Acute and separate modulation of motor and cognitive performance in parkinsonian rats by bilateral stimulation of the subthalamic nucleus☆
Introduction
Basal ganglia–thalamocortical circuits, covering the motor, associative, oculomotor and limbic circuits, are classically considered to be organized in a parallel manner and remain largely segregated from one another (Alexander et al., 1990). Each pathway is thought to be related to specific regions of the basal ganglia but also shares certain key structures (Alexander et al., 1990, Parent and Hazrati, 1995a, Parent and Hazrati, 1995b). One of these structures is the subthalamic nucleus (STN), a disk-shaped nucleus located between the cerebral peduncle ventrally and zona incerta (ZI) dorsally in the upper midbrain (Parent and Hazrati, 1995b). The STN is currently regarded as the “pacemaker” of the basal ganglia (Plenz and Kital, 1999). Under normal conditions, it exhibits a typical single spike activity whereas under pathological conditions such as Parkinson disease (PD) STN neurons switch to burst activity (Beurrier et al., 1999, Beurrier et al., 2002). This abnormal “bursting” mode of action has been implicated in driving the overactivity of the basal ganglia output nuclei consisting of the globus pallidus internus (GPi) and substantia nigra pars reticulata (SNr), and consequently, excessive inhibition of their targets (thalamic and cortical areas) which is thought to cause the typical PD symptoms (Bevan et al., 2002, Liu et al., 2002).
For this reason, treating STN hyperactivity by deep brain stimulation (DBS) is nowadays a widely applied procedure in PD. It is in fact considered to be the treatment of choice because of its long-lasting beneficial effects on motor function (Kleiner-Fisman et al., 2003, Krack et al., 2003, Lopiano et al., 2001, Vingerhoets et al., 2002, Visser-Vandewalle et al., 2004, Volkmann et al., 2001). However, STN DBS has also given rise to undesirable behavioral side-effects such as cognitive impairment (Saint-Cyr et al., 2000). This suggests that the STN not only regulates basal ganglia motor performance, but might also influence basal ganglia associative circuits (Desbonnet et al., 2004). Indeed, it has been shown that the STN also consists of an associative territory (Rodriguez-Oroz et al., 2001) and that lesions and pharmacological blockage of the STN can induce attentional impairments (Baunez and Robbins, 1997, Baunez and Robbins, 1999, Baunez et al., 1995, Baunez et al., 2001, Rodriguez-Oroz et al., 2001). Nevertheless, how these different modalities (motor and cognition) are regulated by the STN has still not been elucidated. One possibility is that these modalities are regulated similarly based on the existence of parallel basal ganglia–thalamocortical circuits. Alternatively, it is hypothesized here that STN DBS affects these circuits separately, dependent of the physiological characteristics of these pathways.
In the present study, to test the hypothesis that the motor and associative circuits have unique electrical properties and can be modulated separately by specific stimuli, we investigated the effects of bilateral STN stimulation on motor and cognitive performance in rats with partial 6-OHDA lesions in a choice reaction time (CRT) task. In this task, several parameters can be measured simultaneously, i.e., the speed of information processing, response inhibition, and motor function (Blokland, 1998). The first two parameters are considered as cognitive parameters, whereas the last parameter is considered to be a measure of motor function (Blokland and Honig, 1999, Blokland et al., 2001a, Blokland et al., 2001b, Desbonnet et al., 2004). In a previous study, in which the use of a bilateral DBS device in freely moving control rats was validated, we have shown that the effects of bilateral STN DBS on cognitive performance depend on the amplitude of the DBS (Desbonnet et al., 2004). We therefore also manipulated the stimulation amplitude in the present study to evaluate the effects of bilateral STN DBS on motor and cognitive performance of partially 6-OHDA lesioned rats in the CRT task.
Section snippets
Subjects and study design
All subjects were Lewis male rats (n = 30, 12 weeks old, bred and housed at the Central Animal Facility of Maastricht University, Maastricht, The Netherlands), with an average body weight of 300 g. Animals were housed individually in standard Makrolon™ cages on sawdust bedding in an air-conditioned room (about 20°C) under a 12/12-h reversed light/dark cycle (lights on from 18:00 to 6:00 h). All animals had free access to food and water. The rats were tested 5 days per week. During this time,
Histological evaluation of the electrode tip
Histological evaluation of brain sections, using HE-staining, confirmed that the bilateral electrodes were implanted in the subthalamic region. In all rats, bilateral electrodes were placed symmetrically (interelectrode variation of <0.1 mm) and the electrode tips were both situated within the STN, with the exception of one rat. In this rat, both electrodes were at the level of the zona incerta (ZI). There was an intrasubthalamic variation in electrode positions. In three rats, both electrodes
Discussion
In the present study, we have demonstrated that bilateral intrastriatal 6-OHDA infusion significantly decreased the number of THir cells in the SNc of rats. The total number of THir cells counted in the SNc (on average approximately 12 000) and the reduction in the number of these cells in the SNc (70%) due to bilateral 6-OHDA treatment are in accordance with previously published data (Carvalho and Nikkhah, 2001). Furthermore, our results showed that bilateral striatal 6-OHDA treatment
Acknowledgments
The authors are grateful to Hellen Steinbusch and Hatice Ozen for their technical assistance and Prof. Dr. Emile Beuls for his support.
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Grant information: This study was funded by the Dutch Medical Research Council (ZonMw), grant no: 940-37-027 and the Dutch Brain Foundation (Hersenstichting) grants 10F02.13, 10F03.19 and 10F04.17.