Firing Rate Of Striatal Neurons Research Articles

Selective serotonin reuptake inhibitor treatment retunes emotional valence in primate ventral striatum.

Selective serotonin reuptake inhibitors (SSRIs) are widely used to treat psychiatric disorders with affective biases such as depression and anxiety. How SSRIs exert a beneficial action on emotions associated with life events is still unknown. Here we ask whether and how the effectiveness of the SSRI fluoxetine is underpinned by neural mechanisms in the ventral striatum. To address these issues, we studied the spiking activity of neurons in the ventral striatum of monkeys during an approach-avoidance task in which the valence assigned to sensory stimuli was manipulated. Neural responses to positive and negative events were measured before and during a 4-week treatment with fluoxetine. We conducted PET scans to confirm that fluoxetine binds within the ventral striatum at a therapeutic dose. In our monkeys, fluoxetine facilitated approach of rewards and avoidance of punishments. These beneficial effects were associated with changes in tonic and phasic activities of striatal neurons. Fluoxetine increased the spontaneous firing rate of striatal neurons and amplified the number of cells responding to rewards versus punishments, reflecting a drug-induced positive shift in the processing of emotionally valenced information. These findings reveal how SSRI treatment affects ventral striatum neurons encoding positive and negative valence and striatal signaling of emotional information. In addition to a key role in appetitive processing, our results shed light on the involvement of the ventral striatum in aversive processing. Together, the ventral striatum appears to play a central role in the action of SSRIs on emotion processing biases commonly observed in psychiatric disorders.

Dopamine D4 receptor modulates inhibitory transmission in pallido-pallidal terminals and regulates motor behavior.

Two major groups of terminals release GABA within the Globus pallidus; one group is constituted by projections from striatal neurons, while endings of the intranuclear collaterals form the other one. Each neurons' population expresses different subtypes of dopamine D2-like receptors: D2 R subtype is expressed by encephalin-positive MSNs, while pallidal neurons express the D4 R subtype. The D2 R modulates the firing rate of striatal neurons and GABA release at their projection areas, while the D4 R regulates Globus pallidus neurons excitability and GABA release at their projection areas. However, it is unknown if these receptors control GABA release at pallido-pallidal collaterals and regulate motor behavior. Here, we present neurochemical evidence of protein content and binding of D4 R in pallidal synaptosomes, control of [3 H] GABA release in pallidal slices of rat, electrophysiological evidence of the presence of D4 R on pallidal recurrent collaterals in mouse slices, and turning behavior induced by D4 R antagonist microinjected in amphetamine challenged rats. As in projection areas of pallidal neurons, GABAergic transmission in pallido-pallidal recurrent synapses is under modulation of D4 R, while the D2 R subtype, as known, modulates striato-pallidal projections. Also, as in projection areas, D4 R contributes to control the motor activity differently than D2 R. This study could help to understand the organization of intra-pallidal circuitry.

Corticostriatal synaptic weight evolution in a two-alternative forced choice task: a computational study

In natural environments, mammals can efficiently select actions based on noisy sensory signals and quickly adapt to unexpected outcomes to better exploit opportunities that arise in the future. Such feedback-based changes in behavior rely, in part, on long term plasticity within cortico-basal-ganglia-thalamic networks, driven by dopaminergic modulation of cortical inputs to the direct and indirect pathway neurons of the striatum. While the firing rates of striatal neurons have been shown to adapt across a range of feedback conditions, it remains difficult to directly assess the corticostriatal synaptic weight changes that contribute to these adaptive firing rates. In this work, we simulate the evolution of corticostriatal synaptic weights based on a spike timing-dependent plasticity rule driven by dopamine signaling that is induced by outcomes of actions in the context of a two-alternative forced choice task. Our results establish 1) that this plasticity model can successfully learn to select the most rewarding actions available, 2) that in the effective regime plasticity predominantly impacts direct pathway weights, evolving to drive action selection toward a more-rewarded action, and 3) that there can be coactivation of opposing populations within selected action channels, as observed experimentally. The model performance also agrees with the results of behavioral experiments carried out previously in human subjects using probabilistic reward paradigms.

Striatal firing rate reflects head movement velocity

Although the basal ganglia have long been implicated in the initiation of actions, their contribution to movement remains a matter of dispute. Using wireless multi-electrode recording and motion tracking, we examined the relationship between single-unit activity in the sensorimotor striatum and movement kinematics. We recorded single-unit activity from medium spiny projection neurons and fast-spiking interneurons while monitoring the movements of mice using motion tracking. In Experiment 1, we trained mice to generate movements reliably by water-depriving them and giving them periodic cued sucrose rewards. We found high correlations between single-unit activity and movement velocity in particular directions. This correlation was found in both putative medium spiny projection neurons and fast-spiking interneurons. In Experiment 2, to rule out the possibility that the observed correlations were due to reward expectancy, we repeated the same procedure but added trials in which sucrose delivery was replaced by an aversive air puff stimulus. The air puff generated avoidance movements that were clearly different from movements on rewarded trials, but the same neurons that showed velocity correlation on reward trials exhibited a similar correlation on air puff trials. These experiments show for the first time that the firing rate of striatal neurons reflects movement velocity for different types of movements, whether to seek rewards or to avoid harm.

Behavioral Sensitivity of Temporally Modulated Striatal Neurons

Recent investigations into the neural mechanisms that underlie temporal perception have revealed that the striatum is an important contributor to interval timing processes, and electrophysiological recording studies have shown that the firing rates of striatal neurons are modulated by the time in a trial at which an operant response is made. However, it remains unclear whether striatal firing rate modulations are related to the passage of time alone (i.e., whether temporal information is represented in an “abstract” manner independent of other attributes of biological importance), or whether this temporal information is embedded within striatal activity related to co-occurring contextual information, such as motor behaviors. This study evaluated these two hypotheses by recording from striatal neurons while rats performed a temporal production task. Rats were trained to respond at different nosepoke apertures for food reward under two simultaneously active reinforcement schedules: a variable-interval (VI-15 s) schedule and a fixed-interval (FI-15 s) schedule of reinforcement. Responding during a trial occurred in a sequential manner composing three phases; VI responding, FI responding, VI responding. The vast majority of task-sensitive striatal neurons (95%) varied their firing rates associated with equivalent behaviors (e.g., periods in which their snout was held within the nosepoke) across these behavioral phases, and 96% of cells varied their firing rates for the same behavior within a phase, thereby demonstrating their sensitivity to time. However, in a direct test of the abstract timing hypothesis, 91% of temporally modulated “hold” cells were further modulated by the overt motor behaviors associated with transitioning between nosepokes. As such, these data are inconsistent with the striatum representing time in an “abstract’ manner, but support the hypothesis that temporal information is embedded within contextual and motor functions of the striatum.

C-fos antisense oligonucleotides increase firing rate of striatal neurons in the anaesthetized rat

Extracellular electrophysiological recordings were used to study the firing rate of striatal neurons before and up to 4 h after intrastriatal c-fos antisense oligonucleotide injections in urethane-anesthetized rats. A four-fold increase from baseline neuronal activity was observed between 1 and 3 h upon antisense treatment, but not after control oligonucleotide injections. We conclude that, under urethane anesthesia, which here does not affect c-fos expression in the striatum by itself, neuronal activity appears to be tonically suppressed by basal striatal c-fos expression.

Inhibition of neuronal firing in murine striatal slices by cyclodiene insecticides is mediated by release of dopamine and not GABA antagonism

This study investigated the effects of dieldrin and heptachlor epoxide, members of the cyclodiene class of insecticides, on neuronal firing in murine brain slices. The cyclodienes are environmentally persistent and human exposure to these compounds still occurs. Major physiological effects of cyclodienes include: (1) blockage of 3 GABA A receptors and (2) facilitation of neurotransmitter release with specificity for release of dopamine. Extracellular recordings were used to compare the effects of the cyclodienes to those of the prototypical GABA antagonist, picrotoxinin, on firing rates of striatal neurons. Recordings were made from cells that were inhibited by exogenously applied dopamine, which is an ideal neural substrate for differentiating effects on dopamine release from GABA antagonism. Low micromolar concentrations of cyclodiene caused depression of firing, inconsistent with GABA antagonism. Alternatively, application of picrotoxinin produced a consistent neuronal excitation in slices. The inhibitory action of dieldrin was blocked by the dopamine receptor antagonist fluphenazine, verifying the fact that cyclodiene-released dopamine was mediating the observed depression of striatal neurons. These results suggest that the ability of cyclodienes to evoke neurotransmitter release, especially dopamine, may significantly contribute to the neurotoxicity of these compounds, in vivo.

Decline in striatal dopamine D 1 and D 2 receptor activation in aged F344 rats

Aging differentially affects receptor function. In the present electrophysiological study we compared neuronal responsiveness to locally applied dopamine D 1 and D 2 receptor agonist in the striatum of female Fischer 344 rats aged 3 and 26–27 months. In a subgroup of the old rats, the nigrostriatal dopamine bundle was destroyed unilaterally with 6-hydroxydopamine (6-OHDA) to assess receptor plasticity in response to denervation. Spontaneous firing rate of striatal neurons was higher in aged compared to young rats. Higher doses of the D 1 agonist SKF 38393 or the D 2 agonist quinpirole were required to elicit a 50% change in firing rate in aged compared to young rats. No difference with SKF 38393 or quinpirole was detected between 6-OHDA denervated and control (nonlesioned) striatum in aged rats. Supersensitivity to D 2 agonists has been reported following 6-OHDA lesions in young rats. These observations suggest that D 2 receptors in aged rat striatum might not be as plastic as in younger rats.

Dissociative anesthesia and striatal neuronal electrophysiology

Compared with results obtained in locally anesthetized, paralyzed rats, the dissociative anesthetic ketamine did not alter either the number of spontaneously active striatal neurons or the basal firing rate of striatal neurons; 90% of these cells exhibited the type I striatal neuron waveform. Chloral hydrate anesthesia suppressed both the occurrence and the firing rate of spontaneously active type I cells, but did not alter the activity of type II striatal neurons. Cortical stimulation preferentially activated type II cells in paralyzed rats and in chloral hydrate-anesthetized rats. Thus, under dissociative anesthesia it is possible to study spontaneously active type I striatal neurons. However, a method of activation such as cortical stimulation is necessary to study type II striatal neurons.

Activation of NMDA receptors induces dephosphorylation of DARPP-32 in rat striatal slices

In the caudate-putamen the glutamatergic cortical input and the dopaminergic nigrostriatal input have opposite effects on the firing rate of striatal neurons. Although little is known of the biochemical mechanisms underlying this antagonism, one action of dopamine is to stimulate the cyclic AMP-dependent phosphorylation of DARPP-32 (dopamine and cAMP-regulated phospho-protein, of relative molecular mass 32,000 (32K]. This phosphorylation converts DARPP-32 from an inactive molecule into a potent inhibitor of protein phosphatase-1. Here we show that activation of the NMDA (N-methyl-D-aspartate) subclass of glutamate receptors reverses the cAMP-stimulated phosphorylation of DARPP-32 in striatal slices through NMDA-induced dephosphorylation of DARPP-32. Thus, the antagonistic effects of dopamine and glutamate on the excitability of striatal neurons are reflected in antagonistic effects of these neurotransmitters on the state of phosphorylation of DARPP-32. Our results indicate that stimulation of NMDA receptors leads to the activation of a neuronal protein phosphatase, presumably the calcium-dependent phosphatase calcineurin, and show, in an intact cell preparation, that signal transduction in the nervous system can be mediated by protein dephosphorylation.

The spontaneous firing patterns of forebrain neurons. III. Prevention of induced asymmetries in caudate neuronal firing rates by unilateral thalamic lesions

Unilateral lesions interrupting striatal outputs and inputs (MFB lesions) produce a marked slowing of neuronal firing in the caudate nucleus contralateral to the side of the lesions without affecting neuronal firing in the ipsilateral caudate nucleus. Although the MFB lesion also interrupts the nigrostriatal pathway and depletes the ipsilateral striatum of dipamine and its associated enzymes, the slowing of unit firing rates is apparently due to interruption of striatal outputs rather than inputs. Unilateral thalamic lesions palced ipsilateral to MFB lesions in iether the ventral anterior-ventrolateral nuclei (VA-VL) or in the center median-parafascicular nuclei (CM-PF) prevent the MFB lesion-induced asymmetry in caudate neuronal firing rates. These thalamic lesions do not, however, restore the striatal dopamine content depleted by the MFB lesion. Unilateral CM-PF lesions in otherwise intact cats do not alter caudate unit firing rates nor do they affect striatal dopamine. VA-VL lesions in otherwise intact cats produce a bilateral slowing in the spontaneous firing of neurons in the caudate nuclei, again, whithout altering caudate dopamine concentrations. These results provide further evidence that caudate dopamine concentration per se does not appear to be a potent variable in controlling the spontaneous firing rates of striatal neurons.