Predicting the Responses of Repetitively Firing Neurons to Current Noise

We used phase resetting methods to predict firing patterns of rat subthalamic nucleus (STN) neurons when their rhythmic firing was densely perturbed by noise. We applied sequences of contiguous brief (0.5–2 ms) current pulses with amplitudes drawn from a Gaussian distribution (10–100 pA standard deviation) to autonomously firing STN neurons in slices. Current noise sequences increased the variability of spike times with little or no effect on the average firing rate. We measured the infinitesimal phase resetting curve (PRC) for each neuron using a noise-based method. A phase model consisting of only a firing rate and PRC was very accurate at predicting spike timing, accounting for more than 80% of spike time variance and reliably reproducing the spike-to-spike pattern of irregular firing. An approximation for the evolution of phase was used to predict the effect of firing rate and noise parameters on spike timing variability. It quantitatively predicted changes in variability of interspike intervals with variation in noise amplitude, pulse duration and firing rate over the normal range of STN spontaneous rates. When constant current was used to drive the cells to higher rates, the PRC was altered in size and shape and accurate predictions of the effects of noise relied on incorporating these changes into the prediction. Application of rate-neutral changes in conductance showed that changes in PRC shape arise from conductance changes known to accompany rate increases in STN neurons, rather than the rate increases themselves. Our results show that firing patterns of densely perturbed oscillators cannot readily be distinguished from those of neurons randomly excited to fire from the rest state. The spike timing of repetitively firing neurons may be quantitatively predicted from the input and their PRCs, even when they are so densely perturbed that they no longer fire rhythmically.     

Cloning and characterization of rat neuronal apoptosis inhibitory protein cDNA

The human neuronal apoptosis inhibitory protein (NAIP) gene was originally discovered because of its deletion in infantile spinal muscular atrophy (SMA), a childhood genetic disorder characterized by motor neuron loss and progressive paralysis with muscular atrophy. Although SMA is now known to be caused by deletions of survival motor neuron (SMN), the fact that NAIP is an anti-apoptotic protein is consistent with the NAIP gene modifying SMA severity. Here we report the cloning of a 1.5 kb rat NAIP cDNA fragment which contains BIR-3 (third baculovirus inhibitory repeat) domain. This fragment shows 78% homology to the human NAIP and 86% homology to the murine counterpart. We have investigated the distribution of NAIP mRNA expressing neurons by in situ RT-PCR technique in the rat central nervous system (CNS). Although all of the neurons appeared to express NAIP mRNA ubiquitously, pronounced elevation of NAIP mRNA expression was observed in the areas innervated by glutamatergic neurons after kainic acid (KA) injection. We have raised an anti-rat NAIP antiserum in rabbits using NAIP cDNA and recombinant rat NAIP, and carried out an immunohistological investigation. We observed highly immunoreactive neuronal subpopulations in the retinal ganglion, cerebral cortex, hippocampus, basal forebrain, thalamus, areas of midbrain, Purkinje cells of the cerebellum, and motor neurons in the spinal cord. Increased immunoreactivity of glutamatergic neurons was also observed broadly in the CNS after KA treatment. This study provides additional evidence that expression of mRNA and gene products of NAIP seem to be regulated in response to excessive stimuli or injuries in rat CNS, and these results are compatible with an anti-apoptotic role of NAIP in acute SMA as well as in brain injuries.     

Dynamin Isoforms Decode Action Potential Firing for Synaptic Vesicle Recycling

Presynaptic nerve terminals must maintain stable neurotransmission via synaptic vesicle membrane recycling despite encountering wide fluctuations in the number and frequency of incoming action potentials (APs). However, the molecular mechanism linking variation in neuronal activity to vesicle trafficking is unknown. Here, we combined genetic knockdown and direct physiological measurements of synaptic transmission from paired neurons to show that three isoforms of dynamin, an essential endocytic protein, work individually to match vesicle reuse pathways, having distinct rate and time constants with physiological AP frequencies. Dynamin 3 resupplied the readily releasable pool with slow kinetics independently of the AP frequency but acted quickly, within 20 ms of the incoming AP. Under high-frequency firing, dynamin 1 regulated recycling to the readily releasable pool with fast kinetics in a slower time window of greater than 50 ms. Dynamin 2 displayed a hybrid response between the other isoforms. Collectively, our findings show how dynamin isoforms select appropriate vesicle reuse pathways associated with specific neuronal firing patterns.     

Dynamic Excitatory and Inhibitory Gain Modulation Can Produce Flexible,Robust and Optimal Decision-making

Behavioural and neurophysiological studies in primates have increasingly shown the involvement of urgency signals during the temporal integration of sensory evidence in perceptual decision-making. Neuronal correlates of such signals have been found in the parietal cortex, and in separate studies, demonstrated attention-induced gain modulation of both excitatory and inhibitory neurons. Although previous computational models of decision-making have incorporated gain modulation, their abstract forms do not permit an understanding of the contribution of inhibitory gain modulation. Thus, the effects of co-modulating both excitatory and inhibitory neuronal gains on decision-making dynamics and behavioural performance remain unclear. In this work, we incorporate time-dependent co-modulation of the gains of both excitatory and inhibitory neurons into our previous biologically based decision circuit model. We base our computational study in the context of two classic motion-discrimination tasks performed in animals. Our model shows that by simultaneously increasing the gains of both excitatory and inhibitory neurons, a variety of the observed dynamic neuronal firing activities can be replicated. In particular, the model can exhibit winner-take-all decision-making behaviour with higher firing rates and within a significantly more robust model parameter range. It also exhibits short-tailed reaction time distributions even when operating near a dynamical bifurcation point. The model further shows that neuronal gain modulation can compensate for weaker recurrent excitation in a decision neural circuit, and support decision formation and storage. Higher neuronal gain is also suggested in the more cognitively demanding reaction time than in the fixed delay version of the task. Using the exact temporal delays from the animal experiments, fast recruitment of gain co-modulation is shown to maximize reward rate, with a timescale that is surprisingly near the experimentally fitted value. Our work provides insights into the simultaneous and rapid modulation of excitatory and inhibitory neuronal gains, which enables flexible, robust, and optimal decision-making.     

Decreased neuronal excitability in hippocampal neurons of mice exposed to cyclic hypoxia.

To study the physiological effects of chronic intermittent hypoxia on neuronal excitability and function in mice, we exposed animals to cyclic hypoxia for 8 h daily (12 cycles/h) for approximately 4 wk, starting at 2-3 days of age, and examined the properties of freshly dissociated hippocampal neurons in vitro. Compared with control (Con) hippocampal CA1 neurons, exposed (Cyc) neurons showed action potentials (AP) with a smaller amplitude and a longer duration and a more depolarized resting membrane potential. They also have a lower rate of spontaneous firing of AP and a higher rheobase. Furthermore, there was downregulation of the Na(+) current density in Cyc compared with Con neurons (356.09 +/- 54.03 pA/pF in Cyc neurons vs. 508.48 +/- 67.30 pA/pF in Con, P < 0.04). Na(+) channel characteristics, including activation, steady-state inactivation, and recovery from inactivation, were similar in both groups. The deactivation rate, however, was much larger in Cyc than in Con (at -100 mV, time constant for deactivation = 0.37 +/- 0.04 ms in Cyc neurons and 0.18 +/- 0.01 ms in Con neurons). We conclude that the decreased neuronal excitability in mice neurons treated with cyclic hypoxia is due, at least in part, to differences in passive properties (e.g., resting membrane potential) and in Na(+) channel expression and/or regulation. We hypothesize that this decreased excitability is an adaptive response that attempts to decrease the energy expenditure that is used for adjusting disturbances in ionic homeostasis in low-O(2) conditions.     

Neuronal activity in rat barrel cortex underlying texture discrimination

Rats and mice palpate objects with their whiskers to generate tactile sensations. This form of active sensing endows the animals with the capacity for fast and accurate texture discrimination. The present work is aimed at understanding the nature of the underlying cortical signals. We recorded neuronal activity from barrel cortex while rats used their whiskers to discriminate between rough and smooth textures. On whisker contact with either texture, firing rate increased by a factor of two to ten. Average firing rate was significantly higher for rough than for smooth textures, and we therefore propose firing rate as the fundamental coding mechanism. The rat, however, cannot take an average across trials, but must make an immediate decision using the signals generated on each trial. To estimate single-trial signals, we calculated the mutual information between stimulus and firing rate in the time window leading to the rat's observed choice. Activity during the last 75 ms before choice transmitted the most informative signal; in this window, neuronal clusters carried, on average, 0.03 bits of information about the stimulus on trials in which the rat's behavioral response was correct. To understand how cortical activity guides behavior, we examined responses in incorrect trials and found that, in contrast to correct trials, neuronal firing rate was higher for smooth than for rough textures. Analysis of high-speed films suggested that the inappropriate signal on incorrect trials was due, at least in part, to nonoptimal whisker contact. In conclusion, these data suggest that barrel cortex firing rate on each trial leads directly to the animal's judgment of texture.     

Statistical analysis of temporal evolution in single-neuron firing rates

A fundamental methodology in neurophysiology involves recording the electrical signals associated with individual neurons within brains of awake behaving animals. Traditional statistical analyses have relied mainly on mean firing rates over some epoch (often several hundred milliseconds) that are compared across experimental conditions by analysis of variance. Often, however, the time course of the neuronal firing patterns is of interest, and a more refined procedure can produce substantial additional information. In this paper we compare neuronal firing in the supplementary eye field of a macaque monkey across two experimental conditions. We take the electrical discharges, or 'spikes', to be arrivals in a inhomogeneous Poisson process and then model the firing intensity function using both a simple parametric form and more flexible splines. Our main interest is in making inferences about certain characteristics of the intensity, including the timing of the maximal firing rate. We examine data from 84 neurons individually and also combine results into a hierarchical model. We use Bayesian estimation methods and frequentist significance tests based on a nonparametric bootstrap procedure. We are thereby able to conclude that a substantial fraction of the neurons exhibit important temporal differences in firing intensity across the two conditions, and we quantify the effect across the population of neurons.     

Posterior cingulate cortex mediates outcome-contingent allocation of behavior

Adaptive decision making requires selecting an action and then monitoring its consequences to improve future decisions. The neuronal mechanisms supporting action evaluation and subsequent behavioral modification, however, remain poorly understood. To investigate the contribution of posterior cingulate cortex (CGp) to these processes, we recorded activity of single neurons in monkeys performing a gambling task in which the reward outcome of each choice strongly influenced subsequent choices. We found that CGp neurons signaled reward outcomes in a nonlinear fashion and that outcome-contingent modulations in firing rate persisted into subsequent trials. Moreover, firing rate on any one trial predicted switching to the alternative option on the next trial. Finally, microstimulation in CGp following risky choices promoted a preference reversal for the safe option on the following trial. Collectively, these results demonstrate that CGp directly contributes to the evaluative processes that support dynamic changes in decision making in volatile environments.     

Information flow and temporal coding in primate pattern vision

We perform time-resolved calculations of the information transmitted about visual patterns by neurons in primary visual and inferior temporal cortices. All measurable information is carried in an effective time-varying firing rate, obtained by averaging the neuronal response with a resolution no finer than about 25 ms in primary visual cortex and around twice that in inferior temporal cortex. We found no better way for a neuron receiving these messages to decode them than simply to count spikes for this long. Most of the information tends to be concentrated in one or, more often, two brief packets, one at the very beginning of the response and the other typically 100 ms later. The first packet is the most informative part of the message, but the second one generally contains new information. A small but significant part of the total information in the message accumulates gradually over the entire course of the response. These findings impose strong constraints on the codes used by these neurons.     

Timescales of multineuronal activity patterns reflect temporal structure of visual stimuli

The investigation of distributed coding across multiple neurons in the cortex remains to this date a challenge. Our current understanding of collective encoding of information and the relevant timescales is still limited. Most results are restricted to disparate timescales, focused on either very fast, e.g., spike-synchrony, or slow timescales, e.g., firing rate. Here, we investigated systematically multineuronal activity patterns evolving on different timescales, spanning the whole range from spike-synchrony to mean firing rate. Using multi-electrode recordings from cat visual cortex, we show that cortical responses can be described as trajectories in a high-dimensional pattern space. Patterns evolve on a continuum of coexisting timescales that strongly relate to the temporal properties of stimuli. Timescales consistent with the time constants of neuronal membranes and fast synaptic transmission (5-20 ms) play a particularly salient role in encoding a large amount of stimulus-related information. Thus, to faithfully encode the properties of visual stimuli the brain engages multiple neurons into activity patterns evolving on multiple timescales.     

Long-term electrophysiological activity and pharmacological response of a human induced pluripotent stem cell-derived neuron and astrocyte co-culture

Human induced pluripotent stem cell (hiPSC)-derived neurons may be effectively used for drug discovery and cell-based therapy. However, the immaturity of cultured human iPSC-derived neurons and the lack of established functional evaluation methods are problematic. We here used a multi-electrode array (MEA) system to investigate the effects of the co-culture of rat astrocytes with hiPSC-derived neurons on the long-term culture, spontaneous firing activity, and drug responsiveness effects. The co-culture facilitated the long-term culture of hiPSC-derived neurons for >3 months and long-term spontaneous firing activity was also observed. After >3 months of culture, we observed synchronous burst firing activity due to synapse transmission within neuronal networks. Compared with rat neurons, hiPSC-derived neurons required longer time to mature functionally. Furthermore, addition of the synapse antagonists bicuculline and 6-cyano-7-nitroquinoxaline-2,3-dione induced significant changes in the firing rate. In conclusion, we used a MEA system to demonstrate that the co-culture of hiPSC-derived neurons with rat astrocytes is an effective method for studying the function of human neuronal cells, which could be used for drug screening.     

Optogenetic mimicry of the transient activation of dopamine neurons by natural reward is sufficient for operant reinforcement

Activation of dopamine receptors in forebrain regions, for minutes or longer, is known to be sufficient for positive reinforcement of stimuli and actions. However, the firing rate of dopamine neurons is increased for only about 200 milliseconds following natural reward events that are better than expected, a response which has been described as a "reward prediction error" (RPE). Although RPE drives reinforcement learning (RL) in computational models, it has not been possible to directly test whether the transient dopamine signal actually drives RL. Here we have performed optical stimulation of genetically targeted ventral tegmental area (VTA) dopamine neurons expressing Channelrhodopsin-2 (ChR2) in mice. We mimicked the transient activation of dopamine neurons that occurs in response to natural reward by applying a light pulse of 200 ms in VTA. When a single light pulse followed each self-initiated nose poke, it was sufficient in itself to cause operant reinforcement. Furthermore, when optical stimulation was delivered in separate sessions according to a predetermined pattern, it increased locomotion and contralateral rotations, behaviors that are known to result from activation of dopamine neurons. All three of the optically induced operant and locomotor behaviors were tightly correlated with the number of VTA dopamine neurons that expressed ChR2, providing additional evidence that the behavioral responses were caused by activation of dopamine neurons. These results provide strong evidence that the transient activation of dopamine neurons provides a functional reward signal that drives learning, in support of RL theories of dopamine function.     

Spike synchronization and firing rate in a population of motor cortical neurons in relation to movement direction and reaction time

 We studied the dynamics of precise spike synchronization and rate modulation in a population of neurons recorded in monkey motor cortex during performance of a delayed multidirectional pointing task and determined their relation to behavior. We showed that at the population level neurons coherently synchronized their activity at various moments during the trial in relation to relevant task events. The comparison of the time course of the modulation of synchronous activity with that of the firing rate of the same neurons revealed a considerable difference. Indeed, when synchronous activity was highest, at the end of the preparatory period, firing rate was low, and, conversely, when the firing rate was highest, at movement onset, synchronous activity was almost absent. There was a clear tendency for synchrony to precede firing rate, suggesting that the coherent activation of cell assemblies may trigger the increase in firing rate in large groups of neurons, although it appeared that there was no simple parallel shifting in time of these two activity measures. Interestingly, there was a systematic relationship between the amount of significant synchronous activity within the population of neurons and movement direction at the end of the preparatory period. Furthermore, about 400 ms later, at movement onset, the mean firing rate of the same population was also significantly tuned to movement direction, having roughly the same preferred direction as synchronous activity. Finally, reaction time measurements revealed a directional preference of the monkey with, once again, the same preferred direction as synchronous activity and firing rate. These results lead us to speculate that synchronous activity and firing rate are cooperative neuronal processes and that the directional matching of our three measures – firing rate, synchronicity, and reaction times – might be an effect of behaviorally induced network cooperativity acquired during learning. Received: 16 January 2002 / Accepted in revised form: 26 November 2002 / Published online: 7 April 2003 RID="*" ID="*" Present address: Istituto di Fisiologia Umana, Università di Parma, Via Volturno 39, 43100 Parma, Italy Correspondence to: A. Riehle (e-mail: ariehle@lnf.cnrs-mrs.fr, Tel.: +33-491-164329, Fax: +33-491-774969) Acknowledgements. We wish to thank Sonja Grün, Markus Diesmann, and Bill MacKay for many helpful and exciting discussions and one anonymous referee for her/his helpful comments. Special thanks go to Annette Bastian for her help in data collection, Michèle Coulmance for writing data acquisition and parts of data analysis software, and Marc Martin for animal welfare. This research was supported in part by the CNRS, GIS (Sciences de la Cognition), and ACI Cognitique (Invariants and Variability). FG was supported by the French government (MENRT).     

Changes in impulse activity of neurons of the CA3 area of the hippocampus under the effects of neuromodulator neurotropin]

Neurotropin (Nippon Zoki Co, Ltd) effects on firing patterns of the CA 3 hippocampus neurons in rabbits under a 24-h food deprivation was studied. Neuronal firing was recorded in a state of hunger (40 neurons) and under neurotropin (27 neurons) injected through a catheter implanted into the lateral brain ventricles. Initially, in 20% of neurons histograms had a bimodal interspike interval distribution: 1.5-25 ms and 100-400 ms. Neurotropin (50 microliters) increased the baseline spike rate regularity of hippocampus neurons. Histograms had a monomodal interspike interval distribution. Neurotropin (70 microliters) inhibited firing patterns and histograms, had trimodal interspike interval distribution: 1.5-5 ms; 250-400 ms and 1000 ms. Thus, these data suggested the involvement of neuro-immuno-modulator mechanisms in organization of firing patterns in rabbits.     

The faithful copy neuron

Theoretical and experimental evidence is presented for the presence in nervous tissue of neurons whose firing rate faithfully follow their input stimulus. Such neurons are shown to deliver their spikes with minimum dissipation per spike. This optimal performance is likely accomplished by use of local circuitry that adjusts conductances to match input currents so that the neuron operates near the threshold for firing. This results in an unusual mechanism for neuronal firing that uses background noise to achieve the desired firing rate. This framework takes place dynamically, and the present deliberations apply under time varying conditions. It is shown that an analytically explicit probability distribution function, which depends on one dimensionless parameter, can account for the interspike interval statistics under general time varying conditions. An innovative analysis based on the unsteady firing rate fits data to the appropriate probability distribution function.     

Defining the V5/MT neuronal pool for perceptual decisions in a visual stereo-motion task

In the primate visual cortex, neurons signal differences in the appearance of objects with high precision. However, not all activated neurons contribute directly to perception. We defined the perceptual pool in extrastriate visual area V5/MT for a stereo-motion task, based on trial-by-trial co-variation between perceptual decisions and neuronal firing (choice probability (CP)). Macaque monkeys were trained to discriminate the direction of rotation of a cylinder, using the binocular depth between the moving dots that form its front and rear surfaces. We manipulated the activity of single neurons trial-to-trial by introducing task-irrelevant stimulus changes: dot motion in cylinders was aligned with neuronal preference on only half the trials, so that neurons were strongly activated with high firing rates on some trials and considerably less activated on others. We show that single neurons maintain high neurometric sensitivity for binocular depth in the face of substantial changes in firing rate. CP was correlated with neurometric sensitivity, not level of activation. In contrast, for individual neurons, the correlation between perceptual choice and neuronal activity may be fundamentally different when responding to different stimulus versions. Therefore, neuronal pools supporting sensory discrimination must be structured flexibly and independently for each stimulus configuration to be discriminated.This article is part of the themed issue ‘Vision in our three-dimensional world''.     

Firing synchronization and temporal order in noisy neuronal networks

Noise-induced complete synchronization and frequency synchronization in coupled spiking and bursting neurons are studied firstly. The effects of noise and coupling are discussed. It is found that bursting neurons are easier to achieve firing synchronization than spiking ones, which means that bursting activities are more important for information transfer in neuronal networks. Secondly, the effects of noise on firing synchronization in a noisy map neuronal network are presented. Noise-induced synchronization and temporal order are investigated by means of the firing rate function and the order index. Firing synchronization and temporal order of excitatory neurons can be greatly enhanced by subthreshold stimuli with resonance frequency. Finally, it is concluded that random perturbations play an important role in firing activities and temporal order in neuronal networks.     

变间隔的脉冲改变高频刺激对于脑神经元的作用

通常采用恒定电脉冲间隔的高频刺激(high-frequency stimulation,HFS),进行深部脑刺激治疗帕金森氏症等运动障碍疾病.为了开发适用于不同脑疾病治疗的新刺激模式,近年来脉冲间隔(inter-pulse-interval,IPI)变化的变频刺激模式受到关注.已有研究表明,即使具有相同的平均电脉冲频率,变频刺激与恒频刺激的治疗效果也不同.我们推测,变频刺激的短小IPI变化就足以改变HFS对于神经元的作用.为了验证此推测,本文在大鼠海马CA1区锥体神经元的输入轴突纤维上交替施加恒频刺激(100或133 Hz,即IPI=10 ms或7.5 ms)和随机变频刺激(100～200 Hz,即IPI=5～10 ms,平均频率为133 Hz),记录并分析刺激下游神经元群体的诱发电位,用于定量评价神经元对于恒频和变频刺激的响应.实验结果表明,持续的恒频刺激使得神经元的响应从最初的同步发放形成的群峰电位(population spike,PS)转变为非同步的动作电位发放(即单元锋电位).但是,当刺激切换为变频模式时,却又可以诱发神经元群体同步产生动作电位,重新形成PS波.并且,变频刺激诱发的PS幅值和神经元发放的同步程度可达基线的单脉冲刺激诱发波的水平.但是,PS的发生率只有脉冲刺激频率的7%左右,表明在持续的变频刺激时,多个脉冲累积的作用才能诱发这种同步的神经元发放.而且PS的出现与前导IPI的长度之间存在一定关系.神经元的轴突和突触等结构对于高频刺激的非线性响应可能是变频刺激诱发同步活动的原因.这些结果表明,变频刺激序列中短小的间隔变化可以产生与恒定间隔不同的调控作用.本文的结果对于揭示脑刺激的作用机制,促进新型刺激模式的开发及其在不同类型脑疾病治疗中的应用具有重要意义.     

Dynamic behavior analysis of fractional-order Hindmarsh–Rose neuronal model

Previous experimental work has shown that the firing rate of multiple time-scales of adaptation for single rat neocortical pyramidal neurons is consistent with fractional-order differentiation, and the fractional-order neuronal models depict the firing rate of neurons more verifiably than other models do. For this reason, the dynamic characteristics of the fractional-order Hindmarsh–Rose (HR) neuronal model were here investigated. The results showed several obvious differences in dynamic characteristic between the fractional-order HR neuronal model and an integer-ordered model. First, the fractional-order HR neuronal model displayed different firing modes (chaotic firing and periodic firing) as the fractional order changed when other parameters remained the same as in the integer-order model. However, only one firing mode is displayed in integer-order models with the same parameters. The fractional order is the key to determining the firing mode. Second, the Hopf bifurcation point of this fractional-order model, from the resting state to periodic firing, was found to be larger than that of the integer-order model. Third, for the state of periodically firing of fractional-order and integer-order HR neuron model, the firing frequency of the fractional-order neuronal model was greater than that of the integer-order model, and when the fractional order of the model decreased, the firing frequency increased.     

Dopaminergic Control of the Globus Pallidus through Activation of D2 Receptors and Its Impact on the Electrical Activity of Subthalamic Nucleus and Substantia Nigra Reticulata Neurons

The globus pallidus (GP) receives dopaminergic afferents from the pars compacta of substantia nigra and several studies suggested that dopamine exerts its action in the GP through presynaptic D2 receptors (D2Rs). However, the impact of dopamine in GP on the pallido-subthalamic and pallido-nigral neurotransmission is not known. Here, we investigated the role of dopamine, through activation of D2Rs, in the modulation of GP neuronal activity and its impact on the electrical activity of subthalamic nucleus (STN) and substantia nigra reticulata (SNr) neurons. Extracellular recordings combined with local intracerebral microinjection of drugs were done in male Sprague-Dawley rats under urethane anesthesia. We showed that dopamine, when injected locally, increased the firing rate of the majority of neurons in the GP. This increase of the firing rate was mimicked by quinpirole, a D2R agonist, and prevented by sulpiride, a D2R antagonist. In parallel, the injection of dopamine, as well as quinpirole, in the GP reduced the firing rate of majority of STN and SNr neurons. However, neither dopamine nor quinpirole changed the tonic discharge pattern of GP, STN and SNr neurons. Our results are the first to demonstrate that dopamine through activation of D2Rs located in the GP plays an important role in the modulation of GP-STN and GP-SNr neurotransmission and consequently controls STN and SNr neuronal firing. Moreover, we provide evidence that dopamine modulate the firing rate but not the pattern of GP neurons, which in turn control the firing rate, but not the pattern of STN and SNr neurons.