Analysis of gait in rats with olivocerebellar lesions and ability of the nicotinic acetylcholine receptor agonist varenicline to attenuate impairments

Abstract

Studies have demonstrated that administration of the neuronal nicotinic receptor agonist varenicline to rats with olivocerebellar lesions attenuates balance deficits on a rotorod and balance beam, but the effects of this drug on gait deficits have not been investigated. To accomplish this, male Sprague-Dawley rats were trained to walk on a motorized treadmill at 25 and 35 cm/s and baseline performance determined; both temporal and spatial gait parameters were analyzed. A principal component analysis (PCA) was used to identify the key components of gait, and the cumulative gait index (CGI) was calculated, representing deviations from prototypical gait patterns. Subsequently, animals either remained as non-lesioned controls or received injections of 3-acetylpyridine (3-AP)/nicotinamide to destroy the climbing fibers innervating Purkinje cells. The gait of the non-lesioned group was assessed weekly to monitor changes in the normal population, while the gait of the lesioned group was assessed 1 week following 3-AP administration, and weekly following the daily administration of saline or varenicline (0.3, 1.0, or 3.0 mg free base/kg) for 2 weeks. Non-lesioned animals exhibited a 60–70% increased CGI over time due to increases in temporal gait measures, whereas lesioned animals exhibited a nearly 3-fold increased CGI as a consequence of increases in spatial measures. Following 2 weeks of treatment with the highest dose of varenicline (3.0 mg free base/kg), the swing duration of lesioned animals normalized, and stride duration, stride length and step angle in this population did not differ from the non-lesioned population. Thus, varenicline enabled animals to compensate for their impairments and rectify the timing of the gait cycle.

Deletion of the vesicular acetylcholine transporter from pedunculopontine/laterodorsal tegmental neurons modifies gait

“…; Lambert et al . ). Further studies will be necessary to investigate the exact cholinergic circuits important for the gait disturbance in VAChT En1‐cre‐flox/flox mice.…”

3-Acetylpyridine neurotoxicity in mice

“…A noteworthy difference between gait measurements in rats and mice following administration of 3-AP is that rats exhibit a 12% decrease in swing duration (Lambert et al, 2014; Lambert et al, 2015) while mice exhibit a 15% increase in swing duration. Control rats and mice both exhibit increased swing over time, likely reflecting the increased stride length that occurs with experience on the treadmill.…”

“…An individual blinded to the group assignment of each animal, isolated and analyzed video clips for each animal containing an uninterrupted sequence of 12-14 strides. Based on findings from studies with rats (Lambert et al, 2014; Lambert et al, 2015), 4 primary spatial factors and their associated variability (stride length, stance width, paw angle, paw area at peak stance), and 3 primary temporal factors (propulsion, braking and swing time durations), as well as the maximal rate of change of paw area in contact with the treadmill during the braking phase were determined using DigiGait™ Imaging software (version 12.2) as described (Lambert et al, 2014). Parameters were determined for both hindpaws and forepaws.…”