Activity Of Basal Ganglia Nuclei Research Articles

Therapeutic deep brain stimulation disrupts movement-related subthalamic nucleus activity in parkinsonian mice.

Subthalamic nucleus deep brain stimulation (STN DBS) relieves many motor symptoms of Parkinson's disease (PD), but its underlying therapeutic mechanisms remain unclear. Since its advent, three major theories have been proposed: (1) DBS inhibits the STN and basal ganglia output; (2) DBS antidromically activates motor cortex; and (3) DBS disrupts firing dynamics within the STN. Previously, stimulation-related electrical artifacts limited mechanistic investigations using electrophysiology. We used electrical artifact-free GCaMP fiber photometry to investigate activity in basal ganglia nuclei during STN DBS in parkinsonian mice. To test whether the observed changes in activity were sufficient to relieve motor symptoms, we then combined electrophysiological recording with targeted optical DBS protocols. Our findings suggest that STN DBS exerts its therapeutic effect through the disruption of movement-related STN activity, rather than inhibition or antidromic activation. These results provide insight into optimizing PD treatments and establish an approach for investigating DBS in other neuropsychiatric conditions.

Significance and Translational Value of High-Frequency Cortico-Basal Ganglia Oscillations in Parkinson's Disease.

The mechanisms and significance of basal ganglia oscillations is a fundamental research question engaging both clinical and basic investigators. In Parkinson’s disease (PD), neural activity in basal ganglia nuclei is characterized by oscillatory patterns that are believed to disrupt the dynamic processing of movement-related information and thus generate motor symptoms. Beta-band oscillations associated with hypokinetic states have been reviewed in several excellent previous articles. Here we focus on faster oscillatory phenomena that have been reported in association with a diverse range of motor states. We review the occurrence of different types of fast oscillations and the evidence supporting their pathophysiological role. We also provide a general discussion on the definition, possible mechanisms, and translational value of synchronized oscillations of different frequencies in cortico-basal ganglia structures. Revealing how oscillatory phenomena are caused and spread in cortico-basal ganglia-thalamocortical networks will offer a key to unlock the neural codes of both motor and non-motor symptoms in PD. In preclinical therapeutic research, recording of oscillatory neural activities holds the promise to unravel mechanisms of action of current and future treatments.

Subthalamic Nucleus Neurons Differentially Encode Early and Late Aspects of Speech Production.

Basal ganglia-thalamocortical loops mediate all motor behavior, yet little detail is known about the role of basal ganglia nuclei in speech production. Using intracranial recording during deep brain stimulation surgery in humans with Parkinson's disease, we tested the hypothesis that the firing rate of subthalamic nucleus neurons is modulated in sync with motor execution aspects of speech. Nearly half of 79 unit recordings exhibited firing-rate modulation during a syllable reading task across 12 subjects (male and female). Trial-to-trial timing of changes in subthalamic neuronal activity, relative to cue onset versus production onset, revealed that locking to cue presentation was associated more with units that decreased firing rate, whereas locking to speech onset was associated more with units that increased firing rate. These unique data indicate that subthalamic activity is dynamic during the production of speech, reflecting temporally-dependent inhibition and excitation of separate populations of subthalamic neurons.SIGNIFICANCE STATEMENT The basal ganglia are widely assumed to participate in speech production, yet no prior studies have reported detailed examination of speech-related activity in basal ganglia nuclei. Using microelectrode recordings from the subthalamic nucleus during a single-syllable reading task, in awake humans undergoing deep brain stimulation implantation surgery, we show that the firing rate of subthalamic nucleus neurons is modulated in response to motor execution aspects of speech. These results are the first to establish a role for subthalamic nucleus neurons in encoding of aspects of speech production, and they lay the groundwork for launching a modern subfield to explore basal ganglia function in human speech.

A proactive task set influences how response inhibition is implemented in the basal ganglia.

Increasing a participant's ability to prepare for response inhibition is known to result in longer Go response times and is thought to engage a "top-down fronto-striatal inhibitory task set." This premise is supported by the observation of anterior striatum activation in functional magnetic resonance imaging (fMRI) analyses that focus on uncertain versus certain Go trials. It is assumed that setting up a proactive inhibitory task set also influences how participants subsequently implement stopping. To assess this assumption, we aimed to manipulate the degree of proactive inhibition in a modified stop-signal task to see how this manipulation influences activation when reacting to the Stop cue. Specifically, we tested whether there is differential activity of basal ganglia nuclei, namely the subthalamic nucleus (STN) and anterior striatum, on Stop trials when stop-signal probability was relatively low (20%) or high (40%). Successful stopping was associated with increased STN activity when Stop trials were infrequent and increased caudate head activation when Stop trials were more likely, suggesting a different implementation of reactive response inhibition by the basal ganglia for differing degrees of proactive response control. Hum Brain Mapp 37:4706-4717, 2016. © 2016 Wiley Periodicals, Inc.

171. The neurocircuitry of increased inflammation in depression: Preliminary results

Evidence suggests a cause and effect relationship between inflammatory cytokines and behavioral symptoms relevant to a number of psychiatric illnesses. Previous neuroimaging studies have demonstrated that administration of inflammatory stimuli or cytokines changes activity of basal ganglia nuclei to mediate depressive symptoms, effects that may be mediated by decreased striatal dopamine. Whether the effects of inflammation extend beyond the basal ganglia to other brain regions to contribute to specific behavioral symptoms is unknown. This study examined whether increased inflammation in depression affects functional connectivity between the basal ganglia (striatum) and other brain regions to mediate depressive and neurocognitive symptoms. Wakeful resting-state fMRI pilot data were obtained from 17 currently depressed patients with low versus high inflammation (C-reactive protein ⩽ 3 versus >3 mg/L). Seed-to-whole brain correlations were computed and compared between groups using four predefined striatal seeds. Depressed patients with high inflammation exhibited attenuated functional connectivity between three striatal seeds and thirteen cortical or subcortical brain regions. Of these thirteen significant relationships, inflammation-related compromised connectivity between ventral striatum and both anterior cingulate cortex and amygdala correlated with symptoms of anhedonia and anxiety, whereas decreased connectivity between dorsal striatum and prefrontal cortex was associated with decreased psychomotor performance. Understanding inflammation-associated alterations in neurocircuitry that mediate specific depressive behaviors is important for identifying strategies to diagnose and treat behavioral symptoms in patients with increased inflammation.

Metabolic and electrophysiological changes in the basal ganglia of transgenic Huntington's disease rats

Huntington's disease (HD) is characterized by neuronal loss in the striatum, ultimately leading to an ‘imbalance’ in the electrical activity of the basal ganglia-thalamocortical circuits. To restore this ‘imbalance’ in HD patients, which is held responsible for (some) of the motor symptoms, different basal ganglia nuclei have been targeted for surgical therapies, such as ablative surgery and deep brain stimulation. However, evidence to target brain nuclei for surgical therapies in HD is lacking. We reasoned that a neuronal and metabolic mapping of the basal ganglia nuclei could identify a functional substrate for therapeutic interventions. Therefore, the aim of the present study was to investigate the metabolic and neuronal activity of basal ganglia nuclei in a transgenic rat model of HD (tgHD). Subjects were 10–12month old tgHD rats and wildtype littermates. We examined the striatum, globus pallidus, entopeduncular nucleus, the subthalamic nucleus and substantia nigra at different levels. First, we determined the overall neuronal activity at a supracellular level, by cytochrome oxidase histochemistry. Secondly, we determined the subcellular metabolic activity, by immunohistochemistry for peroxisome proliferator-activated receptor-γ transcription co-activator (PGC-1α), a key player in the mitochondrial machinery. Finally, we performed extracellular single unit recordings in the nuclei to determine the cellular activity. In tgHD rats, optical density analysis showed a significantly increased cytochrome oxidase levels in the globus pallidus and subthalamic nucleus when compared to controls. PGC-1α expression was only enhanced in the subthalamic nucleus and electrophysiological recordings revealed decreased firing frequency of the majority of the neurons in the globus pallidus and increased firing frequency of the majority of the neurons in the subthalamic nucleus. Altogether, our results suggest that the globus pallidus and subthalamic nucleus play a role in the neurobiology of HD and can be potential targets for therapeutic interventions.

Effects of noradrenaline and serotonin depletions on the neuronal activity of globus pallidus and substantia nigra pars reticulata in experimental parkinsonism

Parkinson's disease (PD) is characterized by a degeneration of dopaminergic neurons and also by a degradation of noradrenergic neurons from the locus coeruleus and serotonergic neurons from the dorsal raphe. However, the effect of these depletions on the neuronal activity of basal ganglia nuclei is still unknown. By using extracellular single-unit recordings, we have addressed this question by testing the effects of selective depletions of noradrenaline (NA) (with N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4)) and serotonin (5-HT) (with 4-chloro-l-phenylalanine (pCPA)) on the neuronal activity of globus pallidus (GP) and substantia nigra pars reticulata (SNr) neurons in the 6-hydroxydopamine (6-OHDA) rat model of PD and sham-lesioned rats. We showed that 6-OHDA–induced dopamine (DA) depletion resulted in an increased number of GP and SNr neurons discharging in a bursty and irregular manner, confirming previous studies. These pattern changes were region-dependently influenced by additional monoamine depletion. Although the number of irregular and bursty neurons in 6-OHDA rats tended to decrease in the GP after NA depletion, it did not change after pCPA treatment in both GP and SNr. Furthermore, a significant interaction between DA and 5-HT depletions was observed on the firing rate of SNr neurons. By themselves, NA depletion did not change GP or SNr neuronal activity, whereas 5-HT depletion decreased the firing rate and increased the proportion of bursty and irregular neurons in both brain regions, suggesting that 5-HT, but not NA, plays a major role in the modulation of both the firing rate and patterns of GP and SNr neurons. Finally, our data suggest that, in addition to the primary role of DA in the control of basal ganglia activity, NA and 5-HT depletion also contribute to the dysregulation of the basal ganglia in PD by changes to neuronal firing patterns.

Parkinson's disease: From pathophysiology to new therapeutical approaches

Event Abstract Back to Event Parkinson's disease: From pathophysiology to new therapeutical approaches Abdelhamid Benazzouz1* 1 CNRS UMR 5227, Laboratoire MAC, France Parkinson’s disease (PD) is neurodegenerative disorder characterized by the manifestation of three cardinal motor symptoms: akinesia, rigidity and rest tremor. These symptoms are the consequence of a progressive degeneration of dopamine neurons in the pars compacta of substantia nigra, which results in a depletion of dopamine in the striatum and other brain structures. Functionally, the depletion of dopamine induces a disorganization of the neuronal activity in basal ganglia nuclei and especially in the subthalamic nucleus (STN), which plays a key role in the control of movement. Several studies in rodent and non human primate models of PD have shown that the depletion of dopamine induced dramatic changes in the discharge pattern of STN neurons. The regular activity recorded in the normal situation was replaced by bursty and irregular pattern of activity, in the pathological situation. During the last two decades, deep brain stimulation (DBS) of the STN has proven to be highly effective in reducing all the cardinal motor symptoms in animal models of the disease as well as in parkinsonian patients suffering from a severe form of PD. However, despite these clinical achievements, the precise action mechanisms of STN-DBS still need to be fully characterized at molecular and cellular level. Our experimental studies have suggested that STN-DBS, at parameters improving motor symptoms, reduced the abnormal hyperactivity of STN neurons. Recently, DBS of other brain regions has proven to be capable of providing significant benefits for several complex motor neuropathologies as essential tremor and dystonia, and also some pharmaco-resistant psychiatric disorders such as Tourette syndrome, obsessive-compulsive disorder and severe depression. Conference: 2nd NEUROMED Workshop, Fez, Morocco, 10 Jun - 12 Jun, 2010. Presentation Type: Oral Presentation Topic: Oral Session 1: Brain diseases and their treatment Citation: Benazzouz A (2010). Parkinson's disease: From pathophysiology to new therapeutical approaches. Front. Neurosci. Conference Abstract: 2nd NEUROMED Workshop. doi: 10.3389/conf.fnins.2010.12.00003 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 03 Jun 2010; Published Online: 03 Jun 2010. * Correspondence: Abdelhamid Benazzouz, CNRS UMR 5227, Laboratoire MAC, Bordeaux, France, Abdelhamid.Benazzouz@u-bordeaux2.fr Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Abdelhamid Benazzouz Google Abdelhamid Benazzouz Google Scholar Abdelhamid Benazzouz PubMed Abdelhamid Benazzouz Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Involvement of Basal Ganglia Network in Motor Disabilities Induced by Typical Antipsychotics

BackgroundClinical treatments with typical antipsychotic drugs (APDs) are accompanied by extrapyramidal motor side-effects (EPS) such as hypokinesia and catalepsy. As little is known about electrophysiological substrates of such motor disturbances, we investigated the effects of a typical APD, α-flupentixol, on the motor behavior and the neuronal activity of the whole basal ganglia nuclei in the rat.Methods and FindingsThe motor behavior was examined by the open field actimeter and the neuronal activity of basal ganglia nuclei was investigated using extracellular single unit recordings on urethane anesthetized rats. We show that α-flupentixol induced EPS paralleled by a decrease in the firing rate and a disorganization of the firing pattern in both substantia nigra pars reticulata (SNr) and subthalamic nucleus (STN). Furthermore, α-flupentixol induced an increase in the firing rate of globus pallidus (GP) neurons. In the striatum, we recorded two populations of medium spiny neurons (MSNs) after their antidromic identification. At basal level, both striato-pallidal and striato-nigral MSNs were found to be unaffected by α-flupentixol. However, during electrical cortico-striatal activation only striato-pallidal, but not striato-nigral, MSNs were found to be inhibited by α-flupentixol. Together, our results suggest that the changes in STN and SNr neuronal activity are a consequence of increased neuronal activity of globus pallidus (GP). Indeed, after selective GP lesion, α-flupentixol failed to induce EPS and to alter STN neuronal activity.ConclusionOur study reports strong evidence to show that hypokinesia and catalepsy induced by α-flupentixol are triggered by dramatic changes occurring in basal ganglia network. We provide new insight into the key role of GP in the pathophysiology of APD-induced EPS suggesting that the GP can be considered as a potential target for the treatment of EPS.

Compensatory regulation of striatal neuropeptide gene expression occurs before changes in metabolic activity of basal ganglia nuclei

Compensatory mechanisms delay the appearance of parkinsonian symptoms. However, both the order of appearance and potential interactions of compensatory mechanisms acting within the nigrostriatal pathway as well as inside and outside the basal ganglia are not clear. We hypothesize that, after the striatal dopaminergic homeostasis breakdown, a modification in the expression of several striatal markers (neuropeptide precursors and dopamine receptors) may occur before a change in the activity of both globus pallidus (GP) and substantia nigra pars reticulata (SNr) in response to a partial nigrostriatal lesion. The present data show, in MPTP-treated mice, that preproenkephalin-A and preprotachykinin mRNA expression and D 3 receptor binding are modified without changes in cytochrome oxidase metabolic activity in both GP and SNr, respectively. These changes in neuropeptide expression would compensate for the dopamine depletion-induced changes in inhibitory GABAergic input from the striatum to GP and SNr. It also indicates that nondopaminergic compensatory mechanisms inherent to the basal ganglia are activated before those residing outside the basal ganglia.

Changes in the Mitochondrial Enzyme Activity in Striatal Projection Areas after Unilateral Excitotoxic Striatal Lesions: Partial Restoration by Embryonic Striatal Transplants

It is well established that the activity of cytochrome oxidase (CO), a mitochondrial enzyme, reflects the long-term, steady-state levels of neuronal activity. The present study investigated the long-term effects of unilateral striatal lesions induced by quinolinic acid on CO activity in primary striatal targets, including the globus pallidus (GP), entopeduncular nucleus (EP), and substantia nigra pars reticulata (SNR) and a secondary striatal projection area, such as subthalamic nucleus (STN), in rats. The activity of CO was determined by measuring staining intensity on brain sections processed for CO histochemistry. We also examined whether intrastriatal transplants of embryonic striatal tissue could affect the lesion-induced changes in the CO activity of those brain structures. Unilateral striatal lesions were found to lead to increases in the CO activity of the GP, EP, and SNR ipsilateral to the lesions. By contrast, the activity of the ipsilateral STN was decreased following striatal lesions, probably due to the increased inhibitory effect of the GP on the STN. Intrastriatal implantation of the lateral ganglionic eminence (LGN), but not the medial ganglionic eminence (MGE), reversed the lesion-induced changes in the CO activity of the GP and STN with concomitant attenuation of apomorphine-induced rotational asymmetry. The grafts failed to affect the activity of either the EP or SNR. The present results indicate that striatal lesions induce changes in the functional activity of basal ganglia nuclei and that the LGE grafts placed in the damaged striatum partly reverse the alterations in the functional state of the basal ganglia circuitry.

Intrastriatal Mesencephalic Grafts Affect Neuronal Activity in Basal Ganglia Nuclei and Their Target Structures in a Rat Model of Parkinson’s Disease

Nigrostriatal dopamine (DA) lesions lead to changes of neuronal activity in basal ganglia nuclei such as the globus pallidus (GP, the rodent homolog of lateral globus pallidus), entopeduncular nucleus (EP, the rodent homolog of medial globus pallidus), substantia nigra pars reticulata (SNR), and subthalamic nucleus (STN). We investigated in rats whether embryonic mesencephalic DA neurons grafted in the striatum may affect the lesion-induced alterations of neuronal activity in these structures. Regional neuronal activity was determined by use of quantitative cytochrome oxidase histochemistry. It was also examined in lesioned rats whether the grafts may regulate the expression of c-Fos after systemic administration of apomorphine in the basal ganglia nuclei as well as their target structures, including the ventromedial thalamic nucleus (VM), superior colliculus (SC), and pedunculopontine nucleus (PPN). Lesioned rats exhibited an increased activity of CO in the GP, EP, SNR, and STN ipsilateral to the lesion. Intrastriatal nigral grafts reversed the increases in the CO activity in the EP and SNR, whereas the grafts failed to affect the enzyme activity in the GP or STN. Apomorphine induced an increased expression of c-Fos in the GP, STN, VM, SC, and PPN on the lesioned side. The enhanced expression of this protein in all the structures except for the STN was attenuated by nigral grafts. The present results indicate that intrastriatal DA neuron grafts can normalize the lesion-induced changes of neuronal activity in the output nuclei of the basal ganglia as well as their target structures.

Prospects of glutamate antagonists in the therapy of Parkinson's disease.

It has been suggested that the excitatory amino acid glutamate, acting as both a neurotoxin and a neurotransmitter, might play a central role in the pathophysiology of Parkinson's disease (PD). Intrinsic energetic defects of the neurons of the substantia nigra pars compacta, the brain area where the degenerative process of PD takes place, may render nigral neurons highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. Degeneration of dopamine nigral neurons and striatal dopaminergic denervation cause a cascade of functional modifications in the activity of basal ganglia nuclei. Due to the close relationship that links dopaminergic and glutamatergic neurotransmission, glutamate is directly involved in the functional alterations of basal ganglia circuitry that lead to the development of parkinsonian motor symptoms. Drugs counteracting the effects of glutamate might therefore provide new protective and symptomatic strategies for therapy of PD.

Glutamate and Parkinson's disease.

Altered glutamatergic neurotransmission and neuronal metabolic dysfunction appear to be central to the pathophysiology of Parkinson's disease (PD). The substantia nigra pars compacta--the area where the primary pathological lesion is located--is particularly exposed to oxidative stress and toxic and metabolic insults. A reduced capacity to cope with metabolic demands, possibly related to impaired mitochondrial function, may render nigral highly vulnerable to the effects of glutamate, which acts as a neurotoxin in the presence of impaired cellular energy metabolism. In this way, glutamate may participate in the pathogenesis of PD. Degeneration of dopamine nigral neurons is followed by striatal dopaminergic denervation, which causes a cascade of functional modifications in the activity of basal ganglia nuclei. As an excitatory neurotransmitter, glutamate plays a pivotal role in normal basal ganglia circuitry. With nigrostriatal dopaminergic depletion, the glutamatergic projections from subthalamic nucleus to the basal ganglia output nuclei become overactive and there are regulatory changes in glutamate receptors in these regions. There is also evidence of increased glutamatergic activity in the striatum. In animal models, blockade of glutamate receptors ameliorates the motor manifestations of PD. Therefore, it appears that abnormal patterns of glutamatergic neurotransmission are important in the symptoms of PD. The involvement of the glutamatergic system in the pathogenesis and symptomatology of PD provides potential new targets for therapeutic intervention in this neurodegenerative disorder.