Subthalamic nucleus lesions induce deficits as well as benefits in the hemiparkinsonian rat

Abstract

Lesions of the subthalamic nucleus can restore some imbalances in motor output of the basal ganglia induced by nigrostriatal dopamine depletion, and have been proposed as a potential therapy for Parkinson's disease. Although there is substantial supporting evidence from experimental studies in both rats and primates, there is less information on the effects of subthalamic lesions alone. In order to characterize potential side effects, the present study evaluates the behavioural effects of unilateral excitotoxic lesions of the subthalamic nucleus in rats that have previously received either unilateral saline or 6-hydroxydopamine injections into the nigrostriatal bundle on the same side. The 6-hydroxydopamine lesions induced ipsilateral orientation asymmetries in head position and body axis bias, rotational asymmetries following injections of direct or indirect dopamine agonists, neglect of contralateral stimuli, and a reduction in the numbers of pellets retrieved with the contralateral paw in a skilled reaching task. Subsequent excitotoxic lesions of the subthalamic nucleus reduced (but did not abolish) rotational asymmetries, had no effects on the measures of neglect and skilled paw-reaching, and produced contralateral orientation biases in head turning and body axis curling. Rats that received subthalamic lesions alone exhibited de novo impairments comprising contralateral biases in the orientation tests. These results support a neuromodulatory role of the subthalamic nucleus in regulating motor outputs of the basal ganglia, and caution that there may be distinct side effects of the lesion by itself. Whereas some impairments attributable to dopamine depletion may be alleviated by subthalamic manipulations, other symptoms are not, or may even be aggravated.

Enhanced Food-Related Motivation after Bilateral Lesions of the Subthalamic Nucleus

“…Lesions or high-frequency stimulation of STN in PD patients (Limousin et al, 1995) and in animal models of PD (Bergman et al, 1990, Benazzouz et al, 1993Baunez et al, 1995;Henderson et al, 1999) indeed improve motor symptoms. However, inactivation of the STN in these conditions can also impair additional aspects of behavior (Baunez et al, 1995;Henderson et al, 1999;Trépanier et al, 2000;Krack et al, 2001). Because the STN is a key structure involved in the classical parallel loops linking the basal ganglia to various cortical areas (Alexander et al, 1986) with motor, associative, and limbic components, the STN might influence a wide range of behavioral functions.…”

Lesion of the subthalamic nucleus reverses motor deficits but not death of nigrostriatal dopaminergic neurons in a rat 6-hydroxydopamine-lesion model of Parkinson's disease

“…However, we found no improvement of hypokinesia in the open-field test. STN lesion has been shown to improve some, but not all, parkinsonian signs (14). Despite the lack of total recovery of motor function, STN lesion blocked the progression of motor impairment from the first to the second behavioral test in 6-OHDA-treated animals.…”

“…In experimental models of PD induced by parkinsonian neurotoxins such as 6-hydroxydopamine (6-OHDA) or 1-methyl-2-phenyl-1,2,3,6-tetrahydropyridine (MPTP), inhibition of STN function by ablation (12)(13)(14)(15), HFS (16,17) or pharmacological antagonism (18,19) has been reported to ameliorate some of the parkinsonian motor deficits and even to protect nigrostriatal dopaminergic neurons against the injury induced by these neurotoxins. On the other hand, some investigators were unable to find any neuroprotective effects of STN inactivation on SNpc neuron survival (20)(21)(22).…”

Parkinsonian Motor Deficits Are Reflected by Proportional A9/A10 Dopamine Neuron Degeneration in the Rat

“…In this test, modified from Henderson et al (20), the rat's head position relative to the body was measured at 4 weeks postlesion (Fig. 1).…”

“…More recently, ipsilateral orientation asymmetries have been described on the basis of head-turning data in the unilaterally mfblesioned rat (20). Previously designed to determine the effect of subthalamic nucleus lesion in primate models of PD, the head-turning test aims to determine subtle changes in the rat's sensorimotor behavior, spontaneous side bias, and overall activity levels (4,5,20,21). In this data set, spontaneous head turning showed that as A9 DA lesion increases so does side bias.…”