Chapter 12 - Effects of GPi and STN inactivation on physiological, motor, cognitive and motivational processes in animal models of Parkinson’s disease

https://doi.org/10.1016/S0079-6123(10)83012-2Get rights and content

Abstract

Loss of the dopaminergic input to the striatum, characterizing Parkinson’s disease, leads to the hyper-activity of two key nuclei of the basal ganglia (BG): the subthalamic nucleus (STN) and the internal segment of the globus pallidus (GPi). The anatomo-physiological organization of the BG and their output suggested that interfering with such hyper-activity could restore motor function and improve parkinsonism. Several animal models in rodents and primates, as well as clinical studies and neurosurgical treatments, have confirmed such hypothesis. This chapter will review the physiological and behavioural data obtained by inactivating the GPi or the STN by means of lesions, pharmacological approaches and deep brain stimulation. The consequences of these treatments will be examined at levels ranging from cellular to complex behavioural changes. Some of this experimental evidence suggested new and effective clinical treatments for PD, which are now routinely used worldwide. However, further studies are necessary to better understand the consequences of GPi and STN manipulation especially at the cognitive level in order to improve functional neurosurgical treatments for Parkinson’s disease by minimizing risks of side-effects.

Introduction

The basal ganglia (BG) are a group of interconnected deep brain structures receiving massive glutamatergic inputs from the cortex and the thalamus, mainly via the striatum (caudate/putamen nuclei) and in a lesser extent via the subthalamic nucleus (STN). BG are mainly implicated in motor behaviour and learning, as well as in cognitive and motivational processes. In 1989, Albin et al. synthesized the data available regarding the anatomo-physiological organization of the BG and proposed a model functioning via two segregated pathways going from the striatum to the output BG nuclei, that is, the direct and indirect pathways. The output BG nuclei include the internal segment of the globus pallidus (GPi), or entopeduncular nucleus (EP) in rodents, and the substantia nigra pars reticulata (SNr). GPi/EP and SNr are GABAergic structures innervating mainly the motor thalamic nuclei and receiving inputs from the striatum via two major pathways, one directly from the striatum (the direct pathway) and the other (the indirect pathway) via the external globus pallidus (GPe, or GP in rodents) and the STN. This organization has been described for five parallel loops originating from various cortical areas and innervating different sectors of each structure, defining functional segregated loops: the motor, oculomotor, dorsolateral prefrontal, lateral orbitofrontal and limbic loops (Alexander et al., 1986). DeLong (1990) further improved this model of the motor loop by introducing the dysfunctions associated with the loss of substantia nigra pars compacta (SNc) neurons producing dopamine (DA), and the ensuing striatal DA depletion characterizing Parkinson’s disease (PD). This model, illustrated in Fig. 1 suggested that both the STN and the GPi are hyper-active in PD, leading to akinetic-like symptoms (DeLong, 1990). It became then obvious that an interesting alternative strategy to DArgic treatments for PD could be to reduce this hyper-activity at the level of either the STN or the GPi. This chapter will thus review the physiological and behavioural data obtained using this strategy, using various means of inactivation, that is lesions, pharmacological inactivation or deep brain stimulation (DBS) at high-frequency stimulation (HFS). This latter technique, first applied in the STN of PD patients by the group of Benabid in Grenoble, France (Limousin et al., 1995), is currently used worldwide with great success. However, there are still remaining questions regarding its mechanism of action (Gubellini et al., 2009).

During the last 50 years, several different animal models of PD have been developed to better understand the pathophysiological mechanisms of this neurodegenerative disorder. Acute models were the first to be introduced by using monoamine depleting agents, such as reserpine (that blocks the vesicular monoamine transporter), and later by using DA receptor antagonists, such as haloperidol. Nowadays, the two most common and relevant PD models are based on toxins that impair oxidative phosphorylation by inhibiting the complex I of the mitochondria, leading to DAergic neuron loss: 6-hydroxydopamine (6-OHDA), which is injected into the SNc or the striatum of rodents and selectively kills DAergic neurons (after blocking the noradrenaline transporter), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is injected systemically in non-human primates and certain mice strains and is transformed into the toxic product 1-methyl-4-phenylpyridinium that is introduced into DAergic neurons by the DA transporter (Gubellini et al., 2010).

Section snippets

GPi manipulation in PD

Neurons of the EP recorded in vitro show a spontaneous action potential discharge activity at frequencies of 4–10 Hz at membrane potentials around –50 mV (Nakanishi et al., 1990, Shin et al., 2007). In primate PD models (MPTP lesion), the discharge activity of GPi neurons changes towards a more irregular pattern characterized by bursts of action potentials, which is consistent with findings in PD patients (Hutchison et al., 1994). There is no consensus about the change in their mean firing rate,

STN manipulation in PD

The STN belongs to the indirect pathway of the BG, as well as to the so-called hyper-direct pathway from the cortex to the BG output structure through the STN itself. STN is a glutamatergic structure innervating mainly the GPi/EP and the SNr, but also the GPe, the ventral pallidum, the pedunculopontine nucleus, and to a lesser extent the striatum and nucleus accumbens, and also the DAergic nuclei (ventral tegmental area and SNc). The major inputs to the STN arise from various cortical areas

General conclusion

In conclusion, this review of the literature leads to the following comments:

At the cellular level, electrical stimulation of the GPi and the STN has a profound effect on the firing activity of their neurons. Rather than a mere inhibition of action potential discharge, HFS time-locks the activity of STN neurons at frequencies correlated to those of HFS. On the other hand, GPi stimulation seems also to exert an overall inhibitory effect. At neurophysiological level, it is now clear that the

Acknowledgements

This work has been supported by grants from the Centre National de la Recherche Scientifique (CNRS) to CB and PG, the Université de la Méditerranée to PG, the Université de Provence to CB, the Agence Nationale pour la Recherche (ANR-05-JC05_48262 and ANR-09-MNPS-028-01 to CB and the ANR-05-NEUR-021 to PG), the Fondation de France to PG, the MILDT-InCa-INSERM grant to CB and the Fondation pour la Recherche sur le Cerveau to CB.

References (168)

  • L. Desbonnet et al.

    Premature responding following bilateral stimulation of the rat subthalamic nucleus is amplitude and frequency dependent

    Brain Research

    (2004)
  • X. Drouot et al.

    Functional recovery in a primate model of Parkinson’s disease following motor cortex stimulation

    Neuron

    (2004)
  • D.M. Eagle et al.

    Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition

    Neuroscience and Biobehavioral Reviews

    (2010)
  • N. El Massioui et al.

    Learning and memory dissociation in rats with lesions to the subthalamic nucleus or to the dorsal striatum

    Neuroscience

    (2007)
  • A. Eusebio et al.

    Oscillatory activity in the basal ganglia

    Parkinsonism & Related Disorders

    (2007)
  • P. Gubellini et al.

    Downstream mechanisms triggered by mitochondrial dysfunction in the basal ganglia: From experimental models to neurodegenerative diseases

    Biochimica et Biophysica Acta

    (2010)
  • P. Gubellini et al.

    Deep brain stimulation in neurological diseases and experimental models: From molecule to complex behavior

    Progress in Neurobiology

    (2009)
  • P.J. Hahn et al.

    Pallidal burst activity during therapeutic deep brain stimulation

    Experimental Neurology

    (2008)
  • D. Harnack et al.

    Placebo-controlled chronic high-frequency stimulation of the subthalamic nucleus preserves dopaminergic nigral neurons in a rat model of progressive parkinsonism

    Experimental Neurology

    (2008)
  • O.K. Hassani et al.

    Increased subthalamic neuronal activity after nigral dopaminergic lesion independent of disinhibition via the globus pallidus

    Neuroscience

    (1996)
  • J.R. Hollerman et al.

    Subthalamic nucleus cell firing in the 6-OHDA-treated rat: Basal activity and response to haloperidol

    Brain Research

    (1992)
  • C.R. Honey et al.

    Circling behaviour in 6-hydroxydopamine-lesioned rats given pulsed levodopa is reduced more by lesions in the entopeduncular nucleus/substantia nigra pars reticulata than in the subthalamic nucleus

    Neuroscience Letters

    (1998)
  • E. Kafetzopoulos et al.

    Turning behavior after unilateral lesion of the subthalamic nucleus in the rat

    Behavioural Brain Research

    (1983)
  • J.P. Lefaucheur et al.

    Improvement of motor performance and modulation of cortical excitability by repetitive transcranial magnetic stimulation of the motor cortex in Parkinson’s disease

    Clinical Neurophysiology

    (2004)
  • R. Levy et al.

    Re-evaluation of the functional anatomy of the basal ganglia in normal and parkinsonian states

    Neuroscience

    (1997)
  • G.E. Alexander et al.

    Parallel organization of functionally segregated circuits linking basal ganglia and cortex

    Annual Review of Neuroscience

    (1986)
  • A. Alkhani et al.

    Pallidotomy for Parkinson disease: A review of contemporary literature

    Journal of Neurosurgery

    (2001)
  • M.E. Anderson et al.

    Effects of high-frequency stimulation in the internal globus pallidus on the activity of thalamic neurons in the awake monkey

    Journal of Neurophysiology

    (2003)
  • T.Z. Aziz et al.

    Lesion of the subthalamic nucleus for the alleviation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in the primate

    Movement Disorders

    (1991)
  • J.J. Bacci et al.

    Differential effects of prolonged high frequency stimulation and of excitotoxic lesion of the subthalamic nucleus on dopamine denervation-induced cellular defects in the rat striatum and globus pallidus

    European Journal of Neuroscience

    (2004)
  • K.B. Baker et al.

    Subthalamic nucleus deep brain stimulus evoked potentials: Physiological and therapeutic implications

    Movement Disorders

    (2002)
  • I. Bar-Gad et al.

    Complex locking rather than complete cessation of neuronal activity in the globus pallidus of a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primate in response to pallidal microstimulation

    Journal of Neuroscience

    (2004)
  • M.S. Baron et al.

    Effects of transient focal inactivation of the basal ganglia in parkinsonian primates

    Journal of Neuroscience

    (2002)
  • C. Baunez et al.

    Evidence for functional differences between entopeduncular nucleus and substantia nigra: Effects of APV (DL-2-amino-5-phosphonovaleric acid) microinfusion on reaction time performance in the rat

    European Journal of Neuroscience

    (1996)
  • C. Baunez et al.

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

    European Journal of Neuroscience

    (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 (Berl)

    (1999)
  • C. Baunez et al.

    Enhanced food-related motivation after bilateral lesions of the subthalamic nucleus

    Journal of Neuroscience

    (2002)
  • C. Baunez et al.

    Bilateral high-frequency stimulation of the subthalamic nucleus on attentional performance: Transient deleterious effects and enhanced motivation in both intact and parkinsonian rats

    European Journal of Neuroscience

    (2007)
  • C. Baunez et al.

    The subthalamic nucleus exerts opposite control on cocaine and ‘natural’ rewards

    Nature Neuroscience

    (2005)
  • 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

    European Journal of Neuroscience

    (2001)
  • 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

    Journal of Neuroscience

    (1995)
  • A. Benazzouz et al.

    Alleviation of experimental hemiparkinsonism by high-frequency stimulation of the subthalamic nucleus in primates: A comparison with l-dopa treatment

    Movement Disorders

    (1996)
  • A. Benazzouz et al.

    Reversal of rigidity and improvement in motor performance by subthalamic high-frequency stimulation in MPTP-treated monkeys

    European Journal of Neuroscience

    (1993)
  • A. Benazzouz et al.

    High-frequency stimulation of both zona incerta and subthalamic nucleus induces a similar normalization of basal ganglia metabolic activity in experimental parkinsonism

    The FASEB Journal

    (2004)
  • H. Bergman et al.

    Physiology of MPTP tremor

    Movement Disorders

    (1998)
  • H. Bergman et al.

    Reversal of experimental parkinsonism by lesions of the subthalamic nucleus

    Science

    (1990)
  • H. Bergman et al.

    The primate subthalamic nucleus. II. Neuronal activity in the MPTP model of parkinsonism

    Journal of Neurophysiology

    (1994)
  • C. Beurrier et al.

    Subthalamic stimulation elicits hemiballismus in normal monkey

    NeuroReport

    (1997)
  • C. Beurrier et al.

    High-frequency stimulation produces a transient blockade of voltage-gated currents in subthalamic neurons

    Journal of Neurophysiology

    (2001)
  • C. Beurrier et al.

    Slowly inactivating sodium current (I(NaP)) underlies single-spike activity in rat subthalamic neurons

    Journal of Neurophysiology

    (2000)
  • Cited by (22)

    • Human subthalamic nucleus – Automatic auditory change detection as a basis for action selection

      2017, Neuroscience
      Citation Excerpt :

      The human subthalamic nucleus (STN) fulfills an important role in the shaping of motor behavior (Baunez and Gubellini, 2010).

    • The modulatory role of subthalamic nucleus in cognitive functions - A viewpoint

      2015, Clinical Neurophysiology
      Citation Excerpt :

      In line with observations made in humans, the encoding of cognitive (Baunez and Lardeux, 2011), behavioural (Teagarden and Rebec, 2007), and reward-based (Lardeux et al., 2009) tasks in STN was found in rats. Animal models brought relevant data on non-motor effects of STN manipulation well before it was shown in humans (reviewed by Baunez and Gubellini 2010). Study by Baunez in 1995 for the first time revealed possible side effects that might be related to the involvement of STN in non-motor behaviour.

    • Mapping brain regions in which deep brain stimulation affects schizophrenia-like behavior in two rat models of schizophrenia

      2013, Brain Stimulation
      Citation Excerpt :

      So far, there have been no reports on the effects of DBS in schizophrenia though its establishment is ambitiously promoted [16,17]. Importantly, DBS is not merely a therapeutic technique as it may also serve as an experimental tool in animal studies (i.e. [18–29]). With its capacity to selectively affect neuronal function of specific brain regions it may also allow for delineating functional and neurobiological circuitries in the healthy and diseased brain (i.e. [30]).

    • Deep brain stimulation of the subthalamic nucleus increases premature responding in a rat gambling task

      2013, Behavioural Brain Research
      Citation Excerpt :

      Our results are consistent with a mechanism of DBS action which involves more than just a transient change in excitability of local tissue and extends beyond the actual stimulation period. Previous studies have found various cellular and synaptic changes following repeated DBS, such as alternations in neuronal firing, neurotransmitter release and transcription factor levels [14,23], which could account for the prolonged effects of stimulation long after the current was turned off. Future studies should address the temporal effects of STN-DBS, in order to establish how long the observed deficit in inhibitory control persists for after discontinuation of STN-DBS.

    View all citing articles on Scopus
    View full text