Firing Pattern Of Dopamine Neurons Research Articles

Selective Optogenetic Dopamine Terminal Stimulation Reveals Role of GABAergic Signaling in Individual Differences in Dopamine Release

An estimated 70.5% of Americans aged 12 or older report having used an illicit substance at least once, while about 10‐20% of those individuals ultimately develop a substance use disorder (SUD). These data highlight substantial individual variability in the risk of developing SUD following initial drug use. Identifying markers of increased risk provides a significant opportunity to identify at‐risk populations and to aid in the prevention of the development of SUD. In preclinical rodent models, locomotor response to a novel environment predicts drug use vulnerability. Rodents that demonstrate higher locomotor response to an inescapable novel environment (high responders; HR) acquire self‐administration (SA) of drugs more rapidly and at lower doses compared to low responders (LR). Striatal dopamine (DA) signaling is critical for the acquisition of drug SA and tonic/phasic firing patterns of DA neurons encode information about salient environmental stimuli and rewards. HR rats show increased phasic DA signaling to reward‐predictive cues compared to LR rats. Dopamine release dynamics are tightly controlled by local modulation within the nucleus accumbens (NAc), including by nicotinic acetylcholine receptors (nAChRs), but the mechanisms by which this local modulation may contribute to differential DA release is not fully understood. Our lab has previously shown that locomotor response to a novel environment predicts nAChR modulation of phasic DA signals in the NAc. Specifically, desensitization or blockade of α6β2‐containing (α6β2*) nAChRs within the NAc was found to augment phasic DA signals in brain slices of HR rats, and reduce phasic DA signals in LR rats. However, these studies utilized non‐specific electrical stimulation to record DA release. In the present study, we used ex vivo fast‐scan cyclic voltammetry with an optogenetic approach to selectively stimulate DA neuron terminals or cholinergic interneurons (CINs) within the NAc to examine the specific contributions of acetylcholine (ACh) to the overall DA response in HR and LR rats. We find that, contrary to previous results with electrical stimulation, selective DA phasic stimulation results in lower DA release in HRs compared to LRs, while blockade of α6β2* nAChRs using light stimulation results in higher DA release in HRs. This suggests that additional circuitry is likely involved in differential DA signaling within the NAc. Given the tonic activity of CINs and presence of nAChRs on GABA interneurons, we next used pharmacological manipulations to examine the possibility of GABA signaling contributing to individual differences in DA release. Here, we find that antagonism of GABA receptors blocks the previously seen differential effects of α6β2* nAChR antagonism on DA release, suggesting that GABA interneurons do play a critical role in differential DA signaling in HRs versus LRs. In sum, these data help form a clearer understanding of the mechanisms underlying individual differences in DA signaling, which may be a primary driver of differences in sensitivity to the reinforcing effects of drugs of abuse. Investigating these mechanisms allows us to better identify behavioral and neurochemical markers of SUD vulnerability in humans and to ultimately stimulate development of individualized and effective treatments.

Response to Novelty Predicts α7 Nicotinic Receptor and Voltage‐Gated Calcium Channel Modulation of Dopamine Release

An estimated 70.5% of Americans aged 12 or older report having used an illicit substance at least once, while about 10-20% of those individuals ultimately develop a substance use disorder (SUD). These data highlight substantial individual variability in the risk of developing SUD following initial drug use. Identifying markers of increased risk provides a significant opportunity to identify at-risk populations and to aid in the prevention of the development of SUD. In preclinical rodent models, locomotor response to a novel environment predicts drug use vulnerability. Rodents that demonstrate higher locomotor response to an inescapable novel environment (high responders; HR) acquire self-administration (SA) of drugs more rapidly and stably compared to low responders (LR). Striatal dopamine (DA) signaling is critical for the acquisition of drug SA and tonic/phasic firing patterns of DA neurons encode information about salient environmental stimuli and rewards. HR rats show increased phasic DA signaling to reward-predictive cues compared to LR rats. Dopamine release dynamics are tightly controlled by local modulation within the nucleus accumbens (NAc), including through glutamatergic signaling and modulation by nicotinic acetylcholine receptors (nAChRs), but the mechanisms by which this local modulation may contribute to differential DA release is not fully understood. Our lab has previously shown that locomotor response to a novel environment predicts nAChR modulation of phasic DA signals in the NAc. Specifically, desensitization or blockade of α6β2-containing nAChRs within the NAc was found to augment phasic DA signals in brain slices of HR rats, and reduce phasic DA signals in LR rats. However, other nAChR subtypes may also contribute to individual differences in DA signaling, including α7 nAChRs localized to striatal glutamate terminals. In the present study, we used ex vivo fast-scan cyclic voltammetry to examine how antagonism of α7 nAChRs impacts DA release across a range of stimulation frequencies in the NAc of HR and LR animals and examine what mechanisms may be mediating this effect. We find that modulation of DA release by α7 nAChRs can be predicted by response to novelty at phasic-like stimulations. Given the role that nAChRs play in calcium (Ca2+) entry into the cell, we additionally tested the possibility that differential Ca2+ utilization is one mechanism underlying differential DA modulation by nAChRs and utilized pharmacological manipulations to test possible voltage-gated Ca2+ channel (VGCC) subtype-specific effects. Here, we demonstrate that lowered Ca2+ concentration unmasks a diverging DA release profile between HRs and LRs at phasic-like stimulation frequencies and find that P/Q-type VGCCs appear to drive these individual differences in Ca2+ utilization. In sum, these data help form a more coherent understanding of the mechanisms underlying individual differences in vulnerability. Investigating these mechanisms allows us to better identify behavioral and neurochemical markers of substance abuse risk in humans and to ultimately stimulate development of more individualized and effective treatments.

In vivo patch-clamp recordings reveal distinct subthreshold signatures and threshold dynamics of midbrain dopamine neurons

The in vivo firing patterns of ventral midbrain dopamine neurons are controlled by afferent and intrinsic activity to generate sensory cue and prediction error signals that are essential for reward-based learning. Given the absence of in vivo intracellular recordings during the last three decades, the subthreshold membrane potential events that cause changes in dopamine neuron firing patterns remain unknown. To address this, we established in vivo whole-cell recordings and obtained over 100 spontaneously active, immunocytochemically-defined midbrain dopamine neurons in isoflurane-anaesthetized adult mice. We identified a repertoire of subthreshold membrane potential signatures associated with distinct in vivo firing patterns. Dopamine neuron activity in vivo deviated from single-spike pacemaking by phasic increases in firing rate via two qualitatively distinct biophysical mechanisms: 1) a prolonged hyperpolarization preceding rebound bursts, accompanied by a hyperpolarizing shift in action potential threshold; and 2) a transient depolarization leading to high-frequency plateau bursts, associated with a depolarizing shift in action potential threshold. Our findings define a mechanistic framework for the biophysical implementation of dopamine neuron firing patterns in the intact brain.

Post-pubertal Difference in Nigral Dopaminergic Cells Firing in the Schizophrenia Model Prepared by Perinatal Challenges of a Cytokine, EGF

Schizophrenia in humans typically develops during and after adolescence; however, the biological underpinning for the specificity of this onset time window remains to be determined. In the present study, we investigated this knowledge gap using our own animal model for schizophrenia. Rodents and monkeys challenged with a cytokine, epidermal growth factor (EGF), as neonates are known to exhibit various behavioral and cognitive abnormalities at the post-pubertal stage. We used the EGF-challenged mice as an animal model for schizophrenia to evaluate the electrophysiological impact of this modeling on nigral dopamine neurons before and after puberty. In vivo single unit recording revealed that the burst firing of putative dopamine neurons in substantia nigra pars compacta was significantly higher in the post-pubertal stage of the EGF model than in that of control mice; in contrast, this difference was not observed in the pre-pubertal stage. The increase in burst firing was accompanied by a decline in Ca2+-activated K+ (ISK) currents, which influence the firing pattern of dopamine neurons. In vivo local application of the SK channel blocker apamin (80 μM) to the substantia nigra was less effective at increasing burst firing in the EGF model than in control mice, suggesting the pathologic role of the ISK decrease in this model. Thus, these results suggest that the aberrant post-pubertal hyperactivity of midbrain dopaminergic neurons is associated with the temporal specificity of the behavioral deficit of this model, and support the hypothesis that this dopaminergic aberration could be implicated in the adolescent onset of schizophrenia.

Pathogenic Pathways in Early-Onset Autosomal Recessive Parkinson's Disease Discovered Using Isogenic Human Dopaminergic Neurons.

SummaryParkinson's disease (PD) is a complex and highly variable neurodegenerative disease. Familial PD is caused by mutations in several genes with diverse and mostly unknown functions. It is unclear how dysregulation of these genes results in the relatively selective death of nigral dopaminergic neurons (DNs). To address this question, we modeled PD by knocking out the PD genes PARKIN (PRKN), DJ-1 (PARK7), and ATP13A2 (PARK9) in independent isogenic human pluripotent stem cell (hPSC) lines. We found increased levels of oxidative stress in all PD lines. Increased death of DNs upon differentiation was found only in the PARKIN knockout line. Using quantitative proteomics, we observed dysregulation of mitochondrial and lysosomal function in all of the lines, as well as common and distinct molecular defects caused by the different PD genes. Our results suggest that precise delineation of PD subtypes will require evaluation of molecular and clinical data.

Impaired recruitment of dopamine neurons during working memory in mice with striatal D2 receptor overexpression

The dopamine (DA) system plays a major role in cognitive functions through its interactions with several brain regions including the prefrontal cortex (PFC). Conversely, disturbances in the DA system contribute to cognitive deficits in psychiatric diseases, yet exactly how they do so remains poorly understood. Here we show, using mice with disease-relevant alterations in DA signaling (D2R-OE mice), that deficits in working memory (WM) are associated with impairments in the WM-dependent firing patterns of DA neurons in the ventral tegmental area (VTA). The WM-dependent phase-locking of DA neurons to 4 Hz VTA-PFC oscillations is absent in D2R-OE mice and VTA-PFC synchrony deficits scale with their WM impairments. We also find reduced 4 Hz synchrony between VTA DA neurons and selective impairments in their representation of WM demand. These results identify how altered DA neuron activity—at the level of long-range network activity and task-related firing patterns—may underlie cognitive impairments.

Ventral Tegmental Area Dopamine Neurons Firing Model Reveals Prenatal Nicotine Induced Alterations.

The dopamine (DA) neurons found in the ventral tegmental area (VTA) are widely involved in the addiction and natural reward circuitry of the brain. Their firing patterns were shown to be important modulators of dopamine release and repetitive burst-like firing activity was highlighted as a major firing pattern of DA neurons in the VTA. In the present study we use a state space model to characterize the DA neurons firing patterns, and trace transitions of neural activity through bursting and non-bursting states. The hidden semi-Markov model (HSMM) framework, which we use, offers a statistically principled inference of bursting states and considers VTA DA firing patterns to be generated according to a Gamma process. Additionally, the explicit Gamma-based modeling of state durations allows efficient decoding of underlying neural information. Consequently, we decode and segment our single unit recordings from DA neurons in VTA according to the sequence of statistically discriminated HSMM states. The segmentation is used to study bursting state characteristics in data recorded from rats prenatally exposed to nicotine (6 mg/kg/day starting with gestational day 3) and rats from saline treated dams. Our results indicate that prenatal nicotine exposure significantly alters burst firing patterns of a subset of DA neurons in adolescent rats, suggesting nicotine exposure during gestation may induce severe effects on the neural networks involved in addiction and reward.

Reduction of the Morphine Maintenance by Blockade of the NMDA Receptors during Extinction Period in Conditioned Place Preference Paradigm of Rats

Introduction:Activation of N-methyl-d-aspartate (NMDA) glutamate receptors in the nucleus accumbens is a component of drug-induced reward mechanism. In addition, NMDA receptors play a major role in brain reward system and activation of these receptors can change firing pattern of dopamine neurons. Blockade of glutamatergic neurotransmission reduces the expression of conditioned place preference (CPP) induced by morphine. Therefore, in this study, by using an NMDA receptor antagonist, DL-2-Amino-5-phosphonopentanoic acid sodium salt (AP5), the role of NMDA receptors on the maintenance and reinstatement of morphine-CPP was investigated.Methods:Forty-three adult male albino Wistar rats were used in this study. After subcutaneous administration of effective dose of morphine (5 mg/kg) during CPP paradigm, the animals received intracerebroventricular doses of AP5(1, 5, and 25 mM/5μL saline) during extinction period (free morphine stage). Conditioning score was recorded during extinction period and reinstatement phase. Besides, another group of the animals received a single dose administration of AP5(5 mM) just before the administration of ineffective dose of morphine (1 mg/kg) in reinstatement phase.Results:The results revealed that two doses of this antagonist (5 and 25 mM) significantly shortened the extinction period of morphine-CPP but did not reduce reinstatement induced by priming dose of morphine. Moreover, the single dose administration of AP5(5 mM) just before prime-morphine injection decreased reinstatement of morphine-CPP.Conclusion:These findings indicate that blockade of NMDA receptors during extinction period reduces maintenance but not reinstatement of morphine. In addition, blocking these receptors in reinstatement phase decreases reinstatement to extinguished morphine.

Increased dopamine D2 receptor activity in the striatum alters the firing pattern of dopamine neurons in the ventral tegmental area

There is strong evidence that the core deficits of schizophrenia result from dysfunction of the dopamine (DA) system, but details of this dysfunction remain unclear. We previously reported a model of transgenic mice that selectively and reversibly overexpress DA D2 receptors (D2Rs) in the striatum (D2R-OE mice). D2R-OE mice display deficits in cognition and motivation that are strikingly similar to the deficits in cognition and motivation observed in patients with schizophrenia. Here, we show that in vivo, both the firing rate (tonic activity) and burst firing (phasic activity) of identified midbrain DA neurons are impaired in the ventral tegmental area (VTA), but not in the substantia nigra (SN), of D2R-OE mice. Normalizing striatal D2R activity by switching off the transgene in adulthood recovered the reduction in tonic activity of VTA DA neurons, which is concordant with the rescue in motivation that we previously reported in our model. On the other hand, the reduction in burst activity was not rescued, which may be reflected in the observed persistence of cognitive deficits in D2R-OE mice. We have identified a potential molecular mechanism for the altered activity of DA VTA neurons in D2R-OE mice: a reduction in the expression of distinct NMDA receptor subunits selectively in identified mesolimbic DA VTA, but not nigrostriatal DA SN, neurons. These results suggest that functional deficits relevant for schizophrenia symptoms may involve differential regulation of selective DA pathways.

Dopamine system: manager of neural pathways

There are a growing number of roles that midbrain dopamine (DA) neurons assume, such as, reward, aversion, alerting and vigor. Here I propose a theory that may be able to explain why the suggested functions of DA came about. It has been suggested that largely parallel cortico-basal ganglia-thalamo-cortico loops exist to control different aspects of behavior. I propose that (1) the midbrain DA system is organized in a similar manner, with different groups of DA neurons corresponding to these parallel neural pathways (NPs). The DA system can be viewed as the “manager” of these parallel NPs in that it recruits and activates only the task-relevant NPs when they are needed. It is likely that the functions of those NPs that have been consistently activated by the corresponding DA groups are facilitated. I also propose that (2) there are two levels of DA roles: the How and What roles. The How role is encoded in tonic and phasic DA neuron firing patterns and gives a directive to its target NP: how vigorously its function needs to be carried out. The tonic DA firing is to provide the needed level of DA in the target NPs to support their expected behavioral and mental functions; it is only when a sudden unexpected boost or suppression of activity is required by the relevant target NP that DA neurons in the corresponding NP act in a phasic manner. The What role is the implementational aspect of the role of DA in the target NP, such as binding to D1 receptors to boost working memory. This What aspect of DA explains why DA seems to assume different functions depending on the region of the brain in which it is involved. In terms of the role of the lateral habenula (LHb), the LHb is expected to suppress maladaptive behaviors and mental processes by controlling the DA system. The demand-based smart management by the DA system may have given animals an edge in evolution with adaptive behaviors and a better survival rate in resource-scarce situations.

Bursting as a source of non‐linear determinism in the firing patterns of nigral dopamine neurons

Nigral dopamine (DA) neurons in vivo exhibit complex firing patterns consisting of tonic single-spikes and phasic bursts that encode information for certain types of reward-related learning and behavior. Non-linear dynamical analysis has previously demonstrated the presence of a non-linear deterministic structure in complex firing patterns of DA neurons, yet the origin of this non-linear determinism remains unknown. In this study, we hypothesized that bursting activity is the primary source of non-linear determinism in the firing patterns of DA neurons. To test this hypothesis, we investigated the dimension complexity of inter-spike interval data recorded in vivo from bursting and non-bursting DA neurons in the chloral hydrate-anesthetized rat substantia nigra. We found that bursting DA neurons exhibited non-linear determinism in their firing patterns, whereas non-bursting DA neurons showed truly stochastic firing patterns. Determinism was also detected in the isolated burst and inter-burst interval data extracted from firing patterns of bursting neurons. Moreover, less bursting DA neurons in halothane-anesthetized rats exhibited higher dimensional spiking dynamics than do more bursting DA neurons in chloral hydrate-anesthetized rats. These results strongly indicate that bursting activity is the main source of low-dimensional, non-linear determinism in the firing patterns of DA neurons. This finding furthermore suggests that bursts are the likely carriers of meaningful information in the firing activities of DA neurons.

Effects of Chronic, Systemic Treatment with the Dopamine Receptor Agonist R-Apomorphine in Partially Lesioned Rat Model of Parkinson's Disease: An Electrophysiological Study of Substantia Nigra Dopamine Neurons

Previous studies have suggested that R-apomorphine (R-APO), a non-selective dopamine (DA) receptor agonist, has neuroprotective effects in the experimental models of Parkinson's disease (PD). In this study, we investigated the effects of chronic, systemic treatment with R-APO in the firing activity of substantia nigra pars compacta (SNc) DA neurons in 6-hydroxydopamine (6-OHDA) partially lesioned rats. In the 6-OHDA-lesioned rats treated with vehicle, injection of 6-OHDA (20.1 microg) into the striatum produced a partial lesion causing 41% loss of tyrosine hydroxylase-immunoreactive (TH-ir) neurons in the SNc. In the partially lesioned rats, chronic, systemic treatment of R-APO (10 mg/kg/day, s.c., 11 days) attenuated loss of TH-ir neurons in the SNc. The partial lesion of the nigrostriatal pathway and R-APO treatment did not change the firing rate and firing pattern of DA neurons in the SNc of rats. In contrast, the R-APO treatment increased the number of spontaneously active DA neurons of the SNc in the partially lesioned rats, while the lesion decreased the number of spontaneously active DA neurons. In addition, the chronic R-APO treatment decreased the responsiveness of the DA neurons to intravenously administrated R-APO in the partially lesioned rats. These results indicate that chronic, systemic R-APO treatment has the neuroprotective effect, and reverses the decrease in the number of spontaneously active DA neurons in the SNc whereas the treatment induces a reduction in the sensitivity of DA receptors in the SNc to R-APO stimulation in this model.

A doubly stochastic model for the quantification and classification of burstiness and regularity in single spike trains

A doubly stochastic model for the quantification and classification of burstiness and regularity in single spike trains

Effects of S‐citalopram, citalopram, and R‐citalopram on the firing patterns of dopamine neurons in the ventral tegmental area, N‐methyl‐D‐aspartate receptor‐mediated transmission in the medial prefrontal cortex and cognitive function in the rat

Escitalopram, the S-enantiomer of citalopram, possesses superior efficacy compared to other selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. Escitalopram binds to an allosteric site on the serotonin transporter, which further enhances the blockade of serotonin reuptake, whereas R-citalopram antagonizes this positive allosteric modulation. Escitalopram's effects on neurotransmitters other than serotonin, for example, dopamine and glutamate, are not well studied. Therefore, we here studied the effects of escitalopram, citalopram, and R-citalopram on dopamine cell firing in the ventral tegmental area, using single-cell recording in vivo and on NMDA receptor-mediated currents in pyramidal neurons in the medial prefrontal cortex using in vitro electrophysiology in rats. The cognitive effects of escitalopram and citalopram were also compared using the novel object recognition test. Escitalopram (40-640 μg/kg i.v.) increased both firing rate and burst firing of dopaminergic neurons, whereas citalopram (80-1280 μg/kg) had no effect on firing rate and only increased burst firing at high dosage. R-citalopram (40-640 μg/kg) had no significant effects. R-citalopram (320 μg/kg) antagonized the effects of escitalopram (320 μg/kg). A very low concentration of escitalopram (5 nM), but not citalopram (10 nM) or R-citalopram (5 nM), potentiated NMDA-induced currents in pyramidal neurons. Escitalopram's effect was antagonized by R-citalopram and blocked by the dopamine D(1) receptor antagonist SCH23390. Escitalopram, but not citalopram, improved recognition memory. Our data suggest that the excitatory effect of escitalopram on dopaminergic and NMDA receptor-mediated neurotransmission may have bearing on its cognitive-enhancing effect and superior efficacy compared to other SSRIs in major depression.

Role of endogenous acetylcholine in the control of the dopaminergic system via nicotinic receptors

Nicotinic acetylcholine receptors (nAChRs) are pentameric membrane protein receptors activated by the addictive drug, nicotine. However, sometimes underestimated, under physiological conditions the endogenous neurotransmitter acetylcholine is the agonist. In this mini-review, I will discuss the evidence in favour of an important role for this cholinergic activation of the dopaminergic (DAergic) system. I will focus on the literature implicating the action of acetylcholine on the somato-dendritic compartment of these neurons. This modulation is responsible for a variety of phenotypes in knock-out animals of nAChR subunits. These include locomotion, exploratory behaviour, dopamine (DA) release, and DA neuron firing patterns. The novel techniques brought to bear on these analyses, lentiviral re-expression, and repression, of nAChR subunits, and transgenic expression of hypersensitive receptors will be discussed.

Prominent Burst Firing of Dopaminergic Neurons in the Ventral Tegmental Area during Paradoxical Sleep

Dopamine is involved in motivation, memory, and reward processing. However, it is not clear whether the activity of dopamine neurons is related or not to vigilance states. Using unit recordings in unanesthetized head restrained rats we measured the firing pattern of dopamine neurons of the ventral tegmental area across the sleep-wake cycle. We found these cells were activated during paradoxical sleep (PS) via a clear switch to a prominent bursting pattern, which is known to induce large synaptic dopamine release. This activation during PS was similar to the activity measured during the consumption of palatable food. Thus, as it does during waking in response to novelty and reward, dopamine could modulate brain plasticity and thus participate in memory consolidation during PS. By challenging the traditional view that dopamine is the only aminergic group not involved in sleep physiology, this study provides an alternative perspective that may be crucial for understanding the physiological function of PS and dream mentation.

Emerging concepts: novel integration of in vivo approaches to localize the function of nicotinic receptors

Nicotinic acetylcholine receptors (nAChRs) are important targets of the neuromodulator acetylcholine (ACh) and the drug nicotine. The role of their different subunits has been analysed for a decade by the creation of knock-out (KO) mice using homologous recombination. This technique shows that a given subunit is necessary for a given function. However, for ubiquitously expressed genes, it cannot demonstrate the localization for a given subunit in which its expression is sufficient, especially for behavioural phenotypes. Sufficient in this context means that the brain region requiring the expression of the gene product has been localized. Novel strategies have therefore been developed to re-express, region specifically, nAChR subunits on a KO background using lentiviral vectors. Localized regeneration of fully functional high-affinity nAChRs in defined brain regions has proven that these receptors are sufficient to restore a variety of functions: nicotine-induced dopamine release, nicotine self-administration in mice, dopamine neuron firing patterns, and exploratory and locomotor behaviours in a sequential locomotor task testing executive function were thus defined as depending exclusively on the 'knock-back' of beta2*-nAChRs into the ventral tegmental area. These analyses highlight the important role of endogenous cholinergic regulation of a variety of functions. The novel integrated use of restricted re-expressed nAChR subunits with in vivo electrophysiology and automated quantitative behavioural analysis enables the further analysis of defined neuronal circuits in nicotine addiction and higher cognitive function.

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 (≥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 μM). 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, prediction error and associative learning: A model-based account

The notion of prediction error has established itself at the heart of formal models of animal learning and current hypotheses of dopamine function. Several interpretations of prediction error have been offered, including the model-free reinforcement learning method known as temporal difference learning (TD), and the important Rescorla–Wagner (RW) learning rule. Here, we present a model-based adaptation of these ideas that provides a good account of empirical data pertaining to dopamine neuron firing patterns and associative learning paradigms such as latent inhibition, Kamin blocking and overshadowing. Our departure from model-free reinforcement learning also offers: 1) a parsimonious distinction between tonic and phasic dopamine functions; 2) a potential generalization of the role of phasic dopamine from valence-dependent “reward” processing to valence-independent “salience” processing; 3) an explanation for the selectivity of certain dopamine manipulations on motivation for distal rewards; and 4) a plausible link between formal notions of prediction error and accounts of disturbances of thought in schizophrenia (in which dopamine dysfunction is strongly implicated). The model distinguishes itself from existing accounts by offering novel predictions pertaining to the firing of dopamine neurons in various untested behavioral scenarios.

Slow Oscillatory Firing: A Major Firing Pattern of Dopamine Neurons in the Ventral Tegmental Area

Using spectral analysis and in vivo single-unit recording in rats, the present study revealed a pronounced slow oscillation (SO) in the firing activity of about half the dopamine (DA) neurons recorded in the ventral tegmental area. DA neurons in this group tended to fire repetitive spike clusters, making them appear to be rhythmic bursting cells. However, only some of these burst-like events met the traditional "80/160 ms" burst criteria entirely. The observation that the SO could be found in nonbursting DA cells, occurred at frequencies different from those of bursts, and persisted after bursts were digitally removed from spike trains further supports the suggestion that the SO is different from the traditionally defined bursting. Interspike intervals (ISIs) had been thought to be bimodally distributed in bursting DA neurons. This study found that some nonbursting DA cells also had a bimodal ISI distribution and a significant number of bursting cells did not. In the majority of cells where less than half the spikes occurred in bursts, a bimodal ISI distribution was highly predictive of the presence of the SO. Results further showed that the generation of the SO required forebrain inputs to DA neurons but not the adrenergic alpha1 receptor activation responsible for psychostimulant-induced increases in the SO. Taken together, these results suggest that the SO is distinct from the traditionally defined bursting and represents a major firing pattern of DA neurons in the ventral tegmental area.