Activity Of Striatal Neurons Research Articles

The adenosine A2A antagonist KF17837 reverses the locomotor suppression and tremulous jaw movements induced by haloperidol in rats: possible relevance to parkinsonism

Recent evidence indicates that adenosine A2A receptors modulate the activity of striatal neurons, and that antagonists of this receptor may have actions in various animal models related to motor function. Four experiments were conducted to study the effects of systemic injections of the adenosine A2A antagonist KF17837 on the behavioral effects produced by repeated administration of the dopamine (DA) antagonist haloperidol. In the first two experiments, it was shown that repeated 0.5 mg/kg haloperidol severely suppressed open-field locomotor activity, and that KF17837 (0.0–20.0 mg/kg) did not significantly increase open-field locomotor activity. The third experiment demonstrated that injections of KF17837 (0.0–20.0 mg/kg) completely reversed the suppression of locomotion induced by haloperidol, and also increased rearing behavior in haloperidol-treated rats. Previous research has reported that haloperidol induces tremulous jaw movements that have many of the characteristics of parkinsonian tremor. The fourth experiment demonstrated that i.p. injections of KF17837 (0.0–20.0 mg/kg) also suppressed haloperidol-induced tremulous jaw movements. Taken together, the results of these experiments indicate that adenosine A2A antagonism can reverse the locomotor suppression and tremulous movements induced by DA antagonism. This profile of activity is consistent with the hypothesis that antagonism of adenosine A2A receptors can result in an antiparkinsonian effect in animal models.

Rapid intravenous loading of levodopa for human research: clinical results

Levodopa has several advantages as a pharmacological challenge agent for human neuroscience research. Exogenous levodopa changes striatal neuronal activity and increases extracellular dopamine concentrations, and with adequate inhibition of peripheral metabolism levodopa does not change mean cerebral blood flow. For neuroimaging studies of Parkinson disease (PD) and Tourette syndrome, we sought to rapidly produce a biologically relevant steady-state levodopa concentration and then maintain that concentration for at least an hour. We also wished to minimize side effects, even in individuals without prior levodopa treatment. We designed a two-stage intravenous infusion protocol based on published levodopa pharmacokinetic data. We report results of 125 infusions in 106 subjects, including healthy volunteers, PD patients, and people with chronic tics. At higher doses (target steady-state levodopa concentrations of 2169 and 1200 ng/ml), treatment-naive volunteers had unacceptably frequent side effects. The final infusion protocol, with a target steady-state concentration of 600 ng/ml, was well-tolerated (mild nausea in 11% of subjects was the only side effect occurring significantly more than in single-blind saline infusions), produced the desired plasma levodopa concentration (612±187 ng/ml, mean±S.D.), and produced statistically significant antiparkinsonian benefit (16% mean reduction in a standard rating of parkinsonian motor signs, P<0.0005).

Neural Encoding in Ventral Striatum during Olfactory Discrimination Learning

A growing body of evidence implicates the ventral striatum in using information acquired through associative learning. The present study examined the activity of ventral striatal neurons in awake, behaving rats during go/no-go odor discrimination learning and reversal. Many neurons fired selectively to odor cues predictive of either appetitive (sucrose) or aversive (quinine) outcomes. Few neurons were selective when first exposed to the odors, but many acquired this differential activity as rats learned the significance of the cues. A substantial proportion of these neurons encoded the cues' learned motivational significance, and these neurons tended to reverse their firing selectivity after reversal of odor-outcome contingencies. Other neurons that became selectively activated during learning did not reverse, but instead appeared to encode specific combinations of cues and associated motor responses. The results support a role for ventral striatum in using the learned significance, both appetitive and aversive, of predictive cues to guide behavior.

Ciproxifan, a histamine H3-receptor antagonist/inverse agonist, modulates the effects of methamphetamine on neuropeptide mRNA expression in rat striatum.

We have explored the effect of histamine H3-receptor ligands on the regulation of neuropeptide mRNA expression in the striatum by using in situ hybridization performed with proenkephalin, prodynorphin, substance P and proneurotensin riboprobes. Acute administration of ciproxifan, an H3-receptor antagonist/inverse agonist, or (R)-alpha-methylhistamine, an H3-receptor agonist, did not modify the striatal expression of the neuropeptides by itself. However, ciproxifan strongly and differentially modulated the effect of a single administration of 3 mg/kg methamphetamine on neuropeptide mRNA expression. This modulation was suppressed by the administration of (R)-alpha-methylhistamine and occurred in both the caudate-putamen and nucleus accumbens. Ciproxifan strongly potentiated the decrease of proenkephalin mRNA expression induced by methamphetamine. In contrast, it suppressed the increase in prodynorphin and substance P mRNA expression induced by methamphetamine. Methamphetamine alone or with ciproxifan did not modify proneurotensin mRNA expression. These neurochemical findings indicate that ciproxifan differentially regulates the effect of methamphetamine on the neuropeptides contained in striatonigral and striatopallidal neurons. They suggest that endogenous histamine and dopamine cooperate to modulate the activity of striatal projection neurons and strengthen the interest of H3-receptors as new targets for the treatment of psychotic disorders and drug abuse.

Reorganization of Composition of Striatal Neurons Correlating with Behavior in the Monkey Macaca nemestrina

The available experimental data do not provide a sufficiently complete picture of the neuronal activity connected with some action of the animal, as they have been obtained under different experimental protocols and as a result of study of different cells. The present work was aimed at studying activity of the same neuron group at different moments of animal's behavior. A monkey (Macaca nemestrina) was taught to perform a behavioral program consisting of several functional heterogeneous actions. The impulsive activity of striatal neurons was recorded in the central region of putamen with coordinates A 16.5, L7, and H 8–10 [18]. The activity of each neuron was recorded during 13 consecutive stages of the same behavioral task. As a whole, in 59 putamen neurons, 767 fragments of neuronal activity were studied. It was shown that the same neurons could be involved at different behavioral stages when the animal performed different actions. At individual stages, the number of neurons common with other behavioral stages reached 70–80% of all reactive cells at the stage. The number of the neurons common within the rest of 12 stages was determined for every program stage. The number of such common neurons established in the experiment was in 142 out of 156 cases higher than their number that could be expected on the basis of statistical relations. The data obtained indicate that the reorganization in composition of behavior-reactive cells at every behavioral stage occurs mainly by using the same neurons but not only the neurons that are specialized for the given action. The polymodality of individual striatal neurons is unlikely to be connected with that they have several functions, but results from that the same neuron can be a constituent of neuronal mosaics of different configurations corresponding to different behavioral moments.

Compartment-specific changes in striatal neuronal activity during expression of amphetamine sensitization are the result of drug hypersensitivity.

Repeated exposure to drugs of abuse induces behavioural sensitization, i.e. a persistent hypersensitivity to the psychomotor stimulant effects of these drugs. This may be the result of increased responsiveness, to drugs, of mesostriatal dopamine systems and their projections, but it has also been suggested that acute and sensitized behavioural responses to psychostimulant drugs involve activation of distinct neuronal circuits. In order to distinguish between these possibilities, we studied amphetamine-induced c-fos immunoreactivity in subregions of rat striatum (patch and matrix compartments of caudate-putamen and nucleus accumbens core and shell) in drug-naive rats, as well as during long-term expression of amphetamine sensitization. We found that, in sensitized animals, amphetamine (1.0 mg/kg) evoked an increase in the ratio of c-fos-immunopositive cells in striatal patch and matrix compartments, suggesting a preferential involvement of striatal patches in the sensitized response to amphetamine. In drug-naive rats, amphetamine (0.5-5.0 mg/kg) dose-dependently increased c-fos expression in all striatal subregions. Remarkably, the highest dose of amphetamine also evoked an increase in patch : matrix ratio of c-fos immunoreactivity. In nucleus accumbens core and shell of amphetamine- and saline-pretreated animals, amphetamine (1.0 mg/kg) evoked comparable increases in c-fos expression. These data indicate that distinct striatal compartments display a differential sensitivity to amphetamine in both drug-naive and amphetamine-sensitized animals. In addition, they suggest that the shift in amphetamine-induced c-fos expression from striatal matrix to patches in sensitized animals is the consequence of a change in the sensitivity to amphetamine, rather than a long-term circuitry reorganization that is exclusive to the sensitized state.

Tissue plasminogen activator is required for corticostriatal long-term potentiation.

Several experimental data indicate that tissue plasminogen activator (tPA) is involved in memory formation and synaptic plasticity in different brain areas. In the attempt to highlight the role of this serine protease in striatal neuron activity, mice lacking tPA have been used for electrophysiological, immunohistochemical and Western blot experiments. Disruption of tPA gene prevented corticostriatal long-term potentiation, an NMDA-dependent form of synaptic plasticity requiring the stimulation of both dopamine and acetylcholine receptors. Spontaneous and evoked glutamatergic transmission was intact in the striatum of tPA-deficient mice, as was the nigrostriatal dopamine innervation and the expression of dopamine D1 receptors. Conversely, the sensitivity of striatal cholinergic interneurons to dopamine D1 receptor stimulation was lost in these mutants, suggesting that tPA facilitates long-term potentiation (LTP) induction in the striatum by favouring the D1 receptor-mediated excitation of acetylcholine-producing interneurons. The demonstration that tPA ablation interferes with the induction of corticostriatal LTP and with the dopamine receptor-mediated control of cholinergic interneurons might help to explain the altered striatum-dependent learning deficits observed in tPA-deficient mice and provides new insights into the molecular mechanisms underlying synaptic plasticity in the striatum.

Differential activation of monkey striatal neurons in the early and late stages of procedural learning.

The basal ganglia is a key structure for procedural learning. To examine in what aspects of procedural learning the basal ganglia participate, we recorded from striatal neurons (phasically active neurons) in monkeys while the animals were performing a sequential button press task (the 2 x 5 task) and compared the neuronal activity between two conditions: (1) while learning new sequences and (2) while executing overlearned sequences. Among 147 neurons recorded in two monkeys, 45 neurons were activated preferentially for new sequences (new-preferring neurons), 34 for overlearned sequences (learned-preferring neurons), and 68 were activated non-selectively (non-selective neurons). New-preferring neurons were more abundant in the "association" region [association striatum (AS); caudate nucleus and rostral putamen anterior to the anterior commissure], while the learned-preferring neurons were more abundant in the "sensorimotor" region [sensorimotor striatum (SM); putamen posterior to the anterior commissure]. In addition to the learning dependency, the AS and SM neurons were activated in different task periods: many AS neurons were activated during the delay period, while the SM neurons were more activated with reaching and button presses. These data, together with the data from our previous blockade study, suggest that the "association" and "sensorimotor" regions of the basal ganglia contribute preferentially to the early and late stages of procedural learning, respectively.

Fetal Striatal Transplants Restore Electrophysiological Sensitivity to Dopamine in the Lesioned Striatum of Rats with Experimental Huntington’s Disease

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson’s disease and Huntington’s chorea. With the loss of neurons in the striatum of patients with Huntington’s disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of γ-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.

Relationship between obsessive-compulsive disorder and chaos

Pharmacological treatment using serotonin reuptake inhibitors is often useful for patients with obsessive-compulsive disorder (OCD). Brain imaging studies indicated that hyperactivity of the striatum observed in OCD patients is normalized after successful pharmacological treatment. But, so far, there is no available model, which can explain both of these phenomena. This report proposes a hypothesis that serotonin reuptake inhibitors can induce chaos in the activity of striatal neurons and this chaotic behavior is essential to improve OCD symptoms and normalize the hyperactivity in the striatum. Moreover, it can be explained also by this model that there exists a subtype of patients for whom pharmacological treatment is not useful. As a method, simulation using the Hodgkin–Huxley equations and the chaotic neural network, which can reproduce the chaotic behavior in the real neuron, are used.

Fetal striatal transplants restore electrophysiological sensitivity to dopamine in the lesioned striatum of rats with experimental Huntington's disease.

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson's disease and Huntington's chorea. With the loss of neurons in the striatum of patients with Huntington's disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of gamma-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.

Two-State Membrane Potential Transitions of Striatal Spiny Neurons as Evidenced by Numerical Simulations and Electrophysiological Recordings in Awake Monkeys

Spontaneous membrane potential fluctuations of striatal spiny projection neurons play a crucial role in their spike generation. Previous intracellular recording studies in anesthetized rats have shown that the membrane potential of striatal spiny neurons shifts between the depolarized "up" state and the hyperpolarized "down" state. Here we report evidence for the occurrence of such two-state membrane potential transitions by numerical simulations and electrophysiological recordings in awake monkeys. Data from our simulations of a striatal spiny neuron model demonstrated that spike latency histograms of the model neuron displayed two separate (i.e., early and late) peaks in response to excitatory cortical input, corresponding to neuronal activity in the up or down state, respectively. Then, we addressed experimentally whether the latency distribution of cortically induced spike firing of striatal spiny neurons might show dual peaks. Striatal neuron activity was extracellularly recorded in response to electrical stimulation in the two cortical motor-related areas, the primary motor cortex and the supplementary motor area, of awake monkeys. Analysis of spike latency histograms has defined that striatal spiny neurons typically exhibit two temporally distinct peaks, as obtained by the numerical simulations. Thus, the membrane potential shifts between the up and down states appear to occur in striatal spiny neurons of the behaving animal.

Activation of dopamine D1-like receptors excites LTS interneurons of the striatum.

Dopamine (DA) has a crucial role in the modulation of striatal neuron activity. Along with projection cells, striatal interneurons receive dense dopaminergic innervation from midbrain neurons, thus, also suggesting that these intrinsic cells represent a synaptic target for DA action in the striatum. In the present study, we investigated the effects of DA on low-threshold spike (LTS) interneurons of the rat striatum, by means of in vitro whole-cell patch-clamp electrophysiological recordings. Dopamine depolarized LTS cells, a pharmacological effect prevented by D1- but not D2-like DA receptor antagonists. The membrane depolarization produced by DA was sufficient to trigger action potential discharge in the recorded cells and was insensitive to tetrodotoxin and glutamate receptor antagonists. In addition, this pharmacological effect was mimicked by D1- but not D2-like DA receptor agonists, implying the selective involvement of D1-like receptors in this action.

Inhibition of nitric oxide synthase influences the activity of striatal neurons in the rat

The activity of single units in the striatum of urethane-anesthetized rats was recorded before and after the systemic administration of 7-nitro-indazole (7-NI; 50 mg/kg intraperitoneally), a selective inhibitor of neuronal nitric oxide (NO) synthase. Two neuronal types were clearly distinguishable electrophysiologically, on the basis of either discharge frequency pattern or features of the individual spike waveform (spike duration, negative phase/total duration ratio, and negative phase/total amplitude ratio). Only sporadically discharging neurons (basal firing rate, <0.1 spikes/s) were influenced by 7-NI, which caused a statistically significant increase in their firing rate. In contrast, the activity of continuously discharging neurons (basal firing rate, 4–6 spikes/s) was not affected. We hypothesize that NO neurotransmission could exert a tonic inhibitory influence upon sporadically discharging striatal neurons, which are presumably striatal output neurons.

Activation of metabotropic glutamate receptor mediates upregulation of transcription factor mRNA expression in rat striatum induced by acute administration of amphetamine

Metabotropic glutamate receptors (mGluRs) are densely expressed on the medium spiny projection neurons of rat striatum. Intrastriatal injection of an mGluR agonist increases motor activity and dopamine release in the striatum. This study investigated the roles of mGluRs in the regulation of behavioral activity and transcription factor gene expression in striatal neurons in normal and amphetamine-treated rats. Acute injection of a behaviorally active dose of amphetamine (4.0 mg/kg, i.p.) elevated basal levels of the transcription factor c- fos and zif/268 mRNAs in the dorsal striatum as revealed by quantitative in situ hybridization. Pharmacological blockade of mGluRs with bilateral injections of a non-selective mGluR antagonist, ( S)-α-methyl-4-carboxyphenylglycine (MCPG), into the dorsal striatum at 10 but not 0.4 nmol significantly attenuated amphetamine-stimulated c- fos mRNA expression in this area. In contrast to c- fos, striatal zif/268 induction stimulated by amphetamine was not altered by pretreatment with MCPG. MCPG by itself did not affect basal levels of either gene expression in the striatum. No significant effects of MCPG were found on spontaneous or amphetamine-stimulated behavioral activities. These data indicate that blockade of total mGluRs in the dorsal striatum has a selective effect on dopamine-stimulated gene expression. Activation of the MCPG-sensitive mGluRs is required for the upregulation of transcription factor c- fos, although not zif/268, mRNA expression in the striatum in response to acute injection of amphetamine.

In Vivo Extracellular Recording of Striatal Neurons in the Awake Rat Following Unilateral 6-Hydroxydopamine Lesions

The purpose of this study was to further understand the functional effects of dopaminergic input to the dorsal striatum and to compare the effects of dopaminergic lesions in awake and anesthetized animals. We examined the effects of unilateral 6-hydroxydopamine (6-OHDA) lesions of the ascending dopaminergic bundle on the firing properties of dorsal striatal neurons in the awake freely moving rat using chronically implanted microwire electrode arrays. We recorded extracellular activity of striatal neurons under baseline conditions and following the systemic injection of apomorphine in awake and anesthetized subjects. Firing rates were higher in the hemisphere ipsilateral to the 6-OHDA lesion compared to rates of neurons from the contralateral unlesioned hemisphere. Striatal firing rates from sham and no-surgery control rats were, in general, higher than those from the contralateral unlesioned striatum of experimental subjects. Apomorphine (0.05 mg/kg, sc) normalized the differences in firing rates in lesioned animals by increasing firing of neurons within the contralateral unlesioned side, while simultaneously decreasing firing of neurons within the ipsilateral lesioned side. Mean firing rates were substantially higher in awake animals than in subjects anesthetized with chloral hydrate, perhaps reflecting anesthesia-induced decreases in excitatory input to striatal neurons. Chloral hydrate anesthesia decreased firing rates of neurons in the lesioned, unlesioned, and control striata to a similar degree, although absolute firing rates of neurons from the 6-OHDA-lesioned striata remained elevated over all other groups. Unilateral 6-OHDA lesions also altered the pattern of spike output in the awake animal as indicated by an increase in the number of bursts per minute following dopaminergic deafferentation. This and other burst parameters were altered by apomorphine. Our findings show that effects of dopaminergic deafferentation can be measured in the awake behaving animal; this model should prove useful for testing the behavioral and functional effects of experimental manipulations designed to reduce or reverse the effects of dopaminergic cell loss. In addition, these results suggest that the contralateral changes in striatal function which occur in the unilateral dopaminergic lesion model should be considered when evaluating experimental results.

Altered dopaminergic transmission in the anorexic anx/anx mouse striatum.

We demonstrate abnormal dopaminergic neurotransmission in anorexic mice, homozygous for a recessive mutation (anx) causing starvation and motor disturbances. Isolated neurons from anx/anx striatum displayed a markedly increased activity of the Na+,K+-ATPase compared with normal littermates. Dopamine down-regulates Na+,K+-ATPase activity in striatal medium spiny neurons in rat, mouse and guinea pig. However, addition of dopamine in vitro failed to suppress the increased activity in anx/anx striatal neurons. Striatal dopamine and its metabolites, but not norepinephrine, were slightly but significantly lower in anx/anx mice than in normal littermates. We suggest that abnormal dopaminergic transmission may contribute to the anx phenotype.

Age-related changes in striatal function of freely-moving F344 rats.

Multi-wire electrode arrays were used to record extracellular electrophysiological activity in striatal medium spiny-like neurons of freely-moving young (6-8 months) and aged (24-26 months) Fischer 344 rats. While overall basal firing rates did not differ between the two groups, d-amphetamine (5.0 mg/kg) increased firing rates more in the young rats. D-Amphetamine had heterogeneous effects on firing rates, however, exciting 63% of the neurons while inhibiting 37%. Neurons were classified according to their response to d-amphetamine (excited vs. inhibited) to examine age-related differences in firing rates and bursting activity. In the d-amphetamine-excited neurons, pre-drug intraburst firing rates were higher in the old rats. This effect was reversed by d-amphetamine. D-Amphetamine increased the percentage of spikes within bursts to a greater extent in the aged animals and decreased burst durations greater in the young group. In d-amphetamine-inhibited neurons, firing rates were diminished in the old rats more than they were in the young rats. These results demonstrate age-related alterations in striatal electrophysiological activity that may help explain motor deficits seen in senescence.

Temporal Difference Model Reproduces Anticipatory Neural Activity

Anticipatory neural activity preceding behaviorally important events has been reported in cortex, striatum, and midbrain dopamine neurons. Whereas dopamine neurons are phasically activated by reward-predictive stimuli, anticipatory activity of cortical and striatal neurons is increased during delay periods before important events. Characteristics of dopamine neuron activity resemble those of the prediction error signal of the temporal difference (TD) model of Pavlovian learning (Sutton & Barto, 1990). This study demonstrates that the prediction signal of the TD model reproduces characteristics of cortical and striatal anticipatory neural activity. This finding suggests that tonic anticipatory activities may reflect prediction signals that are involved in the processing of dopamine neuron activity.

Relationship between EEG potentials and intracellular activity of striatal and cortico-striatal neurons: an in vivo study under different anesthetics.

The functions of the basal ganglia are achieved through excitation of striatal output neurons (SONs) by converging cortical glutamergic afferents. We assessed the relationship between different patterns of activity in cortico-striatal (C-S) cells and the electrical behavior of SONs in vivo. Intracellular activities of rat C-S neurons in the orofacial motor cortex and of SONs, located in the projection field of this cortical region, were recorded under different anesthetics, which generate various temporal patterns of cortical activity. A surface electroencephalogram (EEG) of the orofacial motor cortex was simultaneously performed with intracellular recordings and EEG waves were used as correlates of a coherent synaptic activity in cortical neurons. Under barbiturate anesthesia C-S neurons showed rhythmic (5--7 Hz) supra-threshold depolarizations in phase with large amplitude EEG waves. The correlative activity of SONs was characterized by large amplitude oscillation-like synaptic depolarizations that could trigger action potentials. Under ketamine-xylazine anesthesia C-S neurons exhibited a step-like behavior consisting of depolarizing plateaus (up states), leading to multiple spike discharges, interrupted by hyperpolarizing periods (down states). The related activity of SONs was step-like membrane potential fluctuations with firing confined to the early part of the striatal up state. In C-S neurons and SONs up states coincided with slow recurrent EEG waves (approximately 1 Hz). Finally, under neurolept-analgesia an apparently disorganized EEG activity was associated with a lack of rhythmic discharge in C-S neurons. This uncorrelated activity in C-S neurons resulted in an absence of spontaneous firing as well as of large amplitude synaptic depolarizations in SONs. In the present study we demonstrate that SONs shape their input-output relationship by filtering out uncorrelated synaptic activity and that a minimal synchronization in the cortico-striatal afferents is required to produce significant synaptic depolarization in SONs.