Papers by francois windels
Neurochemical Modifications Induced By High Frequency Stimulation of the Subthalamic Nucleus in Rats
Springer eBooks, 2002
The subthalamic nucleus (STN) which contains glutamatergic neurons (Smith and Parent, 1988) has c... more The subthalamic nucleus (STN) which contains glutamatergic neurons (Smith and Parent, 1988) has come under focus in Parkinson’s disease (PD) from recent advances in the understanding of the functional organization of the basal ganglia in normal and pathological conditions. Based on this organization, normal movements would depend on an equilibrium between the activity of two output pathways from the neostriatum:
European Journal of Neuroscience, Jan 31, 2003
Cholinergic interneurons innervate virtually all medium spiny striatal cells, but the relevance o... more Cholinergic interneurons innervate virtually all medium spiny striatal cells, but the relevance of this input in regulating the activity and afferent responsiveness of these cells remains unclear. Studies in anaesthetized animals and slice preparations have shown that iontophoretic acetylcholine (ACh) either weakly excites or inhibits striatal neurons. These differential responses may reflect cholinergic receptor heterogeneity but may be also related to the different activity states of recorded units and different afferent inputs specific in each preparation. Single-unit recording was combined with iontophoresis in awake, unrestrained rats to examine the effects of ACh and selective muscarinic (oxotremorine M or Oxo-M) and nicotinic agonists (nicotine or NIC) on dorsal and ventral striatal neurons. These effects were tested on naturally silent, spontaneously active and glutamate-stimulated units. We found that iontophoretic ACh primarily inhibited spontaneously active and glutamate-stimulated units; the direction of the ACh response, however, was dependent on the firing rate. The effects of ACh were generally mimicked by Oxo-M and, surprisingly, by NIC, which is known to excite units in most central structures, including striatal neurons in anaesthetized preparation. Given that NIC receptors are absent on striatal cells but located primarily on dopamine terminals, we assessed the effects of NIC after complete blockade of dopamine receptors induced by systemic administration of a mixture of D1 and D2 antagonists. During dopamine receptor blockade the number of NIC-induced inhibitions dramatically decreased and NIC had mainly excitatory effects on striatal neurons. Thus, our data suggest that under physiologically relevant conditions ACh acts as a state-dependent neuromodulator, and its action involves not only postsynaptic but also presynaptic cholinoreceptors located on dopamine-and glutamate-containing terminals.
Oscillations in the Basolateral Amygdala: Aversive Stimulation Is State Dependent and Resets the Oscillatory Phase
Journal of Neurophysiology, Sep 1, 2009
Nature Communications, Jun 8, 2021
Polyunsaturated free fatty acids (FFAs) such as arachidonic acid, released by phospholipase activ... more Polyunsaturated free fatty acids (FFAs) such as arachidonic acid, released by phospholipase activity on membrane phospholipids, have long been considered beneficial for learning and memory and are known modulators of neurotransmission and synaptic plasticity. However, the precise nature of other FFA and phospholipid changes in specific areas of the brain during learning is unknown. Here, using a targeted lipidomics approach to characterise FFAs and phospholipids across the rat brain, we demonstrated that the highest concentrations of these analytes were found in areas of the brain classically involved in fear learning and memory, such as the amygdala. Auditory fear conditioning led to an increase in saturated (particularly myristic and palmitic acids) and to a lesser extent unsaturated FFAs (predominantly arachidonic acid) in the amygdala and prefrontal cortex. Both fear conditioning and changes in FFA required activation of NMDA receptors. These results suggest a role for saturated FFAs in memory acquisition.
Pallidal Origin of GABA Release within the Substantia Nigra Pars Reticulata during High-Frequency Stimulation of the Subthalamic Nucleus
The Journal of Neuroscience, May 18, 2005
Kluwer Academic Publishers eBooks, Jun 26, 2006
Clinical Neurophysiology, Dec 1, 2017
Highlights 1. Description of neuronal activity in medial-anterior Globus pallidus internus (GPia)... more Highlights 1. Description of neuronal activity in medial-anterior Globus pallidus internus (GPia) of Tourette's patients. 2. Populations of neurons with specific firing patterns can be identified in GPi sub-territories. 3. First characterization of GPia local field potentials in Tourette's patients.
Brain Research, May 1, 2006
Although it is evident that general anesthesia should affect impulse activity and neurochemical r... more Although it is evident that general anesthesia should affect impulse activity and neurochemical responses of central neurons, there are limited studies in which these parameters were compared in both awake and anesthetized animal preparations. We used single-unit recording coupled with iontophoresis to examine impulse activity and responses of substantia nigra pars reticulata (SNr) neurons to GABA, glutamate (GLU), and dopamine (DA) in rats in awake, unrestrained conditions and during chloral hydrate anesthesia. SNr neurons in both conditions had similar organization of impulse flow, but during anesthesia, they have lower mean rates and discharge variability than in awake conditions. In individual units, discharge rate in awake, quietly resting rats was almost threefold more variable than during anesthesia. These cells in both conditions were highly sensitive to iontophoretic GABA, but the response was stronger during anesthesia. In contrast to virtually no responses to GLU in awake conditions, most SNr neurons during anesthesia were excited by GLU; the response occurred preferentially in slow-firing units, which were atypical of awake conditions. Consistent with no postsynaptic DA receptors on SNr neurons, iontophoretic DA was ineffective in altering discharge rates in awake conditions, but often induced weak excitations during anesthesia. Although SNr neurons are autoactive, generating discharges without any excitatory input (i.e., in vitro), their impulse activity and responses to natural neurochemical inputs are strongly affected by general anesthesia. Some alterations appear to be specific to the general anesthetic used, while others probably reflect changes in the activity of afferent inputs, brain metabolism and neurotransmitter uptake that are typical to any type of general anesthesia. Therefore, an awake, freely moving animal preparation appears to be advantageous for studying impulse activity and neurochemical interactions at single-neuron level during physiologically relevant conditions.
Neuroscience, 2006
Substantia nigra reticulata is the major output structure of the basal ganglia involved in somato... more Substantia nigra reticulata is the major output structure of the basal ganglia involved in somatosensory integration and organization of movement. While previous work in vitro and in anesthetized animal preparations suggests that these neurons are autoactive and points to GABA as a primary input regulating their activity, single-unit recording coupled with iontophoresis was used in awake, unrestrained rats to further clarify the role of tonic and phasic GABA input in maintenance and fluctuations of substantia nigra reticulata neuronal activity under physiologically relevant conditions. In contrast to glutamate, which was virtually ineffective at stimulating substantia nigra reticulata neurons in awake rats, all substantia nigra reticulata neurons tested were inhibited by iontophoretic GABA and strongly excited by bicuculline, a GABA-A receptor blocker. The GABA-induced inhibition had short onset and offset latencies, a fading response pattern (a rapid decrease in rate followed by its relative restoration), and was independent of basal discharge rate. The bicuculline-induced excitation was inversely related to discharge rate and current (dose)-dependent in individual units. However, the average discharge rate during bicuculline applications at different currents increased to a similar plateau (ϳ60 impulses/s), which was about twice the mean basal rates. The excitatory effects of bicuculline were phasically inhibited or completely blocked by brief GABA applications and generally mimicked by gabazine, another selective GABA antagonist. These data as well as neuronal inhibitions induced by nipecotic acid, a selective GABA uptake inhibitor, suggest that substantia nigra reticulata neurons in awake, quietly resting conditions are under tonic, GABA-mediated inhibition. Therefore, because of inherent autoactivity and specifics of afferent inputs, substantia nigra reticulata neurons are very sensitive to phasic alterations in GABA input, which appears to be the primary factor determining fluctuations in their activity states under physiological conditions. While these cells are relatively insensitive to direct activation by glutamate, and resistant to a continuous increase in GABA input, they appear to be very sensitive to a diminished GABA input, which may release them from tonic inhibition and determine their functional hyperactivity.
European Journal of Neuroscience, Sep 1, 2006
Dopamine (DA) neurons located in the substantia nigra pars compacta release DA not only via axona... more Dopamine (DA) neurons located in the substantia nigra pars compacta release DA not only via axonal terminals, affecting neurotransmission within the striatum, but also via dendrites, some of which densely protrude into the substantia nigra pars reticulata (SNr). Although the interaction of dendritically released DA with somatodendritic autoreceptors regulates DA cell activity, released DA may also affect SNr neurons. These cells, however, lack postsynaptic DA receptors, making it unclear how locally released DA modulates their activity. Although previous work in brain slices suggests that DA might modulate the activity of GABA inputs, thus affecting SNr neurons indirectly, it remains unclear how increased or decreased DA release might affect these cells exposed to normal afferent inputs. To explore this issue, we examined the effects of iontophoretic DA and amphetamine on SNr neurons in awake, unrestrained rats. DA had no consistent effects on SNr cells but amphetamine, known to induce DA release, dosedependently inhibited most of them. This effect was blocked by SCH23390, a selective D1 receptor blocker, which itself strongly increased neuronal discharge rate. As GABA input is a major factor regulating the activity of SNr neurons, our data suggest that dendritically released DA, by interacting with D1 receptors on striato-nigral and pallido-nigral afferents, is able to decrease this input, thus releasing SNr neurons from tonic, GABA-mediated inhibition. Surprisingly, a full DA receptor blockade (SCH23390 + eticlopride) did not result in the expected increase in SNr discharge rate, suggesting that other mechanisms are responsible for behavioral abnormalities following acute disruption of DA transmission.
Journal of Neuroscience Research, Apr 15, 2003
High-frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treat... more High-frequency stimulation (HFS) of the subthalamic nucleus (STN) proves to be an efficient treatment for alleviating motor symptoms in Parkinson's disease (PD). However, the mechanisms of HFS underlying these clinical effects remain unknown. Using intracerebral microdialysis, we previously reported that HFS induces, in normal rats, a significant increase of extracellular glutamate (Glu) in the globus pallidus (GP in rats or GPe in primates) and the substantia nigra pars reticulata (SNr), whereas ␥-aminobutyric acid (GABA) was increased only in the SNr. Bradykinesia can be improved by STN stimulation in a frequency-dependent manner, a plateau being reached around 130 Hz. The aim of the present study was to determine whether neurochemical changes are also frequency dependent. Electrical STN stimulation was applied at various frequencies (10, 60, 130, and 350 Hz) in normal rats. The results show that, for Glu, the amplitude of increase detected in GP and SNr is maximal at 130 Hz and is maintained at 350 Hz. No modifications of GABA were observed in GP whatever the frequency applied, whereas, in SNr, GABA increased from 60 to 350 Hz. Our results provide new neurochemical data implicating STN target structures in deep-brainstimulation mechanisms.
Neuroreport, Jul 17, 2006
It is hypothesized that substantia nigra pars reticulata neurons become overactive during a de¢ci... more It is hypothesized that substantia nigra pars reticulata neurons become overactive during a de¢cit of dopamine transmission. In this study, we examined how acute dopamine receptor blockade (SCH23390 and eticlopride) a¡ects impulse activity of substantia nigra pars reticulata neurons and their response to iontophoretic g-amino-n-butyric acid in awake, unrestrained rats. No changes in discharge rate were found during complete dopamine receptor blockade, but these neurons showed a diminished response to g-amino-n-butyric acid, suggesting g-amino-n-butyric acid receptor hyposensitivity. This may result from tonic increase in g-amino-n-butyric acid input from the striatum and globus pallidus, which are activated during dopamine receptor blockade. As substantia nigra pars reticulata neurons are autoactive and resistant to tonic increases in g-amino-n-butyric acid input, changes in their responsiveness to phasic g-amino-n-butyric acid inputs, not tonic increase discharge rate, may underlie movement disturbance following dopamine de¢cit.
Advanced Functional Materials, Dec 23, 2019
Organic photodetectors (OPDs) are promising candidates for next-generation light sensors as they ... more Organic photodetectors (OPDs) are promising candidates for next-generation light sensors as they combine unique material properties with high-level performance in converting photons into current. However, low-level light detection is often limited by device dark current. Here, we show that the This article is protected by copyright. All rights reserved. 2 open-circuit voltage (V oc) regime of OPDs is efficient for detecting low light signals (<100 µW cm-2). We show that the light-dependence of V oc exhibits two distinct regimes as function of irradiance: linear and logarithmic. Whereas the observed logarithmic regime is well understood in organic photovoltaic cells (OPVs), we show experimentally and theoretically that the linear regime is due to the non-infinite shunt resistance of the device. Overall, OPDs composed of rubrene and fullerene show photovoltage light sensitivity across 9 orders of magnitude with a detection limit as low as 400 pW cm-2. A photovoltage responsivity of 1.75 V m 2 W-1 demonstrates the highly efficient performance without the necessity to correct high dark current. This approach opens up new possibilities for resolving low light signals and provides simplified design rules for OPDs.
GABA, Not Glutamate, Controls the Activity of Substantia Nigra Reticulata Neurons in Awake, Unrestrained Rats
The Journal of Neuroscience, Jul 28, 2004
medRxiv (Cold Spring Harbor Laboratory), Oct 27, 2020
Deep brain stimulation (DBS) is a promising treatment for severe, treatment-resistant obsessive-c... more Deep brain stimulation (DBS) is a promising treatment for severe, treatment-resistant obsessive-compulsive disorder (OCD). Here, nine participants (four females, mean age 47.9 ±10.7 years) were implanted with DBS electrodes bilaterally in the bed nucleus of the stria terminalis (BNST). Following a one-month postoperative recovery phase, participants entered a three-month randomised, double-blind, sham-controlled phase before a twelvemonth period of open-label stimulation incorporating a course of cognitive behavioural therapy (CBT). The primary outcome measure was OCD symptoms as rated with the Yale-Brown Obsessive-Compulsive Scale (YBOCS). In the blinded phase, there was a significant benefit of active stimulation over sham (p = 0.025, mean difference 4.9 points). After the open phase, the mean reduction in YBOCS was 16.6 ±1.9 points (߯ 2 (11) = 39.8, = 3.8 x 10 -5 ), with seven participants classified as responders. CBT resulted in an additive YBOCS reduction of 4.8 ±3.9 points (p = 0.011). There were two serious adverse events related to the DBS device, the most severe of which was an infection during the open phase necessitating device explantation. There were no psychiatric adverse events related to stimulation. An analysis of the structural connectivity of each participant's individualised stimulation field isolated right-hemispheric fibres associated with YBOCS reduction. These included subcortical tracts incorporating the amygdala, hippocampus and stria terminalis, in addition to cortical regions in the ventrolateral and ventromedial prefrontal cortex, parahippocampal, parietal and extrastriate visual cortex. In conclusion, this study provides further evidence supporting the efficacy and tolerability of DBS for individuals with otherwise treatmentrefractory OCD and identifies a connectivity fingerprint associated with clinical benefit.
Journal of Neuropathology and Experimental Neurology, Dec 1, 2003
High frequency stimulation (HFS) (130 Hz) of the subthalamic nucleus (STN) provides beneficial ef... more High frequency stimulation (HFS) (130 Hz) of the subthalamic nucleus (STN) provides beneficial effects in patients suffering from severe parkinsonism, but the mechanisms underlying these clinical results remain to be clarified. To date, very little is known concerning the effects of STN-HFS on neurochemical transmission in the different basal ganglia nuclei and in particular the striatum. This study examines the effects of STN-HFS in intact and hemiparkinsonian rats on extracellular striatal glutamate (Glu) and GABA levels by means of intracerebral microdialysis. Unilateral STN-HFS was found to induce a significant bilateral increase of striatal Glu and GABA both in intact and in dopamine-lesioned animals. In intact rats, these increases were reversed by local administration of the D1 antagonist SCH 23390, but were potentiated by the D2 antagonist sulpiride. Potentiation was also observed after local administration of both D1 and D2 antagonists whose amplitude was similar to that measured in hemiparkinsonian rats. These data furnish the first evidence that STN-HFS influences striatal amino-acid transmission and that this influence is modulated by dopamine. They provide evidence that the effects of STN-HFS are not only restricted to the direct STN targets, but also involve adaptive changes within other structures of the basal ganglia circuitry.
Journal of Neuropathology and Experimental Neurology, 2001
The subthalamic nucleus (STN) has come under focus in Parkinson disease (PD) because of recent ad... more The subthalamic nucleus (STN) has come under focus in Parkinson disease (PD) because of recent advances in the understanding of the functional organization of the basal ganglia in normal and pathological conditions. Manipulations of the STN have been described to compensate for some imbalance in motor output of the basal ganglia in animal models of PD and have been proposed as a potential therapeutic target in humans. Indeed, high frequency stimulation (HFS) (130 Hz) of the STN has beneficial effects in severe parkinsonian patients but the precise mechanisms underlying these clinical results remain to be elucidated. To date, very little is known concerning the effect of HFS-STN on striatal dopaminergic transmission. Since it has been reported that dopaminergic medication may be reduced in PD patients under HFS-STN, our goal was to study the effect of HFS-STN on striatal dopamine (DA) transmission by using intracerebral microdialysis in normal and partially DA denervated rats. Our results show that HFS-STN induces a significant increase of extracellular DA in the striatum of normal and partially DA lesioned rats while striatal extracellular levels of DOPAC were not affected. We conclude that HFS-STN acts directly and/or indirectly on striatal DA levels in control or partially DA lesioned rats.
Étude par microdialyse des variations de glutamate et de GABA dans la substance noire et le globus pallidus induites par la stimulation électrique du noyau subthalamique chez le rat
GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (7510621... more GRENOBLE1-BU Médecine pharm. (385162101) / SudocPARIS-BIUM (751062103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF
Rat auditory fear conditioning quantified free fatty acid and phospholipid abundance data
UQ eSpace, 2021
This data represents the free fatty acid (FFA) and phospholipid (PL) response to auditory fear co... more This data represents the free fatty acid (FFA) and phospholipid (PL) response to auditory fear conditioning (AFC) across the rat brain in the presence or absence of a memory blocking agent. Four experimental conditions were used, each applied to a cohort of 8 rat: saline injected (control) animals, unpaired AFC stimuli (SU); saline injected animals, paired stimuli (SP); CPP (NMDA antagonist) injected animals, unpaired AFC stimuli (CU); CPP injected animals, paired AFC stimuli (CP). Tissue was collected from 6 brain regions CeA – central amygdala, BLA – basolateral amygdala, PFC – prefrontal coretex, DH – dorsal hippocampus, VH – ventral hippocampus, CB – cerebellum Lipidomics analysis using targeted LCMSMS was performed for FFA – free fatty acid, PA – phosphatidic acid, PC- phosphatidylcholine, PE – phosphatidylcholine, PG – phosphatidylglycerol, PS – phosphatidylserine Data contains the quantified abundance for each targeted lipid species for each of the 4 AFC conditions, 8 animals, 6 brain regions
Journal of Medical Case Reports, 2022
Background The globus pallidus internus is the main target for the treatment of dystonia by deep ... more Background The globus pallidus internus is the main target for the treatment of dystonia by deep brain stimulation. Unfortunately, for some genetic etiologies, the therapeutic outcome of dystonia is less predictable. In particular, therapeutic outcomes for deep brain stimulation in craniocervical and orolaryngeal dystonia in DYT6-positive patients are poor. Little is known about the neurophysiology of the globus pallidus internus in DYT6-positive dystonia, and how symptomatic treatment affects the neural activity of this region. Case presentation We present here the case of a 55-year-old Caucasian female DYT6-dystonic patient with blepharospasm, spasmodic dysphonia, and oromandibular dystonia where single-unit and local field potential activity was recorded from the globus pallidus internus during two deep brain stimulation revision surgeries 4 years apart with no symptomatic improvement. Botulinum toxin injections consistently improved dysphonia, while some of the other symptoms we...
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Papers by francois windels