In a rat model of parkinsonism, lesions of the subthalamic nucleus reverse increases of reaction time but induce a dramatic premature responding deficit

Abstract

Lesions of the subthalamic nucleus (STN) have been found to reduce the severe akinetic motor symptom produced in animal models of Parkinson's disease, such as in monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or in monoamine-depleted rats. However, little is known about the effect of STN exclusion on subtle motor deficits induced by moderate dopaminergic lesions in complex motor tasks. The present study was thus performed on rats trained in a reaction time (RT) task known to be extremely sensitive to variations of dopamine transmission in the striatum. Animals were trained to release a lever after the onset of a visual stimulus within a time limit to obtain a food reward. Discrete dopamine depletion produced by infusing the neurotoxin 6-hydroxydopamine (6-OHDA) bilaterally into the dorsal part of the striatum, produced motor initiation deficits which were revealed by an increase in the number of delayed responses (lever release after the time limit) and a lengthening of RTs. In contrast, bilateral excitotoxic lesion of the STN with ibotenic acid induced severe behavioral deficits which were opposite to those produced by the dopaminergic lesion, as shown by an increase in the number of premature responses (lever release before the onset of the visual stimulus) and a decrease of RTs. Surprisingly, the performance of the animals bearing a double lesion (striatal dopaminergic lesion followed 14 d later by STN ibotenic lesion) was still impaired 40 d after the ibotenic lesion. As expected, the 6-OHDA-induced motor initiation deficits were reversed by a subsequent STN lesion. However, the dramatic increase of premature responses contributing to major behavioral deficits induced by the STN lesion remained unchanged. Thus, the bilateral lesion of the STN was found to alleviate the motor deficits in this model of parkinsonism, but essentially produced over time, long lasting deficits that might be related to dyskinesia or cognitive impairment. The present results strongly support the recent concept of a predominant control of the STN on basal ganglia output structures.

Effect of Bilateral 6-Hydroxydopamine Lesions of the Medial Forebrain Bundle on Reaction Time

“…Indeed, the deficit during the last two weeks of testing was characterized by a non-significant (Baunez et al 1995a(Baunez et al , 1995bDöbrössy and Dunnett 1997).…”

Deep Brain Stimulation for Movement Disorders of Basal Ganglia Origin: Restoring Function or Functionality?

“…While much sparser than the indirect pathway, the hyperdirect projection has received increasing attention. By circumventing the striatum, it may provide a mechanism for cortical inputs to influence GPi and SNr output with shorter latencies and thereby assist in situations that require rapid Bstop^responses to external and internal triggers [17,19,[28][29][30][31][32][33][34][35][36][37][38][39][40][41].…”

Deep brain stimulation in Parkinson disease—what went wrong?

“…In the 6-hydroxy-dopamine rat model of PD, lesion of the STN improved akinesia but induced impulsive behaviour [37], suggesting that STN manipulation could induce cognitive side effects. This finding led to studies investigating the role of STN in cognitive functions in the rat [38,39] in parallel with clinical studies assessing cognitive and nonmotor functions in PD patients subjected to STN DBS [22,[40][41][42][43].…”