Acute and separate modulation of motor and cognitive performance in parkinsonian rats by bilateral stimulation of the subthalamic nucleus

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Abstract

The subthalamic nucleus (STN) is involved in motor and cognitive performance through its key role in the basal ganglia–thalamocortical circuits, but how these different modalities (motor and cognition) are controlled (similar vs. dissimilar) has not yet been elucidated. In the present study, the effects of bilateral STN deep brain stimulation (DBS) on motor and cognitive performance were investigated in a rat model of Parkinson disease (PD). After being trained in a choice reaction time (CRT) task, rats received bilateral injections of 6-hydroxydopamine (6-OHDA) into the striatum. One group of 6-OHDA animals was implanted bilaterally with stimulation electrodes at the level of the STN. Stimulations were performed at 130 Hz (frequency), 60 μs (pulse width), and varying amplitudes of 1, 3, 30, and 150 μA during the CRT task. Finally, rats were sacrificed and the brains processed for staining to determine the dopaminergic lesion (TH immunohistochemistry) and localization of the electrode tip (HE histochemistry). Bilateral 6-OHDA infusion significantly decreased (70%) the number of dopaminergic cells in the substantia nigra pars compacta (SNc) and increased motor time (MT), proportion of premature responding (PR), and reaction time (RT). Bilateral STN stimulation with an amplitude of 3 μA normalized 6-OHDA-induced deficits in PR and RT. Simulation with an amplitude of 30 μA reversed the lesion-induced deficits in MT and RT. Our data show for the first time that bilateral STN stimulation differentially affected the 6-OHDA-induced motor and cognitive deficits. This means that basal ganglia–thalamocortical motor and associative circuits responsible for specific motor and cognitive performance, which are processed through the STN, have unique physiological properties that can acutely and separately be modulated by specific electrical stimuli.

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.

References (62)

  • W.M. Grill et al.

    Extracellular excitation of central neurons: implications for the mechanism of deep brain stimulation

    Thalamus Relat. Syst.

    (2001)
  • X. Liu et al.

    The oscillatory activity in the Parkinsonian subthalamic nucleus investigated using the macro-electrodes for deep brain stimulation

    Clin. Neurophysiol.

    (2002)
  • A.M. Lozano et al.

    Deep brain stimulation for Parkinson's disease: disrupting the disruption

    Lancet Neurol.

    (2002)
  • A. Moser et al.

    Deep brain stimulation: response to neuronal high frequency stimulation is mediated through GABA(A) receptor activation in rats

    Neurosci. Lett.

    (2003)
  • A. Parent et al.

    Functional anatomy of the basal ganglia: I. The cortico-basal ganglia–thalamo-cortical loop

    Brain Res. Brain Res. Rev.

    (1995)
  • A. Parent et al.

    Functional anatomy of the basal ganglia: II. The place of subthalamic nucleus and external pallidum in basal ganglia circuitry

    Brain Res. Brain Res. Rev.

    (1995)
  • J.B. Ranck

    Which elements are excited in electrical stimulation of mammalian central nervous system: a review

    Brain Res.

    (1975)
  • C. Schmitz et al.

    Recommendations for straightforward and rigorous methods of counting neurons based on a computer simulation approach

    J. Chem. Neuroanat.

    (2000)
  • C. Schmitz et al.

    Design-based stereology in neuroscience

    Neuroscience

    (2005)
  • A.D. Smith et al.

    Effect of bilateral 6-hydroxydopamine lesions of the medial forebrain bundle on reaction time

    Neuropsychopharmacology

    (2002)
  • E.J. Tehovnik

    Electrical stimulation of neural tissue to evoke behavioral responses

    J. Neurosci. Methods

    (1996)
  • Y. Temel et al.

    Monopolar versus bipolar high frequency stimulation in the rat subthalamic nucleus: differences in histological damage

    Neurosci. Lett.

    (2004)
  • J.S. Vles et al.

    Localization and age-related changes of nitric oxide- and ANP-mediated cyclic-GMP synthesis in rat cervical spinal cord: an immunocytochemical study

    Brain Res.

    (2000)
  • G.E. Alexander et al.

    Basal ganglia–thalamocortical circuits: parallel substrates for motor, oculomotor, “prefrontal” and “limbic” functions

  • M. Amalric et al.

    Complex deficits on reaction time performance following bilateral intrastriatal 6-OHDA infusion in the rat

    Eur. J. Neurosci.

    (1995)
  • C. Baunez et al.

    Bilateral lesions of the subthalamic nucleus induce multiple deficits in an attentional task in rats

    Eur. J. Neurosci.

    (1997)
  • C. Baunez et al.

    Effects of transient inactivation of the subthalamic nucleus by local muscimol and APV infusions on performance on the five-choice serial reaction time task in rats

    Psychopharmacology (Berlin)

    (1999)
  • C. Baunez et al.

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

    J. Neurosci.

    (1995)
  • C. Baunez et al.

    Effects of STN lesions on simple vs choice reaction time tasks in the rat: preserved motor readiness, but impaired response selection

    Eur. J. Neurosci.

    (2001)
  • B.P. Bejjani et al.

    Transient acute depression induced by high-frequency deep-brain stimulation

    N. Engl. J. Med.

    (1999)
  • A. Benazzouz et al.

    High frequency stimulation of the STN influences the activity of dopamine neurons in the rat

    NeuroReport

    (2000)
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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.

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