ReviewAfferent modulation of dopamine neuron firing patterns
Introduction
Dopamine (DA)-containing neurons in the pars compacta of the substantia nigra (SNc) and the ventral tegmental area (VTA) exhibit a continuum of patterned activity that ranges from a tonic single spike to a multiple spike bursting discharge 1, 2, 3, 4. Interest in the cellular basis of firing pattern generation has increased recently as a result of a growing body of evidence suggesting that alterations in the temporal organization of DA neuronal spike trains represent a form of information coding. Although DA neurons in the anesthetized animal show little tendency to switch between tonic and phasic modalities, transient changes in firing pattern are observed during natural and schedule-driven behaviors 5, 6, 7••, 8. Neurochemical studies indicate that spikes clustered in bursts are more effective than tonic firing at increasing DA levels in the forebrain 9, 10, 11, 12, 13, 14. In addition, bursting, but not irregular single spike activity, increases the levels of c-Fos expressed in the limbic forebrain, presumably as a consequence of augmented DA release [15]. Taken together, these data strongly suggest that changes in firing pattern represent a physiological mechanism through which DA neurons alter their influence on target neurons.
In marked contrast to the continuum of patterned activity observed in vivo, DA neurons recorded in tissue slices are characterized by a homogeneous pacemaker-like firing pattern that is not typically observed spontaneously in either the anesthetized or awake behaving animal 3, 16, 17, 18. It is generally assumed that loss of irregular single spike and bursting activity in tissue slices occurs as a result of deafferentation. Although several pathways have been identified as candidates for modulating DA cell firing pattern, particular emphasis has been placed on the study of excitatory afferents arising from the prefrontal cortex 19, 20, 21, 22, 23, 24, 25, 26 and subthalamic nucleus 9, 27, 28, 29, 30, 31. The results from a number of these studies have been interpreted as suggesting that the continuum of patterned activity observed spontaneously in vivo is dependent on tonic activation of NMDA receptors. Glutamate- and aspartate-containing projections to the mesencephalic DA cell groups are undoubtedly involved to some degree in modulating firing pattern, particularly such modulations as those elicited in awake behaving animals by appetitive stimuli 5, 6, 32, 33, 34, 35. However, there are a number of inconsistencies in published reports that do not support the contention that tonic activation of NMDA receptors is the sole determinate of DA neuronal firing pattern. In fact, recent evidence suggests that in addition to glutamatergic excitatory projections from the prefrontal cortex and subthalamic nucleus, excitatory projections to DA neurons from cholinergic and glutamatergic neurons in the tegmental pedunculopontine nucleus (PPN) and/or inhibitory GABAergic projections may be modulating DA neuron firing behavior 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 (see Figure 1).
Section snippets
In vivo actions
The ability of glutamate to increase bursting activity has been well documented in vivo using microiontophoretic methods 2, 48. The application of glutamate to DA cells leads to an increase in the intensity of bursting activity (e.g. burst length and frequency), but can also induce bursting in cells exhibiting a spontaneous non-bursting (i.e. irregular) discharge. These effects were initially attributed to activation of NMDA receptors [49]. However, subsequent studies have shown that local
Slow oscillatory potential and firing pattern of DA neurons
As autogenous pacemakers, DA neurons exhibit a sinusoidal oscillation in membrane voltage. This slow oscillatory potential (SOP) appears to involve Ca2+ entry during the depolarizing phase and a subsequent gKCa that participates in the repolarizing phase. The oscillations have been studied extensively in slices and persist within a narrow window between −60 to −40 mV that bridges the 20 mV difference between the apparent resting potential of the cell and the spike threshold potential [70].
When
Action of apamin on firing pattern of DA neurons
In addition to the ensemble of Ca2+ currents responsible for the depolarizing phase of the SOP, an apamin-sensitive gKCa conductance appears to participate in the repolarizing phase of the oscillation 73, 76. Blockade of this current with apamin suppresses the SOP and unmasks, in a subpopulation of DA neurons, a regenerative plateau potential capable of driving bursting activity. Bursts comprise between 3 and 12 spikes on the depolarizing phase of the potential. These spikes become smaller and
Action of cholinergic inputs
The abilility of apamin to evoke bursting in DA neurons leads us to speculate about the existence of an endogenous neuroactive substance modulating gKCa directly or indirectly by regulating Ca2+ conductance (gCa2+). For example, acetylcholine released in the vicinity of DA neurons by afferents originating from the PPN may serve a neuromodulatory role by increasing the tendency of DA neurons to exhibit bursts in response to glutamatergic input. This modulatory effect of acetylcholine may occur
Conclusions
Much work is still necessary in order to understand fully the underlying mechanism(s) responsible for modulating firing patterns of SNs DA neurons from regular to bursting. The above discussion, however, strongly suggests that the specific pathway(s) responsible for modulation of DA neuronal firing pattern cannot be attributed solely to tonic activation of NMDA receptors. It is likely that the neurotransmitters or modulators involved originate from both glutamatergic and cholinergic afferents.
Achnowledgements
This work was supported by National Institutes of Health (NIH) grants, National Institute of Neurological Disorders and Stroke (NINDS) grants (NS-20702 and NS-26473 to ST Kitai, and NS-36843 to JC Callaway); and a National Institute of Mental Health (NIMH) grant (MH-48543 to PD Sheppard).
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
References (103)
- et al.
Effects of apamin on the discharge properties of putative dopamine-containing neurons in vitro
Brain Res
(1988) - et al.
Statistical properties of neuronal spike trains in the substantia nigra: cell types and their interactions
Brain Res
(1977) - et al.
Mesencephalic dopaminergic unit activity in the behaviorally conditioned rat
Life Sci
(1981) - et al.
Firing properties of substantia nigra dopaminergic neurons in freely moving rats
Life Sci
(1985) - et al.
Burst activity of ventral tegmental dopamine neurons is elicited by sensory stimuli in the awake cat
Brain Res
(1997) - et al.
Nonlinear relationship between impulse flow, dopamine release and dopamine elimination in the rat brain in vivo
Neuroscience
(1994) - et al.
Regulation of dopamine release by impulse flow and by autoreceptors as studied by in vivo voltammetry in the rat striatum
Neuroscience
(1985) - et al.
Burst stimulation of the medial forebrain bundle selectively increases Fos-like immunoreactivity in the limbic forebrain of the rat
Neuroscience
(1996) - et al.
Electrophysiological properties of mouse dopamine neurons: in vivo and in vitro studies
Neuroscience
(1984) - et al.
Electrical membrane properties of rat substantia nigra compacta neurons in an in vitro slice preparation
Brain Res
(1986)