Activity Of Substantia Nigra Pars Reticulata Neurons Research Articles

Substantia Nigra Pars Reticulata Projections to the Pedunculopontine Nucleus Modulate Dyskinesia.

Long-term use of levodopa for Parkinson's disease (PD) treatment is often hindered by development of motor complications, including levodopa-induced dyskinesia (LID). The substantia nigra pars reticulata (SNr) and globus pallidus internal segment (GPi) are the output nuclei of the basal ganglia. Dysregulation of SNr and GPi activity contributes to PD pathophysiology and LID. The objective of this study was to determine whether direct modulation of SNr GABAergic neurons and SNr projections to the pedunculopontine nucleus (PPN) regulates PD symptoms and LID in a mouse model. We expressed Cre-recombinase activated channelrhodopsin-2 (ChR2) or halorhodopsin adeno-associated virus-2 (AAV2) vectors selectively in SNr GABAergic neurons of Vgat-IRES-Cre mice in a 6-hydroxydopamine model of PD to investigate whether direct optogenetic modulation of SNr neurons or their projections to the PPN regulates PD symptoms and LID expression. The forepaw stepping task, mouse LID rating scale, and open-field locomotion were used to assess akinesia and LID to test the effect of SNr modulation. Akinesia was improved by suppressing SNr neuron activity with halorhodopsin. LID was significantly reduced by increasing SNr neuronal activity with ChR2, which did not interfere with the antiakinetic effect of levodopa. Optical stimulation of ChR2 in SNr projections to the PPN recapitulated direct SNr stimulation. Modulation of SNr GABAergic neurons alters akinesia and LID expression in a manner consistent with the rate model of basal ganglia circuitry. Moreover, the projections from SNr to PPN likely mediate the antidyskinetic effect of increasing SNr neuronal activity, identifying a potential novel role for the PPN in LID. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Unitary synaptic connections among substantia nigra pars reticulata neurons

Neurons in substantia nigra pars reticulata (SNr) are synaptically coupled by local axon collaterals, providing a potential mechanism for local signal processing. Because SNr neurons fire spontaneously, these synapses are constantly active. To investigate their properties, we recorded spontaneous inhibitory postsynaptic currents (sIPSCs) from SNr neurons in brain slices, in which afferents from upstream nuclei are severed, and the cells fire rhythmically. The sIPSC trains contained a mixture of periodic and aperiodic events. Autocorrelation analysis of sIPSC trains showed that a majority of cells had one to four active unitary inputs. The properties of the unitary IPSCs (uIPSCs) were analyzed for cells with one unitary input, using a model of periodic presynaptic firing and stochastic synaptic transmission. The inferred presynaptic firing rates and coefficient of variation of interspike intervals (ISIs) corresponded well with direct measurements of spiking in SNr neurons. Methods were developed to estimate the success probability, amplitude distributions, and kinetics of the uIPSCs, while removing the contribution from aperiodic sIPSCs. The sIPSC amplitudes were not increased upon release from halorhodopsin silencing, suggesting that most synapses were not depressed at the spontaneous firing rate. Gramicidin perforated-patch recordings indicated that the average reversal potential of spontaneous inhibitory postsynaptic potentials was -64 mV. Because of the change in driving force across the ISI, the unitary inputs are predicted to have a larger postsynaptic impact when they arrive late in the ISI. Simulations of network activity suggest that this very sparse inhibitory coupling may act to desynchronize the activity of SNr neurons while having only a small effect on firing rate.

Serotonin and norepinephrine depletions can promote anxiety and depression in a rat model of Parkinson�s disease: an electrophysiological and behavioural study.

Event Abstract Back to Event Serotonin and norepinephrine depletions can promote anxiety and depression in a rat model of Parkinson’s disease: an electrophysiological and behavioural study. Claire Delaville1*, Jonathan Chetrit2, Sylvia Navailles2, Philippe De Deurwaerdère2 and Abdelhamid Benazzouz2 1 National Institutes of Health, NINDS, United States 2 CNRS, Neurodegenerative Diseases Institute UMR 5293, France The loss of dopamine (DA) neurons has been the pathophysiological focus of the devastating motor conditions of Parkinson’s disease (PD). Beyond DA, PD is a multi-system disorder characterized also by the loss of serotonin (5-HT) neurons from the dorsal raphe nucleus and norepinephrine (NE) neurons from the locus coeruleus. 5-HT and NE are widely recognized in the development of depression and anxiety and both symptoms are reported with a high prevalence in PD patients. However, a specific role for each neurotransmitter in the pathophysiology of PD is not clearly determined. Here, we investigated, in rats, the respective influence of DA, 5-HT and NE depletions on motor and non-motor behaviors as well as on the neuronal activity measured in vivo by single cell extracellular recordings in subthalamic (STN), globus pallidus (GP) and substantia nigra pars reticulata (SNr). DA, 5-HT and NE depletions were achieved by using classic protocols with 6-hydroxydopamine/desipramine, parachlorophenylalanine and DSP-4, respectively. We showed that NE or DA, but not 5-HT depletion significantly decreased locomotor activity and enhanced the proportion of bursty and irregular STN neurons. Anxiety-like states required DA depletion plus the depletion of 5-HT or NE. Anhedonia and “depressive-like” behavior emerged only from the combined depletion of all three monoamines, an effect paralleled by an increase in the firing rate and the proportion of bursty and irregular STN neurons. As for the STN, DA depletion increased the proportion of bursty neurons in GP and SNr. 5-HT, but not NE depletion modified GP and SNr neuronal activity. Thus, our data show that 5-HT and NE modulate specifically the basal ganglia activity and provides evidence for the exacerbation of behavioral deficits when 5-HT and/or NE depletions are combined with DA depletion. These data bring up new insight into the influence of 5-HT system in non-motor symptoms of PD. Keywords: Parkinson Disease, Norepinephrine, Serotonin, non-motor symptoms, Motor Activity Conference: 4th Conference of the Mediterrarnean Neuroscience Society, Istanbul, Turkey, 30 Sep - 3 Oct, 2012. Presentation Type: Symposium Topic: Abstracts Citation: Delaville C, Chetrit J, Navailles S, De Deurwaerdère P and Benazzouz A (2013). Serotonin and norepinephrine depletions can promote anxiety and depression in a rat model of Parkinson’s disease: an electrophysiological and behavioural study.. Conference Abstract: 4th Conference of the Mediterrarnean Neuroscience Society. doi: 10.3389/conf.fnhum.2013.210.00022 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: 26 Jan 2013; Published Online: 11 Apr 2013. * Correspondence: Dr. Claire Delaville, National Institutes of Health, NINDS, Bethesda, Maryland, MD 20892-3702, United States, cdelaville@gmail.com 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 Claire Delaville Jonathan Chetrit Sylvia Navailles Philippe De Deurwaerdère Abdelhamid Benazzouz Google Claire Delaville Jonathan Chetrit Sylvia Navailles Philippe De Deurwaerdère Abdelhamid Benazzouz Google Scholar Claire Delaville Jonathan Chetrit Sylvia Navailles Philippe De Deurwaerdère Abdelhamid Benazzouz PubMed Claire Delaville Jonathan Chetrit Sylvia Navailles Philippe De Deurwaerdère 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.

Deep brain stimulation of the substantia nigra pars reticulata improves forelimb akinesia in the hemiparkinsonian rat

Deep brain stimulation (DBS) employing high-frequency stimulation (HFS) is commonly used in the globus pallidus interna (GPi) and the subthalamic nucleus (STN) for treating motor symptoms of patients with Parkinson's disease (PD). Although DBS improves motor function in most PD patients, disease progression and stimulation-induced nonmotor complications limit DBS in these areas. In this study, we assessed whether stimulation of the substantia nigra pars reticulata (SNr) improved motor function. Hemiparkinsonian rats predominantly touched with their unimpaired forepaw >90% of the time in the stepping and limb-use asymmetry tests. After SNr-HFS (150 Hz), rats touched equally with both forepaws, similar to naive and sham-lesioned rats. In vivo, SNr-HFS decreased beta oscillations (12-30 Hz) in the SNr of freely moving hemiparkinsonian rats and decreased SNr neuronal spiking activity from 28 ± 1.9 Hz before stimulation to 0.8 ± 1.9 Hz during DBS in anesthetized animals; also, neuronal spiking activity increased from 7 ± 1.6 to 18 ± 1.6 Hz in the ventromedial portion of the thalamus (VM), the primary SNr efferent. In addition, HFS of the SNr in brain slices from normal and reserpine-treated rat pups resulted in a depolarization block of SNr neuronal activity. We demonstrate improvement of forelimb akinesia with SNr-HFS and suggest that this motor effect may have resulted from the attenuation of SNr neuronal activity, decreased SNr beta oscillations, and increased activity of VM thalamic neurons, suggesting that the SNr may be a plausible DBS target for treating motor symptoms of DBS.

Subthalamic nucleus electrical stimulation modulates calcium activity of nigral astrocytes.

BackgroundThe substantia nigra pars reticulata (SNr) is a major output nucleus of the basal ganglia, delivering inhibitory efferents to the relay nuclei of the thalamus. Pathological hyperactivity of SNr neurons is known to be responsible for some motor disorders e.g. in Parkinson's disease. One way to restore this pathological activity is to electrically stimulate one of the SNr input, the excitatory subthalamic nucleus (STN), which has emerged as an effective treatment for parkinsonian patients. The neuronal network and signal processing of the basal ganglia are well known but, paradoxically, the role of astrocytes in the regulation of SNr activity has never been studied.Principal FindingsIn this work, we developed a rat brain slice model to study the influence of spontaneous and induced excitability of afferent nuclei on SNr astrocytes calcium activity. Astrocytes represent the main cellular population in the SNr and display spontaneous calcium activities in basal conditions. Half of this activity is autonomous (i.e. independent of synaptic activity) while the other half is dependent on spontaneous glutamate and GABA release, probably controlled by the pace-maker activity of the pallido-nigral and subthalamo-nigral loops. Modification of the activity of the loops by STN electrical stimulation disrupted this astrocytic calcium excitability through an increase of glutamate and GABA releases. Astrocytic AMPA, mGlu and GABAA receptors were involved in this effect.SignificanceAstrocytes are now viewed as active components of neural networks but their role depends on the brain structure concerned. In the SNr, evoked activity prevails and autonomous calcium activity is lower than in the cortex or hippocampus. Our data therefore reflect a specific role of SNr astrocytes in sensing the STN-GPe-SNr loops activity and suggest that SNr astrocytes could potentially feedback on SNr neuronal activity. These findings have major implications given the position of SNr in the basal ganglia network.

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.

Stimulation of serotonin2C receptors elicits abnormal oral movements by acting on pathways other than the sensorimotor one in the rat basal ganglia

Serotonin2C (5-HT 2C) receptors act in the basal ganglia, a group of sub-cortical structures involved in motor behavior, where they are thought to modulate oral activity and participate in iatrogenic motor side-effects in Parkinson's disease and Schizophrenia. Whether abnormal movements initiated by 5-HT 2C receptors are directly consequent to dysfunctions of the motor circuit is uncertain. In the present study, we combined behavioral, immunohistochemical and extracellular single-cell recordings approaches in rats to investigate the effect of the 5-HT 2C agonist Ro-60-0175 respectively on orofacial dyskinesia, the expression of the marker of neuronal activity c-Fos in basal ganglia and the electrophysiological activity of substantia nigra pars reticulata (SNr) neuron connected to the orofacial motor cortex (OfMC) or the medial prefrontal cortex (mPFC). The results show that Ro-60-0175 (1 mg/kg) caused bouts of orofacial movements that were suppressed by the 5-HT 2C antagonist SB-243213 (1 mg/kg). Ro-60-0175 (0.3, 1, 3 mg/kg) dose-dependently enhanced Fos expression in the striatum and the nucleus accumbens. At the highest dose, it enhanced Fos expression in the subthalamic nucleus, the SNr and the entopeduncular nucleus but not in the external globus pallidus. However, the effect of Ro-60-0175 was mainly associated with associative/limbic regions of basal ganglia whereas subregions of basal ganglia corresponding to sensorimotor territories were devoid of Fos labeling. Ro-60-0175 (1–3 mg/kg) did not affect the electrophysiological activity of SNr neurons connected to the OfMC nor their excitatory-inhibitory-excitatory responses to the OfMC electrical stimulation. Conversely, Ro-60-0175 (1 mg/kg) enhanced the late excitatory response of SNr neurons evoked by the mPFC electrical stimulation. These results suggest that oral dyskinesia induced by 5-HT 2C agonists are not restricted to aberrant signalling in the orofacial motor circuit and demonstrate discrete modifications in associative territories.

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.

Subthalamic Stimulation and Neuronal Activity in the Substantia Nigra in Parkinson's Disease

High-frequency stimulation of the subthalamic nucleus (STN) is an effective treatment for severe forms of Parkinson's disease (PD). To study the effects of high-frequency STN stimulation on one of the main output pathways of the basal ganglia, single-unit recordings of the neuronal activity of the substantia nigra pars reticulata (SNr) were performed before, during, and after the application of STN electrical stimulation in eight PD patients. During STN stimulation at 14 Hz, no change in either the mean firing rate or the discharge pattern of SNr neurons was observed. STN stimulation at 140 Hz decreased the mean firing rate by 64% and the mean duration of bursting mode activity of SNr neurons by 70%. The SNr residual neuronal activity during 140-Hz STN stimulation was driven by the STN stimulation. How the decrease in rate and modification of firing pattern of SNr-evoked neural activity, during high-frequency STN stimulation, contribute to the improvement of parkinsonian motor disability remains to be elucidated.

Dopamine action in the substantia nigra pars reticulata: iontophoretic studies in awake, unrestrained rats

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, dose-dependently 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.

Ionic Mechanisms Underlying Autonomous Action Potential Generation in the Somata and Dendrites of GABAergic Substantia Nigra Pars Reticulata NeuronsIn Vitro

Through their repetitive discharge, GABAergic neurons of the substantia nigra pars reticulata (SNr) tonically inhibit the target nuclei of the basal ganglia and the dopamine neurons of the midbrain. As the repetitive firing of SNr neurons persists in vitro, perforated, whole-cell and cell-attached patch-clamp recordings were made from rat brain slices to determine the mechanisms underlying this activity. The spontaneous activity of SNr neurons was not perturbed by the blockade of fast synaptic transmission, demonstrating that it was autonomous in nature. A subthreshold, slowly inactivating, voltage-dependent, tetrodotoxin (TTX)-sensitive Na+ current and a TTX-insensitive inward current that was mediated in part by Na+ were responsible for depolarization to action potential (AP) threshold. An apamin-sensitive spike afterhyperpolarization mediated by small-conductance Ca2+-dependent K+ (SK) channels was critical for the precision of autonomous activity. SK channels were activated, in part, by Ca(2+) flowing throughomega-conotoxin GVIA-sensitive, class 2.2 voltage-dependent Ca2+ channels. Although Cs+/ZD7288 (4-ethylphenylamino-1,2-dimethyl-6-methylaminopyrimidinium chloride)-sensitive hyperpolarization-activated currents were also observed in SNr neurons, they were activated at voltages that were in general more hyperpolarized than those associated with autonomous activity. Simultaneous somatic and dendritic recordings revealed that autonomously generated APs were observed first at the soma before propagating into dendrites up to 120 microm from the somatic recording site. Backpropagation of autonomously generated APs was reliable with no observable incidence of failure. Together, these data suggest that the resting inhibitory output of the basal ganglia relies, in large part, on the intrinsic firing properties of the neurons that convey this signal.

Activity of substantia nigra pars reticulata neurons during smooth pursuit eye movements in monkeys

Nuclei within the basal ganglia (BG), in particular the substantia nigra pars reticulata (SNr), subthalamic nucleus (STN) and caudate nucleus, are known to be involved in the generation of rapid or saccadic eye movements. Neurons in the SNr are active tonically and generally show a pause, but also increase, in discharge rate, for the appearance of visual stimuli and the generation of saccades. Recent experimental results in oculomotor regions of the brainstem reveal overlap in the neuronal pathways used for saccades and smooth pursuit, or slow tracking, eye movements. Whether the overlap of processing for saccades and pursuit extends to the oculomotor BG is unknown. In the present report, we were interested in whether the overlap between the pursuit and saccadic systems extends into the oculomotor BG. Using single-neuron recording and electrical stimulation techniques, we tested whether neurons within the saccade portion of the BG, the SNr, could be involved in smooth pursuit eye movements. Monkeys were required to follow visual targets with either a smooth eye movement or a saccade while we recorded from SNr neurons. We report here on SNr neuronal activity that was modulated during the performance of visually guided saccades and also during the initiation and the maintenance of smooth pursuit eye movements. Importantly, the modulation of neuronal activity during pursuit was present even when catch-up saccades were absent. The majority of SNr neurons was active tonically and their discharge ceased during pursuit, although some neurons also increased their discharge rate during smooth pursuit, similar to the behaviour reported for saccades. We also found that electrical stimulation of the SNr during the initiation of pursuit suppressed ipsiversive and, in some cases, enhanced contraversive pursuit. Our combined recording and stimulation results are consistent with the hypothesis that the overlap between the pursuit and saccadic systems extends, at least somewhat, into the BG and that the signal conveyed by the SNr can be used by the pursuit system. Like the signal for saccades, the SNr may provide a permissive disinhibition for pursuit eye movements. We hypothesize that alterations in this signal in BG diseased states such as Parkinson's may explain in part the deficits observed in smooth pursuit eye movements of these patients.

Neuronal activity in the primate substantia nigra pars reticulata during the performance of simple and memory-guided elbow movements.

The basal ganglia participate in motor functions and are implicated in the pathophysiology of movement disorders. It has been shown in primates that the activity of many neurons in one of the basal ganglia output nuclei, the internal segment of the globus pallidus, changes with active or passive movements. The involvement of the second major output nucleus, the substantia nigra pars reticulata (SNr), in movement is less well established. In this study, the electrophysiologic activity of SNr neurons was studied in two awake Rhesus monkeys while the animals were examined and while they performed elbow movements in two different motor tasks (n = 261 cells). Responses to examination were uncommon and subtle. Twenty-one percent of neurons responded to the target step in a step tracking task, mostly with anticipatory responses, although some cells showed directional, movement-related activity. In a delayed-response task, 17% of cells showed anticipatory activity to an instruction cue preceding the target jump, 11% responded directly to the cue, and 11% showed long-lasting postcue activity. Movement-related responses were seen in 21% in this task. Reward responses occurred in 10% of neurons. Responses to more than one event were common. The results demonstrate that few neurons in the SNr respond directly to passive or active movements, but a large proportion shows responses that may be related to memory, attention, or movement preparation. While internal pallidal segment neurons may be preferentially concerned with controlling elemental movement parameters, neurons in the SNr may be more involved in higher motor functions or nonmotor aspects of behavior.

Eye position and memory saccade related responses in substantia nigra pars reticulata

The substantia nigra pars reticulata (SNr), a major output nucleus of the basal ganglia, has been implicated anatomically, pharmacologically and physiologically in the generation of saccadic eye movements. However, the unique contribution of the SNr to saccade generation remains elusive. We studied the activity of SNr neurons while rhesus monkeys made saccades from different initial orbital positions, to determine what effects, if any, eye position had on SNr neuronal activity. We found that there was no effect of eye position on SNr neuronal responses. We also examined the responses of SNr neurons during memory-guided saccades to determine whether SNr discharges were affected by whether the target of the upcoming saccade was visible. We found that there was no change in response properties during memory saccade trials as compared to otherwise identical visually guided trials. SNr neurons appear to carry no information about either eye position or whether a movement is guided by a visible or remembered target. These results suggest that nigral signals are encoded in the same coordinate frame as those in the SC and FEF, but that unlike neuronal responses in these areas, SNr activity is not influenced by whether the saccade target remains visible until the movement is executed.

Glucose sensitivity in mouse substantia nigra pars reticulata neurons in vitro

Glucose sensitivity of substantia nigra pars reticulata (SNr) GABAergic neurons was investigated by extracellular recording in acute slice. Approximately two thirds of the GABAergic SNr neurons tested exhibited a significant increase in spontaneous firing rate as the extracellular glucose concentration was lowered from 10 to 4–6 mM. At lower glucose concentrations, a small proportion of these glucose-sensitive GABAergic SNr neurons exhibited multiple, robust increases in spontaneous firing rate with periods ranging in minutes. Similar changes in firing rate of SNr neurons in response to lowered glucose were detected under blockade of GABA A, NMDA, and non-NMDA receptors, indicating that mechanisms other than those mediated by the major synaptic transmissions in the SNr are involved. These findings suggest involvement of previously unknown glucose dependent alterations of GABAergic SNr neuronal activity in the central regulation of glucose homeostasis.

Spontaneous and Evoked Activity of Substantia Nigra Pars Reticulata Neurons during High-Frequency Stimulation of the Subthalamic Nucleus

The subthalamic nucleus (STN), a major component of the basal ganglia, exerts an excitatory influence on the output structures of this system i.e., the substantia nigra pars reticulata (SNR) and the internal segment of the globus pallidus. High-frequency stimulation of the STN is a method currently used to treat parkinsonian symptoms. The aim of the present study was to analyze the effects of STN high-frequency stimulation on the activity of SNR neurons and to investigate its impact on the transfer of information between the cerebral cortex and the SNR. During STN high-frequency stimulation, the activity of SNR cells was decreased at low-intensity stimulation, whereas it was increased at a higher intensity. The decrease in the discharge of SNR cells likely results from the activation of a GABAergic transmission in the SNR because this effect was blocked by local application of bicuculline. The increased activity likely results from the activation of the glutamatergic subthalamonigral projection because the latency of the evoked excitations was consistent with the conduction time of the subthalamonigral neurons. Finally, during STN high-frequency stimulation, the transmission of cortical information along the direct trans-striatal pathway was preserved, whereas the functionality of the trans-subthalamic pathways was partly preserved or completely blocked depending on the stimulation intensity. The present data indicate that STN high-frequency stimulation influences the activity of SNR cells through activation of their excitatory and inhibitory synaptic afferent pathways as well as antidromic activation of the projection neurons.

Role of Primate Substantia Nigra Pars Reticulata in Reward-Oriented Saccadic Eye Movement

To test the hypothesis that the basal ganglia are related to reward-oriented saccades, we examined activity of substantia nigra pars reticulata (SNr) neurons by using a one-direction-rewarded version of the memory-guided saccade task (1DR). Many SNr neurons changed (decreased or increased) their activity after and before a visual cue (post-cue and pre-cue activity). Post-cue decreases or increases tended to be larger to a contralateral cue. They were often modulated prospectively by the presence or absence of reward, either positively (enhanced in the rewarded condition) or negatively (enhanced in the nonrewarded condition). The positive reward modulation was more common among decreasing type neurons, whereas no such preference was observed among increasing type neurons. The reward-contingent decrease in SNr neuronal activity would facilitate rewarded saccades by inducing disinhibition in superior colliculus (SC) neurons. In contrast, the increase in SNr activity would suppress a saccade less selectively (rewarded or nonrewarded) by augmenting inhibition of SC neurons. The post-cue activity was often preceded by anticipatory pre-cue activity. Most typically, post-cue decrease was preceded by pre-cue decrease, selectively when the contralateral side was rewarded. This would reinforce the reward-oriented nature of SNr neuronal activity. The decreases and increases in SNr activity may be derived directly and indirectly, respectively, from the caudate (CD), where neurons show reward-contingent pre-cue and post-cue activity. These results suggest that the CD-SNr-SC mechanism would promote saccades oriented to reward.

Amphetamine inhibits behavior-related neuronal responses in substantia nigra pars reticulata of rats working for sucrose reinforcement

Changes in activity of basal ganglia neurons, especially those in the striatum, are thought to underlie the characteristic behavioral patterns produced by d-amphetamine (AMPH). To study the role of the substantia nigra pars reticulata (SNr), a major basal ganglia output nucleus, we recorded from SNr neurons before and after a behaviorally activating dose of AMPH (0.5 mg/kg) in rats trained to nosepoke for sucrose reinforcement. Before AMPH, task-related behaviors were associated primarily with increases or both increases and decreases in SNr firing. Although these same behavior-related patterns persisted after AMPH, their relative magnitude was significantly attenuated. Units unresponsive during task events were unaffected by AMPH. Thus, rather than change the overall level of SNr firing, a behaviorally active dose of AMPH exerts context-dependent effects on the activity of SNr neurons.

Protective role of ATP-sensitive potassium channels in hypoxia-induced generalized seizure.

Adenosine triphosphate (ATP)-sensitive potassium (K(ATP)) channels are activated by various metabolic stresses, including hypoxia. The substantia nigra pars reticulata (SNr), the area with the highest expression of K(ATP) channels in the brain, plays a pivotal role in the control of seizures. Mutant mice lacking the Kir6.2 subunit of K(ATP) channels [knockout (KO) mice] were susceptible to generalized seizures after brief hypoxia. In normal mice, SNr neuron activity was inactivated during hypoxia by the opening of the postsynaptic K(ATP) channels, whereas in KO mice, the activity of these neurons was enhanced. K(ATP) channels exert a depressant effect on SNr neuronal activity during hypoxia and may be involved in the nigral protection mechanism against generalized seizures.

The novel antiepileptic drug levetiracetam (ucb L059) induces alterations in GABA metabolism and turnover in discrete areas of rat brain and reduces neuronal activity in substantia nigra pars reticulata

Levetiracetam (( S)-α-ethyl -2-oxo-pyrrolidine acetamide, ucb L059) is a novel anticonvulsant drug presently in clinical development. Its mechanism of action is unknown although a recently reported novel specific binding site for [ 3H]levetiracetam, unique to brain, may be involved. This binding site has not yet been characterized, but some evidence suggested a possibly indirect interaction with the GABA system. We therefore examined levetiracetam's effects on GABA metabolism and turnover in several rat brain regions after systemic administration of anticonvulsant doses. Furthermore, in order to study functional effects of levetiracetam on a well defined system of GABAergic neurons in a brain region that has been critically involved in anticonvulsant drug action, we examined levetiracetam's action on spontaneous firing of substantia nigra pars reticulata (SNR) neurons in anesthetized rats. Although levetiracetam did not alter the activity of the GABA synthesizing and degrading enzymes glutamic acid decarboxylase (GAD) and GABA aminotransferase (GABA-T) in vitro, systemic administration induced significant alterations in these enzymes in several brain regions, indicating that these enzyme alterations were no direct drug effects but a consequence of postsynaptic changes in either GABAergic or other neurotransmitter-related systems. In the striatum, levetiracetam, 170 mg/kg i.p., induced a significant increase in GABA-T activity while GAD activity markedly decreased. When GABA turnover was estimated after inhibition of GABA-T by aminooxyacetic acid (AOAA), treatment with levetiracetam (given 15 min prior to injection of AOAA) significantly reduced GABA turnover in the striatum. Since the substantia nigra pars reticulata (SNR) receives a strong GABAergic input from the striatum, we examined if the alterations in GABA metabolism and turnover in the striatum led to functional alterations in neuronal activity in the SNR by recording single unit activity of SNR neurons after i.p. injection of levetiracetam. While injection of vehicle did not affect SNR neuronal activity, a significant decrease in spontaneous neuronal firing was recorded after levetiracetam. Since a substantial body of evidence suggests that the SNR is a critical site at which decrease of neuronal firing results in protection against various seizure types, the suppressive effect of levetiracetam on SNR activity may contribute to the anticonvulsant action of this drug.