Coding movement direction by burst firing in electrosensory neurons

Directional selectivity, in which neurons respond strongly to an object moving in a given direction ("preferred") but respond weakly or not at all to an object moving in the opposite direction ("null"), is a critical computation achieved in brain circuits. Previous measures of direction selectivity have compared the numbers of action potentials elicited by each direction of movement, but most sensory neurons display patterning, such as bursting, in their spike trains. To examine the contribution of patterned responses to direction selectivity, we recorded from midbrain neurons in weakly electric fish and found that most neurons responded with a combination of both bursts and isolated spikes to moving object stimuli. In these neurons, we separated bursts and isolated spikes using an interspike interval (ISI) threshold. The directional bias of bursts was significantly higher than that of either the full spike train or the isolated spike train. To examine the encoding and decoding of bursts, we built biologically plausible models that examine 1) the upstream mechanisms that generate these spiking patterns and 2) downstream decoders of bursts. Our model of upstream mechanisms uses an interaction between afferent input and subthreshold calcium channels to give rise to burst firing that occurs preferentially for one direction of movement. We tested this model in vivo by application of calcium antagonists, which reduced burst firing and eliminated the differences in direction selectivity between bursts, isolated spikes, and the full spike train. Our model of downstream decoders used strong synaptic facilitation to achieve qualitatively similar results to those obtained using the ISI threshold criterion. This model shows that direction selective information carried by bursts can be decoded by downstream neurons using biophysically plausible mechanisms.     

Nicotinic effects on the firing pattern of midbrain dopamine neurons

The effects of systemic administration of nicotine or the nicotinic antagonist mecamylamine on the midbrain dopamine (DA) systems of the rat were studied with single cell recording techniques. Dopamine cells of the zona compacta, substantia nigra (ZC-SN) and the ventral tegmental area (VTA) were identified by their characteristic action potentials, antidromic stimulation methodology and conventional histological procedures. Firing rates as well as firing patterns were determined from computer-generated interspike interval histograms describing burst-firing in relation to single-spike firing. A larger proportion of burst-firing DA cells was found in the VTA when compared with the ZC-SN area. (-)-Nicotine bitartrate (0.5 mg kg-1 i.p.) not only increased the firing rate of ZC-SN neurons but also the amount of burst firing of the ZC-SN neurons and VTA neurons, respectively. Mecamylamine HCl (4.0 mg kg-1 i.p.) decreased the firing rate of VTA cells which, in principle, indicates a tonic nicotinic input in this area. The increase in firing rate of central DA neurons following nicotine administration was found to be associated with increased bursting of the burst firing cells whereas, in contrast, the non-bursting neurons did not respond with burst-firing. Generally, the correlation between nicotine induced changes in firing rate and in burst-firing activity, respectively, was found to be low for midbrain DA neurons. These observations, in conjunction with the previous demonstration of nicotinic receptors in these areas, indicate the existence of a nicotinic input, specifically regulating the firing pattern of these central DA cells. This neuromodulatory effect of nicotine may be significant for its behavioural stimulant action.(ABSTRACT TRUNCATED AT 250 WORDS)     

Artificial electrotonic coupling affects neuronal firing patterns depending upon cellular characteristics

While there have been numerous theoretical studies indicating that electrotonic coupling via gap junctions interacts with the intrinsic characteristics of the coupled neurons to modify their electrical behaviour, little experimental evidence has been provided in coupled mammalian neurons. Using an artificial electrotonic junction, two distant uncoupled neurons were coupled through the computer, and the coupling conductance was varied. Tonically firing CA1 hippocampal pyramidal neurons reduced their spike firing frequency when coupled to thalamic or pyramidal cells, showing that the electrical coupling can be considered as a low-pass filter. The strength of coupling needed to entrain spike bursts of pyramidal neurons was considerably lower than the coupling needed to synchronize two neurons with different cellular characteristics (thalamic and pyramidal cells). Coupling promoted burst firing in a non-bursting cell if it was coupled to a spontaneously bursting neuron.These results support modelling studies that indicate a role for gap-junctional coupling in the synchronization of neuronal firing and the expression of low-frequency bursting.     

Dendritic modulation of burst-like firing in sensory neurons

This report describes the variability of spontaneous firing characteristics of sensory neurons, electrosensory lateral line lobe (ELL) pyramidal cells, within the electrosensory lateral line lobe of weakly electric fish in vivo. We show that these cells' spontaneous firing frequency, measures of spike train regularity (interspike interval coefficient of variation), and the tendency of these cells to produce bursts of action potentials are correlated with the size of the cell's apical dendritic arbor. We also show that bursting behavior may be influenced or controlled by descending inputs from higher centers that provide excitatory and inhibitory inputs to the pyramidal cells' apical dendrites. Pyramidal cells were classified as "bursty" or "nonbursty" according to whether or not spike trains deviated significantly from the expected properties of random (Poisson) spike trains of the same average firing frequency, and, in the case of bursty cells, the maximum within-burst interspike interval characteristic of bursts was determined. Each cell's probability of producing bursts above the level expected for a Poisson spike train was determined and related to spontaneous firing frequency and dendritic morphology. Pyramidal cells with large apical dendritic arbors have lower rates of spontaneous activity and higher probabilities of producing bursts above the expected level, while cells with smaller apical dendrites fire at higher frequencies and are less bursty. The effect of blocking non-N-methyl-D-aspartate (non-NMDA) glutamatergic synaptic inputs to the apical dendrites of these cells, and to local inhibitory interneurons, significantly reduced the spontaneous occurrence of spike bursts and intracellular injection of hyperpolarizing current mimicked this effect. The results suggest that bursty firing of ELL pyramidal cells may be under descending control allowing activity in electrosensory feedback pathways to influence the firing properties of sensory neurons early in the processing hierarchy.     

SK Ca2+-activated K+ channel ligands alter the firing pattern of dopamine-containing neurons in vivo

Apamin-sensitive, SK channels play an important role in generating the rhythmic firing patterns exhibited by midbrain dopamine neurons in vitro. However, their contribution to the firing properties of these cells in intact animals has yet to be determined. In the present series of experiments, extracellular single unit recording techniques were used to assess the central effects of prototypical SK channel ligands on the firing pattern of dopamine neurons in the substantia nigra of the chloral hydrate anesthetized rat. I.v. administration of the SK channel blocker apamin (0.4 mg/kg), increased bursting activity in approximately 50% of the dopamine neurons tested without altering average firing rate. The majority of these cells responded slowly to the effects of apamin, gradually transitioning from an irregular single spike to a phasic discharge composed of the same relative proportion of long (>or=three spike) and short (two spike) bursts as "natural" bursting activity recorded in drug naive animals. Local administration of apamin increased bursting activity in all cells tested. Systemic administration of the SK channel opener, 1-ethyl-2-benzimidazolinone (5-25 mg/kg) also had no effect on average firing rate but suppressed bursting activity and increased the precision of firing. The effects of 1-ethyl-2-benzimidazolinon on firing pattern were abolished when recording electrodes contained apamin (125 microM). These results suggest that SK channels actively contribute to the spontaneous firing patterns exhibited by dopamine neurons in vivo and provide additional support for the proposition that this channel could serve as a useful target for modifying their activity.     

Dopamine neurons in the ventral tegmental area fire faster in adolescent rats than in adults

Adolescence may be a period of vulnerability to drug addiction. In rats, elevated firing activity of ventral tegmental area (VTA) dopamine neurons predicts enhanced addiction liability. Our aim was to determine if dopamine neurons are more active in adolescents than in adults and to examine mechanisms underlying any age-related difference. VTA dopamine neurons fired faster in adolescents than in adults as measured with in vivo extracellular recordings. Dopamine neuron firing can be divided into nonbursting (single spikes) and bursting activity (clusters of high-frequency spikes). Nonbursting activity was higher in adolescents compared with adults. Frequency of burst events did not differ between ages, but bursts were longer in adolescents than in adults. Elevated dopamine neuron firing in adolescent rats was also observed in cell-attached recordings in ex vivo brain slices. Using whole cell recordings, we found that passive and active membrane properties were similar across ages. Hyperpolarization-activated cation currents and small-conductance calcium-activated potassium channel currents were also comparable across ages. We found no difference in dopamine D2-class autoreceptor function across ages, although the high baseline firing in adolescents resulted in autoreceptor activation being less effective at silencing neurons. Finally, AMPA receptor-mediated spontaneous excitatory postsynaptic currents occurred at lower frequency in adolescents; GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents occurred at both lower frequency and smaller amplitude in adolescents. In conclusion, VTA dopamine neurons fire faster in adolescence, potentially because GABA tone increases as rats reach adulthood. This elevation of firing rate during adolescence is consistent with it representing a vulnerable period for developing drug addiction.     

Burst firing of mesencephalic dopamine neurons is inhibited by somatodendritic application of kynurenate

Midbrain dopamine neurons of the zona compacta substantia nigra (SN) and ventral tegmental area (VTA), giving rise to the nigrostriatal and mesolimbocortical midbrain dopamine pathways, respectively, typically display a spontaneous activity consisting of single spikes and bursts. Previously, intracerebroventricular administration of the excitatory amino acid (EAA) antagonist kynurenate has been shown to inhibit burst firing and induce a regular, pacemaker-like firing of ventral tegmental area midbrain dopamine neurons. In the present experiments, zona compacta substantia nigra and ventral tegmental area midbrain dopamine neurons were recorded in the chloral hydrate anaesthetized male rat. Kynurenate was administered locally, either by micro-iontophoresis or by pneumatic (micropressure) ejection. Both forms of local kynurenate application produced an immediate inhibition of burst firing and a slightly increased regularity of firing in both zona compacta substantia nigra and ventral tegmental area midbrain dopamine neurons. The present results indicate that excitatory amino acid nerves tonically modulate midbrain dopamine neuronal burst firing directly on the midbrain dopamine cell bodies, further stressing the importance of excitatory amino acid innervation in the physiological function of midbrain dopamine neurons, particularly in the dynamic aspects involved in the behavioural modulation and pharmacological responses of these psychopharmacologically important neurons.     

Stimulation of the pedunculopontine tegmental nucleus in the rat produces burst firing in A9 dopaminergic neurons.

Stimulation of the medial prefrontal cortex in the rat produces events in midbrain dopaminergic neurons which resemble natural bursts, and which are closely time-locked to the stimulation, albeit with a very long latency. As a consequence, we have previously argued that such bursts are polysynaptically generated via more proximal excitatory amino acidergic afferents, arising, for example, from the pedunculopontine tegmental nucleus. In the present study, single-pulse electrical stimulation applied to this nucleus (and other sites in the rostral pons) was found to elicit responses in the majority of substantia nigra (A9) dopaminergic neurons. Responses usually consisted of long-latency, long-duration excitations or inhibition-excitations. Thirty-seven percent of responses (currents combined) elicited by stimulation of the pedunculopontine tegmental nucleus contained time-locked bursts, the bursts being embedded in the long-duration excitatory phases of excitation and inhibition-excitation responses. Stimulation sites located within 0.5 mm of the pedunculopontine tegmental nucleus were also effective at eliciting time-locked bursts (although less so than sites located in the nucleus itself), whereas more distal sites were virtually ineffective. For responses containing time-locked bursts, a higher percentage of stimulations produced a burst when the response was elicited from within the pedunculopontine tegmental nucleus than when it was elicited from outside: the bursts themselves having a very long latency (median of 96.2 ms; shorter than that of medial prefrontal cortex-induced bursts). Finally, although there was no difference in the distribution within the substantia nigra pars compacta of cells which exhibited time-locked bursting and those which did not, stimulation-induced bursts were elicited more frequently in dopaminergic neurons which were classified as "bursting" on the basis of their basal activity. The pedunculopontine tegmental nucleus appears to be a critical locus in the rostral pons for the elicitation of time-locked bursts in A9 dopaminergic neurons. Since time-locked bursts were more often elicited from cells which exhibited bursting under basal conditions, this suggests that rostral pontine sites, in particular the pedunculopontine tegmental nucleus, may play a role in the natural burst activity of dopaminergic neurons. Given that bursts in dopaminergic neurons are generated in response to primary and secondary reinforcers, the projection from the pedunculopontine tegmental nucleus could be one means by which motivationally relevant information (arising, for example, from the medial prefrontal cortex) reaches these cells.     

The ventral tegmental area revisited: is there an electrophysiological marker for dopaminergic neurons?

The ventral tegmental area (VTA) and in particular VTA dopamine (DA) neurons are postulated to play a central role in reward, motivation and drug addiction. However, most evidence implicating VTA DA neurons in these functions is based on indirect electrophysiological characterization, rather than cytochemical identification. These physiological criteria were first established in the substantia nigra pars compacta (SNc), but their validity in the VTA is uncertain. In the current study we found that while 88 ± 2% of SNc neurons labelled by the neuronal marker NeuN were co-labelled for the catecholamine enzyme tyrosine hydroxylase (TH), a much smaller percentage (55 ± 2%) of VTA neurons co-expressed TH. In addition, using in vitro whole-cell recordings we found that widely accepted physiological criteria for VTA DA neurons, including the hyperpolarization-activated inwardly rectifying non-specific cation current ( I _h), spike duration, and inhibition by DA D2 receptor agonists, do not reliably predict the DA content of VTA neurons. We could not distinguish DA neurons from other VTA neurons by size, shape, input resistance, I _h size, or spontaneous firing rate. Although the absence of an I _h reliably predicted that a VTA neuron was non-dopaminergic, and I _h(−) neurons differ from I _h(+) neurons in firing rate, interspike interval (ISI) standard deviation, and ISI skew, no physiological property examined here is both sensitive and selective for DA neurons in the VTA. We conclude that reliable physiological criteria for VTA DA neuron identification have yet to be determined, and that the criteria currently being used are unreliable.     

Increased phasic dopamine signaling in the mesolimbic pathway during social defeat in rats

While reward-dependent facilitation of phasic dopamine signaling is well documented at both the cell bodies and terminals, little is known regarding fast dopamine transmission under aversive conditions. Exposure to aggressive confrontation is extremely aversive and stressful for many species including rats. The present study used fast-scan cyclic voltammetry and multiunit recording to determine if aggressive encounters and subsequent social defeat affect burst firing of ventral tegmental area (VTA) dopamine neurons and accumbal dopamine transients in defeated rats. Significant increases in the frequency of transient dopamine release were observed during interactions with an aggressive rat but not with a familiar cage mate. In agreement with voltammetric results, significant increases in burst frequency were detected in the VTA dopamine firing patterns during an aggressive confrontation; however, the number of spikes per burst remained unchanged. We found that neurons with lower burst rates under home cage conditions did not switch from nonbursting to bursting types, while neurons with higher burst levels showed amplified increases in bursting. This study demonstrates for the first time that aggressive confrontations in defeated rats are associated with increases in phasic dopamine transmission in the mesolimbic pathway.     

Patterns of neuronal firing in the human lateral thalamus during sleep and wakefulness

The firing patterns of thalamic neurons in mammals undergo a dramatic change as the animal's state changes between sleep and wakefulness. During sleep the normal tonic firing of thalamic neurons changes into a slower bursting mode characterized by repetitive activation of a low-threshold calcium (Ca²⁺) current. The present report describes the patterns of thalamic neuronal firing during sleep and wakefulness in one human patient. Extracellular single neuron activity was recorded during functional stereotactic surgery in the thalamus of a patient with chronic pain, who was observed to fall asleep during the recording. Evolutive power spectra of the thalamic slow wave were used in place of cortical encephalography to confirm the patient's states of sleep and wakefulness. Twenty-nine sites were observed in motor and somatosensory thalamus (Vop, Vim, and Vc) that were characterized by the presence of neurons with bursting activity when the patient was asleep. Such bursting was not observed in the patient when she was awakened. At 14 of these sites we were able to discriminate the bursting activity of single units. In each case the cell stopped firing or its bursting was replaced by a tonic firing pattern when the patient was awakened. In three cases the patient began to lapse back into sleep and the neuron resumed firing in a bursting pattern once again. None of these units had a peripheral receptive field (RF), while several other units recorded in nearby regions that did not fire in a bursting pattern during sleep had kinesthetic or cutaneous RFs. Analysis of the intraburst firing pattern revealed increasing interspike intervals (ISI) for successive action potentials in a burst and that the duration of the first ISI in the burst decreased as the number of ISIs increased. This pattern is similar to that reported to occur as a result of a calcium spike. These data have confirmed for the first time that state-dependent changes in thalamic firing exist in the human and that the physiological substrates at the thalamic level that are involved in human sleep are similar to those observed in animals.     

Synaptic modulation of the interspike interval signatures of bursting pyloric neurons

The pyloric network of the lobster stomatogastric nervous system is one of the best described assemblies of oscillatory neurons producing bursts of action potentials. While the temporal patterns of bursts have been investigated in detail, those of spikes have received less attention. Here we analyze the intraburst firing patterns of pyloric neurons and the synaptic interactions shaping their dynamics in millisecond time scales not performed before. We find that different pyloric neurons express characteristic, cell-specific firing patterns in their bursts. Nonlinear analysis of the interspike intervals (ISIs) reveals distinctive temporal structures ('interspike interval signatures'), which are found to depend on the synaptic connectivity of the network. We compare ISI patterns of the pyloric dilator (PD), lateral pyloric (LP), and ventricular dilator (VD) neurons in 1) normal conditions, 2) after blocking glutamatergic synaptic connections, and 3) in various functional configurations of the three neurons. Manipulation of the synaptic connectivity results in characteristic changes in the ISI signatures of the postsynaptic neurons. The intraburst firing pattern of the PD neuron is regularized by the inhibitory synaptic connection from the LP neuron as revealed in current-clamp experiments and also as reconstructed with a dynamic clamp. On the other hand, mutual inhibition between the LP and VD neurons tend to produce more irregular bursts with increased spike jitter. The results show that synaptic interactions fine-tune the output of pyloric neurons. The present data also suggest a way of processing of synaptic information: bursting neurons are capable of encoding incoming signals by altering the fine structure of their intraburst spike patterns.     

Internal pallidal neuronal activity during mild drug-related dyskinesias in Parkinson's disease: decreased firing rates and altered firing patterns

The neuronal basis of hyperkinetic movement disorders has long been unclear. We now test the hypothesis that changes in the firing pattern of neurons in the globus pallidus internus (GPi) are related to dyskinesias induced by low doses of apomorphine in patients with advanced Parkinson's disease (PD). During pallidotomy for advanced PD, the activity of single neurons was studied both before and after administration of apomorphine at doses just adequate to induce dyskinesias (21 neurons, 17 patients). After the apomorphine injection, these spike trains demonstrated an initial fall in firing from baseline. In nine neurons, the onset of on was simultaneous with that of dyskinesias. In these spike trains, the initial fall in firing rate preceded and was larger than the fall at the onset of on with dyskinesias. Among the three neurons in which the onset of on occurred before that of dyskinesias, the firing rate did not change at the time of onset of dyskinesias. After injection of apomorphine, dyskinesias during on with dyskinesias often fluctuated between transient periods with dyskinesias and those without. Average firing rates were not different between these two types of transient periods. Transient periods with dyskinesias were characterized by interspike interval (ISI) independence, stationary spike trains, and higher variability of ISIs. A small but significant group of neurons demonstrated recurring ISI patterns during transient periods of on with dyskinesias. These results suggest that mild dyskinesias resulting from low doses of apomorphine are related to both low GPi neuronal firing rates and altered firing patterns.     

Four subtypes of motor neurons exhibiting mutually exclusive firing patterns in the spinal ventral horn

Motor neurons (MNs) communications are thought to occur primarily through spike bursts and regularly firing action potential trains. Reports of both burst and nonburst firing MNs suggest that these neurons may regularly fire in a variety of controlled output patterns with unique characteristics. Based on the cellular response to somatic current injection in these neurons, four distinct MN subtypes are identified from the spinal ventral horn. Approximately 42% of MNs exhibited regular firing, with minimal current injection (rheobase) exhibited a short latency, and with stronger current intensities exhibited significant spike frequency adaptation (SFA). Another 30% of MNs exhibited delayed onset at rheobase with a weakly-adapting firing pattern as stimulation increased. The remaining 18% and 10% of MNs exhibited transient firing patterns or exhibited irregular firing patterns when strongly depolarized, respectively. Our results provide a basis for improvement in the classification and study of MNs.     

Complex autonomous firing patterns of striatal low-threshold spike interneurons

During sensorimotor learning, tonically active neurons (TANs) in the striatum acquire bursts and pauses in their firing based on the salience of the stimulus. Striatal cholinergic interneurons display tonic intrinsic firing, even in the absence of synaptic input, that resembles TAN activity seen in vivo. However, whether there are other striatal neurons among the group identified as TANs is unknown. We used transgenic mice expressing green fluorescent protein under control of neuronal nitric oxide synthase or neuropeptide-Y promoters to aid in identifying low-threshold spike (LTS) interneurons in brain slices. We found that these neurons exhibit autonomous firing consisting of spontaneous transitions between regular, irregular, and burst firing, similar to cholinergic interneurons. As in cholinergic interneurons, these firing patterns arise from interactions between multiple intrinsic oscillatory mechanisms, but the mechanisms responsible differ. Both neurons maintain tonic firing because of persistent sodium currents, but the mechanisms of the subthreshold oscillations responsible for irregular firing are different. In LTS interneurons they rely on depolarization-activated noninactivating calcium currents, whereas those in cholinergic interneurons arise from a hyperpolarization-activated potassium conductance. Sustained membrane hyperpolarizations induce a bursting pattern in LTS interneurons, probably by recruiting a low-threshold, inactivating calcium conductance and by moving the membrane potential out of the activation range of the oscillatory mechanisms responsible for single spiking, in contrast to the bursting driven by noninactivating currents in cholinergic interneurons. The complex intrinsic firing patterns of LTS interneurons may subserve differential release of classic and peptide neurotransmitters as well as nitric oxide.     

Dopamine D1/5 receptor modulation of firing rate and bidirectional theta burst firing in medial septal/vertical limb of diagonal band neurons in vivo

The medial septum/vertical limb of diagonal band complex (MS/vDB) consists of cholinergic, GABAergic, and glutamatergic neurons that project to the hippocampus and functionally regulate attention, memory, and cognitive processes. Using tyrosine hydroxlase (TH) immunocytochemistry and dark-field light microscopy, we found that the MS/vDB is innervated by a sparse network of TH-immunoreactive (putative catecholaminergic) terminals. MS/vDB neurons are known to fire in rhythmic theta burst frequency of 3-7 Hz to pace hippocampal theta rhythm. Extracellular single-unit recording in theta and non-theta firing MS/vDB neurons and antidromically identified MS/vDB-hippocampal neurons were made in urethan-anesthetized rats. Tail-pinch noxious stimuli and ventral tegmental area (VTA) stimulation (20 Hz) evoked spontaneous theta burst firing in MS/vDB neurons. Systemic D1/5 antagonists SCH23390 or SCH39166 (0.1 mg/kg iv) alone suppressed the spontaneous theta bursts, suggesting a tonic facilitatory endogenous dopamine D1 "tone" that modulates theta bursts in vivo. Activation of D1/5 receptor by dihydrexidine (10 mg/kg iv) led to an increase in mean firing rate in 60% of all theta and non-theta MS/vDB neurons with an increase in the number of theta bursts and spikes/burst in theta cells. In strong theta firing MS/vDB neurons, D1/5 receptor stimulation suppressed the occurrence of theta burst firing, whereas the overall increase in spontaneous mean firing rate remained. In low baseline theta MS/vDB neurons D1/5 receptor stimulation increases the occurrence of theta bursts along with a net increase in mean firing rate. Atropine injection consistently disrupts theta burst pattern and reduced the time spent in theta firing. Collectively, these data suggest that dopamine D1/5 stimulation enhances the mean firing rate of most MS/vDB neurons and also provides a state-dependent bidirectional modulation of theta burst occurrence. Some of these MS/vDB neurons may be cholinergic or GABAergic that may indirectly regulate theta rhythm in the hippocampus.     

Electrical coupling between model midbrain dopamine neurons: effects on firing pattern and synchrony

The role of gap junctions between midbrain dopamine (DA) neurons in mechanisms of firing pattern generation and synchronization has not been well characterized experimentally. We modified a multi-compartment model of DA neuron by adding a spike-generating mechanism and electrically coupling the dendrites of two such neurons through gap junctions. The burst-generating mechanism in the model neuron results from the interaction of a N-methyl-D-aspartate (NMDA)-induced current and the sodium pump. The firing patterns exhibited by the two model neurons included low frequency (2-7 Hz) spiking, high-frequency (13-20 Hz) spiking, irregular spiking, regular bursting, irregular bursting, and leader/follower bursting, depending on the parameter values used for the permeability for NMDA-induced current and the conductance for electrical coupling. All of these firing patterns have been observed in physiological neurons, but a systematic dependence of the firing pattern on the covariation of these two parameters has not been established experimentally. Our simulations indicate that electrical coupling facilitates NMDA-induced burst firing via two mechanisms. The first can be observed in a pair of identical cells. At low frequencies (low NMDA), as coupling strength was increased, only a transition from asynchronous to synchronous single-spike firing was observed. At high frequencies (high NMDA), increasing the strength of the electrical coupling in an identical pair resulted in a transition from high-frequency single-spike firing to burst firing, and further increases led to synchronous high-frequency spiking. Weak electrical coupling destabilizes the synchronous solution of the fast spiking subsystems, and in the presence of a slowly varying sodium concentration, the desynchronized spiking solution leads to bursts that are approximately in phase with spikes that are not in phase. Thus this transitional mechanism depends critically on action potential dynamics. The second mechanism for the induction of burst firing requires a heterogeneous pair that is, respectively, too depolarized and too hyperpolarized to burst. The net effect of the coupling is to bias at least one cell into an endogenously burst firing regime. In this case, action potential dynamics are not critical to the transitional mechanism. If electrical coupling is indeed more prominent in vivo due to basal level of modulation of gap junctions in vivo, these results may indicate why NMDA-induced burst firing is easier to observe in vivo as compared in vitro.     

Single-unit analysis of the pallidum, thalamus and subthalamic nucleus in parkinsonian patients

Microelectrode-guided stereotactic operations performed in 29 parkinsonian patients allowed the recording of 86 cells located in the globus pallidus and 563 in thalamic nuclei. In the globus pallidus, the average firing rate was significantly higher in the internal (91+/-52 Hz) than in the external (60+/-21 Hz) subdivision. This difference was further accentuated when the average firing rate in the external subdivision was compared with that of the internal part of the internal subdivision (114+/-30 Hz). A rhythmic modulation in globus pallidus activities was observed in 19.7% of the cells, and this only during rest tremor episodes. In these cases, modulation frequency of unit activities was not statistically different from the rest tremor frequency (average: 4.6+/-0.5 vs 4. 4+/-0.4 Hz, respectively). In the medial thalamus, four types of unit activities could be defined. A sporadic type was mainly found in the parvocellular division of the mediodorsal nucleus (96.8% of the cells recorded) and in the centre median-parafascicular complex (74.2%). Two other types of activities characterized by random or rhythmic bursts fulfilling the extracellular criteria of low-threshold calcium spike bursts were concentrated in the central lateral nucleus (62.3%) and the paralamellar division of the mediodorsal nucleus (34.1%). These activities could be recorded independently of the presence of a rest tremor. When a tremor episode occurred, the rhythmic low-threshold calcium spike bursts had an interburst frequency similar to rest tremor frequency, although they were not synchronized with it. The fourth type, the so-called tremor locked, was also characterized by rhythmic bursts which, however, did not display low-threshold calcium spike burst properties. These bursts occurred only when a rest tremor was present and was in-phase with the electromyographic bursts. All tremor-locked cells were located in the centre median-parafascicular complex. In the lateral thalamus, cells exhibiting random or rhythmic low-threshold calcium spike bursts were found preponderantly in the ventral anterior nucleus (53.4%) and in the ventral lateral anterior nucleus (52.7%). Tremor-locked units were confined to the ventral division of the ventral lateral posterior nucleus (35.4%). None of the random or rhythmic low-threshold calcium spike bursting units responded to somatosensory stimuli or voluntary movements, either in the medial or in the lateral thalamus. The presence of low-threshold calcium spike bursts at the thalamic level, together with the paucity (8%) of responses to voluntary movements compared to what is found in normal non-human primates, demonstrate a pathological state of inhibition due to the overactivity of the internal subdivision of the globus pallidus units. Activities of the thalamic cells producing low-threshold calcium spike bursts are not synchronized with each other or with the tremor. However, this does not exclude a causal role of these activities in the generation of tremor. Indeed, it has been demonstrated that even random electrical stimulations of the rolandic cortex in parkinsonian patients induce tremor episodes, probably due to the triggering of rhythmic, low-threshold calcium spike-dependent, thalamocortical activities. Similarly, low-threshold calcium spike bursts could be at the origin of rigidity and dystonia through an activation of the supplementary motor area and of akinesia when reaching the pre-supplementary motor area.We conclude that the intrinsic oscillatory properties of individual neurons, combined with the dynamic properties of the thalamocortical circuitry, are responsible for the three cardinal parkinsonian symptoms.     

Comparative electrophysiology of pyramidal and sparsely spiny stellate neurons of the neocortex

Slices of sensorimotor and anterior cingulate cortex from guinea pigs were maintained in vitro and bathed in a normal physiological medium. Electrophysiological properties of neurons were assessed with intracellular recording techniques. Some neurons were identified morphologically by intracellular injection of the fluorescent dye Lucifer yellow CH. Three distinct neuronal classes of electrophysiological behavior were observed; these were termed regular spiking, bursting, and fast spiking. The physiological properties of neurons from sensorimotor and anterior cingulate areas did not differ significantly. Regular-spiking cells were characterized by action potentials with a mean duration of 0.80 ms at one-half amplitude, a ratio of maximum rate of spike rise to maximum rate of fall of 4.12, and a prominent afterhyperpolarization following a train of spikes. The primary slope of initial spike frequency versus injected current intensity was 241 Hz/nA. During prolonged suprathreshold current pulses the frequency of firing adapted strongly. When local synaptic pathways were activated, all cells were transiently excited and then strongly inhibited. Bursting cells were distinguished by their ability to generate endogenous, all-or-none bursts of three to five action potentials. Their properties were otherwise very similar to regular-spiking cells. The ability to generate a burst was eliminated when the membrane was depolarized to near the firing threshold with tonic current. By contrast, hyperpolarization of regular-spiking (i.e., nonbursting) cells did not uncover latent bursting tendencies. The action potentials of fast-spiking cells were much briefer (mean of 0.32 ms) than those of the other cell types.(ABSTRACT TRUNCATED AT 250 WORDS)     

Withdrawal from intermittent ethanol exposure increases probability of burst firing in VTA neurons in vitro

Changing the activity of ventral tegmental area (VTA) dopamine neurons from pacemaker to burst firing is hypothesized to increase the salience of stimuli, such as an unexpected reward, and likely contributes to withdrawal-associated drug-seeking behavior. Accordingly, pharmacological, behavioral, and electrophysiological data suggest an important role of the VTA in mediating alcohol-dependent behaviors. However, the effects of repeated ethanol exposure on VTA dopamine neuron ion channel function are poorly understood. Here, we repeatedly exposed rats to ethanol (2 g/kg ethanol, ip, twice per day for 5 days), then examined the firing patterns of VTA dopamine neurons in vitro after 7 days withdrawal. Compared with saline-treated animals, the function of the small conductance calcium-dependent potassium channel (SK) was reduced in ethanol-treated animals. Consistent with a role for SK in regulation of burst firing, NMDA applied during firing facilitated the transition to bursting in ethanol-treated but not saline-treated animals; NMDA consistently induced bursting only in saline-treated animals when SK was inhibited. Also, enhanced bursting in ethanol-treated animals was not a result of differences in NMDA-induced depolarization. Further, I(h) was also reduced in ethanol-treated animals, which delayed recovery from hyperpolarization, but did not account for the increased NMDA-induced bursting in ethanol-treated animals. Finally, repeated ethanol exposure and withdrawal also enhanced the acute locomotor-activating effect of cocaine (15 mg/kg, ip). Thus withdrawal after repeated ethanol exposure produced several alterations in the physiological properties of VTA dopamine neurons, which could ultimately increase the ability of VTA neurons to produce burst firing and thus might contribute to addiction-related behaviors.