Chapter 12 - Effects of GPi and STN inactivation on physiological, motor, cognitive and motivational processes in animal models of Parkinson’s disease
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.
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Cited by (22)
Human subthalamic nucleus – Automatic auditory change detection as a basis for action selection
2017, NeuroscienceCitation 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 NeurophysiologyCitation 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.
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2013, Brain StimulationCitation 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 ResearchCitation 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.