28,36]. We recently reported that at unilateral striatal DA depletion levels between 40–60%, rats exhibit substantial forelimb force control deficits, but not decreased force production [6].…”

“…These impairments can increase morbidity and mortality [25], primarily by disrupting the oral phase of swallowing [44]. In contrast to limb deficits (and with the exception of levodopa-induced oral dyskinesias [15]), preclinical attention to the primary effects of nigrostriatal DA depletion on orolingual motor function is a relatively recent development [13,36,41,47]. These studies have reported that unilateral nigrostriatal DA depletion impairs tongue motility and protrusion force.…”

“…Rats’ tongue force and tongue motility were measured as they licked water from an isometric disc as described previously by our lab [43,51] and others [36,41]. Orolingual motor function was measured prior to and for four weeks after treatment with 6-OHDA.…”

Relationships among rat ultrasonic vocalizations, behavioral measures of striatal dopamine loss, and striatal tyrosine hydroxylase immunoreactivity at acute and chronic time points following unilateral 6-hydroxydopamine-induced dopamine depletion

“…Severe striatal dopamine loss following 6-OHDA infusions results in more predictable and reliable deficits to the limb sensorimotor system compared to aspects of cranial (oromotor) function, such as licking and chewing,[25-27] suggesting that these two systems may have a different sensitivity to dopamine depletion. However, the relationships among behavioral measures of lesion severity in the limb, such as forelimb use and apomorphine rotations, and ultrasonic vocalizations are unknown, particularly with mild dopamine depletion.…”