Subthalamic nucleus high-frequency stimulation modulates neuronal reactivity to cocaine within the reward circuit
Introduction
The subthalamic nucleus (STN) belongs to the basal ganglia and is classically associated with motor functions. High-frequency stimulation (HFS) of the STN is the most common surgical therapy applied to Parkinsonian patients (PD) and is very effective in alleviating the motor disorders associated with this pathology: tremor, rigidity and hypokinesia (Benabid, 2003, Limousin et al., 1995). STN is also a critical component of a network controlling non-motor, associative and limbic functions involving the prefrontal cortex, nucleus accumbens and ventral pallidum (for a review, see Baunez and Lardeux, 2011). In line with these non-motor functions, STN HFS is also applied for the treatment of obsessive–compulsive disorders (OCD) (Mallet et al., 2008) and is proposed to be also useful to treat addiction. Indeed if STN HFS has not yet been tested in addicts, some clinical observations in PD after STN HFS have reported craving for sweet food in some cases, or decreased addictive behavior towards dopaminergic treatment in other cases (for a review, see Pelloux and Baunez, 2013). A recent study has also shown that STN stimulation may significantly reduce the compulsive use of dopaminergic drugs in PD patients without increasing the risk of inducing the disorder in previous non-misusers. In addition, most of the addictive behaviors improve after STN deep brain stimulation (DBS) partly as a result of the lower dosage of dopaminergic medication but also possibly through a specific effect of STN DBS in the limbic circuit of motivation and reward (Eusebio et al., 2013).
In preclinical models, we have previously shown that STN lesions or STN HFS decrease motivation for cocaine (Baunez et al., 2005, Rouaud et al., 2010). On the other hand, cocaine administration activates c-Fos expression in the STN in parallel with behavioral sensitization (Uslaner et al., 2001, Uslaner et al., 2003). The effects of STN HFS by itself at the cellular level have been assessed so far mainly on motor structures showing activation of striatal markers (like the cytochrome oxidase and GAD) as well as increased GAD or Fos activity in GP, EP and SNR (Bacci et al., 2004, Oueslati et al., 2007, Salin et al., 2002, Shehab et al., 2014, Vlamings et al., 2009). However, there are no data on the consequences of STN HFS on the neuronal reactivity (activity or plasticity) of the reward circuit.
Our hypothesis is that STN HFS alters the acute cellular effects of cocaine on the reward circuit, which could explain an inhibition of the rewarding properties of cocaine in procedures in which a very limited number of injections were taken (Rouaud et al., 2010). The objectives of the present study were thus to determine (1) the cellular consequences of bilateral STN HFS by itself on motor and limbic structures and (2) whether the cellular reactivity to acute cocaine in these brain areas was affected by STN HFS. For this, c-Fos and Arc mRNA expression were analyzed by in situ hybridization following cocaine injection associated or not with STN HFS. These two immediate early genes (IEG) have different dynamics of induction and functions in relation to synaptic activity (for reviews, see Guzowski, 2002, Lanahan and Worley, 1998) so that they can both reflect the acute response to a given stimulus or subsequent plasticity-related processes. Moreover, one advantage of using Arc as a marker of neuronal activity was the possibility to use the fluorescent method of catFISH (cellular compartmental analysis of temporal activity by Fluorescent In Situ Hybridization) that allows to discriminate cellular responses to two types of temporally separated stimuli (for a review, see Guzowski et al., 2005), in the present case STN HFS and cocaine, by dissociating cytoplasmic from nuclear labeling. Thus, to decipher both STN HFS and cocaine effect in the present study, we have combined classical in situ hybridization and catFISH. We have focused our analysis on a network of interconnected limbic structures (nucleus accumbens, amygdala nuclei, infra-limbic and pre-limbic prefrontal cortex, orbitofrontal cortex) known to be involved in rewarding and motivational processes.
Section snippets
Animals
Adult male Long–Evans rats (n = 24, Janvier Labs, Le Genest-Saint-Isle, France) were housed in pairs and maintained on a 12 hr light/dark cycle (lights on at 07:00 am). The animals had no food restriction. Water was provided ad libitum, except during experimental sessions. All procedures were conducted during the light phase and followed the regulations in accordance with the European Community’s Council Directive (EU Directive 2010⁄6⁄EU86) and our national French Agriculture and Forestry Ministry
Results
Four experimental groups (n = 6/group) were used in the present study: STN HFS OFF-Saline (Sal-OFF), STN HFS OFF-Cocaine (Coc-OFF), STN HFS ON-Saline (Sal-ON), STN HFS ON-Cocaine (Coc-ON). Before starting the in situ hybridization experiments, histological controls were performed to check for electrode’s location. Cresyl violet staining at the STN level showed that four rats were implanted outside the STN and were therefore excluded from the data analysis. The detailed location of the electrodes
Discussion
The present work shows that STN HFS applied bilaterally induces increased neuronal activity as measured by c-Fos expression in the GP and the BLA and also alters cocaine-induced activity in the striatum and nucleus accumbens in a complex manner depending of the marker analyzed, c-Fos or Arc. These two IEGs are classically used to map functionally relevant circuits in different experimental situations (for reviews, see Bramham et al., 2008, Kovacs, 2008). However, they have both different
Conclusion
The present data showed that STN HFS alone has a selective effect on c-Fos gene expression, and in a restricted number of motor or limbic regions, limited to the GP and the BLA. Interestingly, the later effect confirm the functional link between STN and BLA, highlighting the possible consequences of STN manipulation on emotional processes, in line with clinical observations of emotional changes in PD patients subjected to STN DBS.
By comparing Arc and c-Fos, we clearly show that STN HFS
Acknowledgments
The authors thank Dr Victor Ramirez-Amaya for providing the Arc probe and Gilles Courtand for his help with the confocal microscopy. This work was supported by the National Agency for Research (ANR-09-MNPS-028-01), the Fondation de France (Parkinson committee; 2011-00025111), the FRC (Fédération pour la Recherche sur le Cerveau), the CNRS, the Aix Marseille University (AMU) and the University of Bordeaux.
References (54)
Deep brain stimulation for Parkinson’s disease
Curr. Opin. Neurobiol.
(2003)Emotion and motivation: the role of the amygdala, ventral striatum, and prefrontal cortex
Neurosci. Biobehav. Rev.
(2002)Progressive recruitment of cortical and striatal regions by inducible postsynaptic density transcripts after increasing doses of antipsychotics with different receptor profiles: Insights for psychosis treatment
Eur. Neuropsychopharmacol.
(2015)Deep brain stimulation in neurological diseases and experimental models: from molecule to complex behavior
Prog. Neurobiol.
(2009)Mapping behaviorally relevant neural circuits with immediate-early gene expression
Curr. Opin. Neurobiol.
(2005)Confirmation of functional zones within the human subthalamic nucleus: patterns of connectivity and sub-parcellation using diffusion weighted imaging
NeuroImage
(2012)- et al.
Immediate-early genes and synaptic function
Neurobiol. Learn. Mem.
(1998) Reactivity and plasticity in the amygdala nuclei during opiate withdrawal conditioning: differential expression of c-fos and arc immediate early genes
Neuroscience
(2008)Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites
Neuron
(1995)- et al.
Deep brain stimulation for addiction: why the subthalamic nucleus should be favored
Curr. Opin. Neurobiol.
(2013)
Subthalamic nucleus: a key structure for emotional component synchronization in humans
Neurosci. Biobehav. Rev.
High-frequency electrical stimulation of the subthalamic nucleus excites target structures in a model using c-fos immunohistochemistry
Neuroscience
Temporal sequence of ictal discharges propagation in the corticolimbic basal ganglia system during amygdala kindled seizures in freely moving rats
Epilepsy Res.
Bilateral high frequency stimulation of the subthalamic nucleus normalizes COX activity in the substantia nigra of Parkinsonian rats
Brain Res.
Effects of morphine on immediate-early gene expression in the striatum of C57BL/6 J and DBA/2 J mice
Pharmacol. Rep.
Temporal and anatomic patterns of immediate-early gene expression in the forebrain of C57BL/6 and DBA/2 mice after morphine administration
Neuroscience
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
Eur. J. Neurosci.
Frontal cortex-like functions of the subthalamic nucleus
Front. Syst. Neurosci.
The subthalamic nucleus exerts opposite control on cocaine and ‘natural’ rewards
Nat. Neurosci.
Bilateral high-frequency stimulation of the subthalamic nucleus on attentional performance: transient deleterious effects and enhanced motivation in both intact and parkinsonian rats
Eur. J. Neurosci.
High-frequency stimulation of both zona incerta and subthalamic nucleus induces a similar normalization of basal ganglia metabolic activity in experimental parkinsonism
FASEB J.
Alterations of molecular and behavioral responses to cocaine by selective inhibition of Elk-1 phosphorylation
J. Neurosci.
Comparative dynamics of MAPK/ERK signalling components and immediate early genes in the hippocampus and amygdala following contextual fear conditioning and retrieval
Brain Struct. Funct.
The immediate early gene arc/arg3.1: regulation, mechanisms, and function
J. Neurosci.
Simulating the effects of short-term synaptic plasticity on postsynaptic dynamics in the globus pallidus
Front. Syst. Neurosci.
Isolation and characterization of the c-fos(rat) cDNA and analysis of post-translational modification in vitro
Oncogene
High frequency stimulation of the subthalamic nucleus has beneficial antiparkinsonian effects on motor functions in rats, but less efficiency in a choice reaction time task
Eur. J. Neurosci.
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The two authors equally contributed to the work.