Activity Of Midbrain Dopamine Neurons Research Articles

Somatodendritic organization of pacemaker activity in midbrain dopamine neurons.

The slow and regular pacemaking activity of midbrain dopamine (DA) neurons requires proper spatial organization of the excitable elements between the soma and dendritic compartments, but the somatodendritic organization is not clear. Here, we show that the dynamic interaction between the soma and multiple proximal dendritic compartments (PDCs) generates the slow pacemaking activity in DA neurons. In multipolar DA neurons, spontaneous action potentials (sAPs) consistently originate from the axon-bearing dendrite. However, when the axon initial segment was disabled, sAPs emerge randomly from various primary PDCs, indicating that multiple PDCs drive pacemaking. Ca2+ measurements and local stimulation/perturbation experiments suggest that the soma serves as a stably-oscillating inertial compartment, while multiple PDCs exhibit stochastic fluctuations and high excitability. Despite the stochastic and excitable nature of PDCs, their activities are balanced by the large centrally-connected inertial soma, resulting in the slow synchronized pacemaking rhythm. Furthermore, our electrophysiological experiments indicate that the soma and PDCs, with distinct characteristics, play different roles in glutamate- induced burst-pause firing patterns. Excitable PDCs mediate excitatory burst responses to glutamate, while the large inertial soma determines inhibitory pause responses to glutamate. Therefore, we could conclude that this somatodendritic organization serves as a common foundation for both pacemaker activity and evoked firing patterns in midbrain DA neurons.

GPR55 is expressed in glutamate neurons and functionally modulates drug taking and seeking in rats and mice

G protein-coupled receptor 55 (GPR55) has been thought to be a putative cannabinoid receptor. However, little is known about its functional role in cannabinoid action and substance use disorders. Here we report that GPR55 is predominantly found in glutamate neurons in the brain, and its activation reduces self-administration of cocaine and nicotine in rats and mice. Using RNAscope in situ hybridization, GPR55 mRNA was identified in cortical vesicular glutamate transporter 1 (VgluT1)-positive and subcortical VgluT2-positive glutamate neurons, with no detection in midbrain dopamine (DA) neurons. Immunohistochemistry detected a GPR55-like signal in both wildtype and GPR55-knockout mice, suggesting non-specific staining. However, analysis using a fluorescent CB1/GPR55 ligand (T1117) in CB1-knockout mice confirmed GPR55 binding in glutamate neurons, not in midbrain DA neurons. Systemic administration of the GPR55 agonist O-1602 didnt impact ∆9-THC-induced analgesia, hypothermia and catalepsy, but significantly mitigated cocaine-enhanced brain-stimulation reward caused by optogenetic activation of midbrain DA neurons. O-1602 alone failed to alter extracellar DA, but elevated extracellular glutamate, in the nucleus accumbens. In addition, O-1602 also demonstrated inhibitory effects on cocaine or nicotine self-administration under low fixed-ratio and/or progressive-ratio reinforcement schedules in rats and wildtype mice, with no such effects observed in GPR55-knockout mice. Together, these findings suggest that GPR55 activation may functionally modulate drug-taking and drug-seeking behavior possibly via a glutamate-dependent mechanism, and therefore, GPR55 deserves further study as a new therapeutic target for treating substance use disorders.

Subsecond fluctuations in extracellular dopamine encode reward and punishment prediction errors in humans.

In the mammalian brain, midbrain dopamine neuron activity is hypothesized to encode reward prediction errors that promote learning and guide behavior by causing rapid changes in dopamine levels in target brain regions. This hypothesis (and alternatives regarding dopamine's role in punishment-learning) has limited direct evidence in humans. We report intracranial, subsecond measurements of dopamine release in human striatum measured, while volunteers (i.e., patients undergoing deep brain stimulation surgery) performed a probabilistic reward and punishment learning choice task designed to test whether dopamine release encodes only reward prediction errors or whether dopamine release may also encode adaptive punishment learning signals. Results demonstrate that extracellular dopamine levels can encode both reward and punishment prediction errors within distinct time intervals via independent valence-specific pathways in the human brain.

Targeting the Actions of Muscarinic Receptors on Dopamine Systems: New Strategies for Treating Neuropsychiatric Disorders.

Cholinergic regulation of dopamine (DA) signaling has significant implications for numerous disorders, including schizophrenia, substance use disorders, and mood-related disorders. The activity of midbrain DA neurons and DA release patterns in terminal regions are tightly regulated by cholinergic neurons found in both the striatum and the hindbrain. These cholinergic neurons can modulate DA circuitry by activating numerous receptors, including muscarinic acetylcholine receptor (mAChR) subtypes. This review specifically focuses on the complex role of M2, M4, and M5 mAChR subtypes in regulating DA neuron activity and DA release and the potential clinical implications of targeting these mAChR subtypes.

Dopamine-mediated striatal activity and function is enhanced in GlyRα2 knockout animals

The glycine receptor alpha 2 (GlyRα2) is a ligand-gated ion channel which upon activation induces a chloride conductance. Here, we investigated the role of GlyRα2 in dopamine-stimulated striatal cell activity and behavior. We show that depletion of GlyRα2 enhances dopamine-induced increases in the activity of putative dopamine D1 receptor-expressing striatal projection neurons, but does not alter midbrain dopamine neuron activity. We next show that the locomotor response to d-amphetamine is enhanced in GlyRα2 knockout animals, and that this increase correlates with c-fos expression in the dorsal striatum. 3-D modeling revealed an increase in the neuronal ensemble size in the striatum in response to D-amphetamine in GlyRα2 KO mice. Finally, we show enhanced appetitive conditioning in GlyRα2 KO animals that is likely due to increased motivation, but not changes in associative learning or hedonic response. Taken together, we show that GlyRα2 is an important regulator of dopamine-stimulated striatal activity and function.

D2/3 Agonist during Learning Potentiates Cued Risky Choice.

Impulse control and/or gambling disorders can be triggered by dopamine agonist therapies used to treat Parkinson's disease, but the cognitive and neurobiological mechanisms underlying these adverse effects are unknown. Recent data show that adding win-paired sound and light cues to the rat gambling task (rGT) potentiates risky decision-making and impulsivity via the dopamine system, and that changing dopaminergic tone has a greater influence on behavior while subjects are learning task contingencies. Dopamine agonist therapy may therefore be potentiating risk-taking by amplifying the behavioral impact of gambling-related cues on novel behavior. Here, we show that ropinirole treatment in male rats transiently increased motor impulsivity but robustly and progressively increased choice of the high-risk/high-reward options when administered during acquisition of the cued but not uncued rGT. Early in training, ropinirole increased win-stay behavior after large unlikely wins on the cued rGT, indicative of enhanced model-free learning, which mediated the drug's effect on later risk preference. Ex vivo cFos imaging showed that both chronic ropinirole and the addition of win-paired cues suppressed the activity of dopaminergic midbrain neurons. The ratio of midbrain:prefrontal cFos+ neurons was lower in animals with suboptimal choice patterns and tended to predict risk preference across all rats. Network analyses further suggested that ropinirole induced decoupling of the dopaminergic cells of the VTA and nucleus accumbens but only when win-paired cues were present. Frontostriatal activity uninformed by the endogenous dopaminergic teaching signal therefore appeared to perpetuate risky choice, and ropinirole exaggerated this disconnect in synergy with reward-paired cues.SIGNIFICANCE STATEMENT D2/3 receptor agonists, used to treat Parkinson's disease, can cause gambling disorder through an unknown mechanism. Ropinirole increased risky decision-making in rats, but only when wins were paired with casino-inspired sounds and lights. This was mediated by increased win-stay behavior after large unlikely wins early in learning, indicating enhanced model-free learning. cFos imaging showed that ropinirole suppressed activity of midbrain dopamine neurons, an effect that was mimicked by the addition of win-paired cues. The degree of risky choice rats exhibited was uniquely predicted by the ratio of midbrain dopamine:PFC activity. Depriving the PFC of the endogenous dopaminergic teaching signal may therefore drive risky decision-making on-task, and ropinirole acts synergistically with win-paired cues to amplify this.

Unmasking Schizophrenia: Synaptic Pruning in Adolescence Reveals a Latent Physiological Vulnerability in Prefrontal Recurrent Networks

Theories of the pathophysiology in schizophrenia are converging on the synapse. This special issue of Biological Psychiatry collects papers from leading researchers that suggest a hypothesis that multiple factors spanning many levels lead to synaptic dysfunction in recurrent circuits in the prefrontal cortex (PFC). The hypothesis (Figure 1) suggests that the defect within the PFC is established during early development but remains latent through childhood. Pruning of excitatory synapses during adolescence, resulting in lower synaptic density in persons with schizophrenia, triggers the emergence of symptoms. The lower synaptic density results in deficits in cognitive processes, including working memory, because overpruned neural circuits cannot support the relevant computations ( 1 Averbeck B.B. Pruning recurrent neural networks replicates adolescent changes in working memory and reinforcement learning. Proc Natl Acad Sci U S A. 2022; 119e2121331119 Crossref Scopus (0) Google Scholar ). Additionally, excessive prefrontal pruning leads to striatal hyperdopaminergia through increased activation of midbrain dopamine neurons by prefrontal input. The decreased synaptic density following adolescent pruning could be due to genetic or epigenetic effects that lead to an inability to build stable synapses or excessive pruning of established synapses. The excessive pruning could follow from overactive pruning mechanisms or from decreased excitatory synaptic activity due to synaptic changes local to the PFC or prolonged decreases in thalamic input across development. All of these factors may converge to alter spike timing dynamics in prefrontal recurrent circuits in adolescence, reducing synchronous neural activity and accelerating synaptic disconnection via activity-dependent mechanisms ( 2 Zick J.L. Crowe D.A. Blackman R.K. Schultz K. Bergstrand D.W. DeNicola A.L. et al. Disparate insults relevant to schizophrenia converge on impaired spike synchrony and weaker synaptic interactions in prefrontal local circuits. Curr Biol. 2022; 32: 14-25.e4 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ). Further, synaptic pruning is mediated by components of the immune system, and in utero immune challenge may affect adolescent pruning. Decreased synaptic activity can also lead to increased pruning as pruning removes weak synapses. Thus, multiple effects converging on the synapse could lead to a PFC with fewer excitatory synaptic connections, and this decreased recurrent connectivity could lead to cognitive deficits and increased striatal dopamine and psychosis.

Dopamine errors drive excitatory and inhibitory components of backward conditioning in an outcome-specific manner

For over two decades, phasic activity in midbrain dopamine neurons was considered synonymous with the prediction error in temporal-difference reinforcement learning.1-4 Central to this proposal is the notion that reward-predictive stimuli become endowed with the scalar value of predicted rewards. When these cues are subsequently encountered, their predictive value is compared to the value of the actual reward received, allowing for the calculation of prediction errors.5,6 Phasic firing of dopamine neurons was proposed to reflect this computation,1,2 facilitating the backpropagation of value from the predicted reward to the reward-predictive stimulus, thus reducing future prediction errors. There are two critical assumptions of this proposal: (1) that dopamine errors can only facilitate learning about scalar value and not more complex features of predicted rewards, and (2) that the dopamine signal can only be involved in anticipatory cue-reward learning in which cues or actions precede rewards. Recent work7-15 has challenged the first assumption, demonstrating that phasic dopamine signals across species are involved in learning about more complex features of the predicted outcomes, in a manner that transcends this value computation. Here, we tested the validity of the second assumption. Specifically, we examined whether phasic midbrain dopamine activity would be necessary for backward conditioning-when a neutral cue reliably follows a rewarding outcome.16-20 Using a specific Pavlovian-to-instrumental transfer (PIT) procedure,21-23 we show rats learn both excitatory and inhibitory components of a backward association, and that this association entails knowledge of the specific identity of the reward and cue. We demonstrate that brief optogenetic inhibition of VTADA neurons timed to the transition between the reward and cue reduces both of these components of backward conditioning. These findings suggest VTADA neurons are capable of facilitating associations between contiguously occurring events, regardless of the content of those events. We conclude that these data may be in line with suggestions that the VTADA error acts as a universal teaching signal. This may provide insight into why dopamine function has been implicated in myriad psychological disorders that are characterized by very distinct reinforcement-learning deficits.

The Convergence Model of Brain Reward Circuitry: Implications for Relief of Treatment-Resistant Depression by Deep-Brain Stimulation of the Medial Forebrain Bundle

Deep-brain stimulation of the medial forebrain bundle (MFB) can provide effective, enduring relief of treatment-resistant depression. Panksepp provided an explanatory framework: the MFB constitutes the core of the neural circuitry subserving the anticipation and pursuit of rewards: the “SEEKING” system. On that view, the SEEKING system is hypoactive in depressed individuals; background electrical stimulation of the MFB alleviates symptoms by normalizing activity. Panksepp attributed intracranial self-stimulation to excitation of the SEEKING system in which the ascending projections of midbrain dopamine neurons are an essential component. In parallel with Panksepp’s qualitative work, intracranial self-stimulation has long been studied quantitatively by psychophysical means. That work argues that the predominant directly stimulated substrate for MFB self-stimulation are myelinated, non-dopaminergic fibers, more readily excited by brief electrical current pulses than the thin, unmyelinated axons of the midbrain dopamine neurons. The series-circuit hypothesis reconciles this view with the evidence implicating dopamine in MFB self-stimulation as follows: direct activation of myelinated MFB fibers is rewarding due to their trans-synaptic activation of midbrain dopamine neurons. A recent study in which rats worked for optogenetic stimulation of midbrain dopamine neurons challenges the series-circuit hypothesis and provides a new model of intracranial self-stimulation in which the myelinated non-dopaminergic neurons and the midbrain dopamine projections access the behavioral final common path for reward seeking via separate, converging routes. We explore the potential implications of this convergence model for the interpretation of the antidepressant effect of MFB stimulation. We also discuss the consistent finding that psychomotor stimulants, which boost dopaminergic neurotransmission, fail to provide a monotherapy for depression. We propose that non-dopaminergic MFB components may contribute to the therapeutic effect in parallel to, in synergy with, or even instead of, a dopaminergic component.

Specificity of Varenicline in Blocking Mesolimbic Circuit Activation to Natural and Drug Rewards

The mesolimbic dopamine (DA) system reinforces behaviors that are critical for survival. However, drug dependence can occur when drugs of abuse, such as nicotine, highjack this reinforcement system. Pharmacologically targeting the DA system to selectively block drug reinforcement requires a detailed understanding of the neural circuits and molecular pathways that lead to the reward-based activation of mesolimbic circuits. Varenicline is an approved smoking cessation drug that has been shown to block nicotine-evoked DA increases in the nucleus accumbens (NAc) through action on nicotinic acetylcholine receptors. Because these receptors have been implicated in the reinforcement of other addictive substances, we explored the possibility that varenicline could broadly affect reward processing. We used in vivo fiber photometry to monitor midbrain DA neuron activity and striatal DA levels following either natural or drug rewards in mice treated with varenicline. We demonstrate that varenicline pretreatment enhances the suppression of nicotine-evoked DA release by attenuating DA neuron activity in the VTA. Varenicline’s ability to attenuate DA release is highly specific to nicotine, and varenicline slightly elevates DA release when co-administered with morphine or ethanol. Furthermore, varenicline has no effect on DA release in response to naturally rewarding behavior such as food intake or exercise. These results demonstrate the exquisite specificity with which varenicline blocks nicotine reward and highlight the complexity with which different rewards activate the mesolimbic DA system.

Chronic nicotine increases midbrain dopamine neuron activity and biases individual strategies towards reduced exploration in mice

Long-term exposure to nicotine alters brain circuits and induces profound changes in decision-making strategies, affecting behaviors both related and unrelated to drug seeking and consumption. Using an intracranial self-stimulation reward-based foraging task, we investigated in mice the impact of chronic nicotine on midbrain dopamine neuron activity and its consequence on the trade-off between exploitation and exploration. Model-based and archetypal analysis revealed substantial inter-individual variability in decision-making strategies, with mice passively exposed to nicotine shifting toward a more exploitative profile compared to non-exposed animals. We then mimicked the effect of chronic nicotine on the tonic activity of dopamine neurons using optogenetics, and found that photo-stimulated mice adopted a behavioral phenotype similar to that of mice exposed to chronic nicotine. Our results reveal a key role of tonic midbrain dopamine in the exploration/exploitation trade-off and highlight a potential mechanism by which nicotine affects the exploration/exploitation balance and decision-making.

Involvement of Midbrain Dopamine Neuron Activity in Negative Reinforcement Learning in Mice

The activity of the midbrain dopamine system reflects the valence of environmental events and modulates various brain structures to modify an organism's behavior. A series of recent studies reported that the direct and indirect pathways in the striatum are critical for instrumental learning, but the dynamic changes in dopamine neuron activity that occur during negative reinforcement learning are still largely unclear. In the present study, by using a negative reinforcement learning paradigm employing foot shocks as aversive stimuli, bidirectional changes in substantia nigra pars compacta (SNc) dopamine neuron activity in the learning and habituation phases were observed. The results showed that in the learning phase, before mice had mastered the skill of escaping foot shocks, the presence of foot shocks induced a transient reduction in the activity of SNc dopamine neurons; however, in the habituation phase, in which the learned skill was automated, it induced a transient increase. Microinjection of a dopamine D1 receptor (D1R) or D2 receptor (D2R) antagonist into the dorsomedial striatum (DMS) significantly impaired learning behavior, suggesting that the modulatory effects of dopamine on both the direct and indirect pathways are required. Moreover, during the learning phase, excitatory synaptic transmission to DMS D2R-expressing medium spiny neurons (D2-MSNs) was potentiated. However, upon completion of the learning and habituation phases, the synapses onto D1R-expressing medium spiny neurons (D1-MSNs) were potentiated, and those onto D2-MSNs were restored to normal levels. The bidirectional changes in both SNc dopamine neuron activity and DMS synaptic plasticity might be the critical neural correlates for negative reinforcement learning.

Tonic firing mode of midbrain dopamine neurons continuously tracks reward values changing moment-by-moment.

Animal behavior is regulated based on the values of future rewards. The phasic activity of midbrain dopamine neurons signals these values. Because reward values often change over time, even on a subsecond-by-subsecond basis, appropriate behavioral regulation requires continuous value monitoring. However, the phasic dopamine activity, which is sporadic and has a short duration, likely fails continuous monitoring. Here, we demonstrate a tonic firing mode of dopamine neurons that effectively tracks changing reward values. We recorded dopamine neuron activity in monkeys during a Pavlovian procedure in which the value of a cued reward gradually increased or decreased. Dopamine neurons tonically increased and decreased their activity as the reward value changed. This tonic activity was evoked more strongly by non-burst spikes than burst spikes producing a conventional phasic activity. Our findings suggest that dopamine neurons change their firing mode to effectively signal reward values in a given situation.

Tonic GABAergic inhibition, via GABAA receptors containing αβƐ subunits, regulates excitability of ventral tegmental area dopamine neurons.

The activity of midbrain dopamine neurons is strongly regulated by fast synaptic inhibitory γ‐Aminobutyric acid (GABA)ergic inputs. There is growing evidence in other brain regions that low concentrations of ambient GABA can persistently activate certain subtypes of GABAA receptor to generate a tonic current. However, evidence for a tonic GABAergic current in midbrain dopamine neurons is limited. To address this, we conducted whole‐cell recordings from ventral tegmental area (VTA) dopamine neurons in brain slices from mice. We found that application of GABAA receptor antagonists decreased the holding current, indicating the presence of a tonic GABAergic input. Global increases in GABA release, induced by either a nitric oxide donor or inhibition of GABA uptake, further increased this tonic current. Importantly, prolonged inhibition of the firing activity of local GABAergic neurons abolished the tonic current. A combination of pharmacology and immunohistochemistry experiments suggested that, unlike common examples of tonic inhibition, this current may be mediated by a relatively unusual combination of α4βƐ subunits. Lastly, we found that the tonic current reduced excitability in dopamine neurons suggesting a subtractive effect on firing activity.

A Unified Framework for Dopamine Signals across Timescales

Rapid phasic activity of midbrain dopamine neurons is thought to signal reward prediction errors (RPEs), resembling temporal difference errors used in machine learning. However, recent studies describing slowly increasing dopamine signals have instead proposed that they represent state values and arise independent from somatic spiking activity. Here we developed experimental paradigms using virtual reality that disambiguate RPEs from values. We examined dopamine circuit activity at various stages, including somatic spiking, calcium signals at somata and axons, and striatal dopamine concentrations. Our results demonstrate that ramping dopamine signals are consistent with RPEs rather than value, and this ramping is observed at all stages examined. Ramping dopamine signals can be driven by a dynamic stimulus that indicates a gradual approach to a reward. We provide a unified computational understanding of rapid phasic and slowly ramping dopamine signals: dopamine neurons perform a derivative-like computation over values on a moment-by-moment basis.

Beta-caryophyllene inhibits cocaine addiction-related behavior by activation of PPARα and PPARγ: repurposing a FDA-approved food additive for cocaine use disorder.

Cocaine abuse continues to be a serious health problem worldwide. Despite intense research, there is still no FDA-approved medication to treat cocaine use disorder (CUD). In this report, we explored the potential utility of beta-caryophyllene (BCP), an FDA-approved food additive for the treatment of CUD. We found that BCP, when administered intraperitoneally or intragastrically, dose-dependently attenuated cocaine self-administration, cocaine-conditioned place preference, and cocaine-primed reinstatement of drug seeking in rats. In contrast, BCP failed to alter food self-administration or cocaine-induced hyperactivity. It also failed to maintain self-administration in a drug substitution test, suggesting that BCP has no abuse potential. BCP was previously reported to be a selective CB2 receptor agonist. Unexpectedly, pharmacological blockade or genetic deletion of CB1, CB2, or GPR55 receptors in gene-knockout mice failed to alter BCP's action against cocaine self-administration, suggesting the involvement of non-CB1, non-CB2, and non-GPR55 receptor mechanisms. Furthermore, pharmacological blockade of μ opioid receptor or Toll-like receptors complex failed to alter, while blockade of peroxisome proliferator-activated receptors (PPARα, PPARγ) reversed BCP-induced reduction in cocaine self-administration, suggesting the involvement of PPARα and PPARγ in BCP's action. Finally, we used electrical and optogenetic intracranial self-stimulation (eICSS, oICSS) paradigms to study the underlying neural substrate mechanisms. We found that BCP is more effective in attenuation of cocaine-enhanced oICSS than eICSS, the former driven by optical activation of midbrain dopamine neurons in DAT-cre mice. These findings indicate that BCP may be useful for the treatment of CUD, likely by stimulation of PPARα and PPARγ in the mesolimbic system.

Evidence that haloperidol impairs learning and motivation scores in a probabilistic task by reducing the reward expectation

Activation of midbrain dopamine neurons in response to positive prediction errors and reward predictive cues is proposed to “energize” reward seeking behaviors and approach responses to places where the reward is expected. In the present study, we tested the effect of the D2-dopamine receptor antagonist haloperidol on response latencies to enter two arms of a Y-maze with different reward probabilities. Adult male Wistar rats were trained to explore the Y-maze with sucrose pellets placed 30% of times at the end of one arm and 70% of times at the opposite arm. Therefore, the reward expectation was different among arms, and was updated in the trials when the reward was omitted. After training, rats received 0.05, 0.10, 0.15 mg/kg haloperidol, or saline 30 min before the test session. In the last, but not in the first trials, haloperidol caused a dose-dependent increase in arm choice latency and response latency. Saline, but not haloperidol, treated rats presented significantly longer response latencies for the 30% compared to the 70% reward probability arm. Haloperidol also caused a dose-dependent decrease in the number of entries in the 70% reward probability arm, increased the number of non-responses, and caused a dose-dependent increase in the number of re-entries in the 30% reward probability arm after non-rewarded trials. Control experiments suggested that haloperidol did not cause motor impairment or satiation, but rather impaired learning and motivation scores by reducing the reward expectation.

Modulation of brain stimulation reward and locomotor activity by ionotropic glutamate receptors of the tail of the ventral tegmental area

The rostromedial tegmental nucleus also referred to as the tail of the ventral tegmental area (tVTA) contains a cluster of gamma-aminobutyric acid (GABA)ergic neurons that receive dense glutamatergic afferents from the lateral habenula (LHb), and project to dopamine (DA) neurons of the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). In light of previous evidence implicating glutamate transmission in the regulation of midbrain DA neuronal activity, we first assessed the impact of intra-tVTA microinjection of NBQX (0.8 nmol/side) and PPPA (0.825 nmol/side), respectively AMPA and NMDA receptor antagonists, on reward induced by intracranial self-stimulation (ICSS) and on locomotor activity. Since the tVTA contains a large concentration of mu opioid receptors, additional measures were obtained following microinjection of endomorphin-1 (EM-1, 1 nmol/side) to confirm tVTA placements. Then, using small interfering RNAs (siRNAs), we tested the effect of tVTA downregulation of the GluN1 subunit of the NMDA receptor on reward and locomotor activity. Results show that NBQX, PPPA and EM-1 all enhance reward and locomotor activity, effects that were of different magnitude in rostral and intermediate parts of the tVTA. On the other hand, a reduction in GluN1 subunits used a marked decrease in operant responding for ICSS, but failed to alter ICSS reward and the reward-enhancing effect of PPPA. Our results support a role for the tVTA as a main inhibitory component of DA-dependent behavioral measures, and suggest that tVTA NMDA receptors that modulate reward are most likely expressed on tVTA afferent terminals.

Dopamine neurons do not constitute an obligatory stage in the final common path for the evaluation and pursuit of brain stimulation reward.

The neurobiological study of reward was launched by the discovery of intracranial self-stimulation (ICSS). Subsequent investigation of this phenomenon provided the initial link between reward-seeking behavior and dopaminergic neurotransmission. We re-evaluated this relationship by psychophysical, pharmacological, optogenetic, and computational means. In rats working for direct, optical activation of midbrain dopamine neurons, we varied the strength and opportunity cost of the stimulation and measured time allocation, the proportion of trial time devoted to reward pursuit. We found that the dependence of time allocation on the strength and cost of stimulation was similar formally to that observed when electrical stimulation of the medial forebrain bundle served as the reward. When the stimulation is strong and cheap, the rats devote almost all their time to reward pursuit; time allocation falls off as stimulation strength is decreased and/or its opportunity cost is increased. A 3D plot of time allocation versus stimulation strength and cost produces a surface resembling the corner of a plateau (the "reward mountain"). We show that dopamine-transporter blockade shifts the mountain along both the strength and cost axes in rats working for optical activation of midbrain dopamine neurons. In contrast, the same drug shifted the mountain uniquely along the opportunity-cost axis when rats worked for electrical MFB stimulation in a prior study. Dopamine neurons are an obligatory stage in the dominant model of ICSS, which positions them at a key nexus in the final common path for reward seeking. This model fails to provide a cogent account for the differential effect of dopamine transporter blockade on the reward mountain. Instead, we propose that midbrain dopamine neurons and neurons with non-dopaminergic, MFB axons constitute parallel limbs of brain-reward circuitry that ultimately converge on the final-common path for the evaluation and pursuit of rewards.

Reproducing the dopamine pathophysiology of schizophrenia and approaches to ameliorate it: a translational imaging study with ketamine

Patients with schizophrenia show increased striatal dopamine synthesis capacity in imaging studies. The mechanism underlying this is unclear but may be due to N-methyl-D-aspartate receptor (NMDAR) hypofunction and parvalbumin (PV) neuronal dysfunction leading to disinhibition of mesostriatal dopamine neurons. Here, we develop a translational mouse model of the dopamine pathophysiology seen in schizophrenia and test approaches to reverse the dopamine changes. Mice were treated with sub-chronic ketamine (30 mg/kg) or saline and then received in vivo positron emission tomography of striatal dopamine synthesis capacity, analogous to measures used in patients. Locomotor activity was measured using the open-field test. In vivo cell-type-specific chemogenetic approaches and pharmacological interventions were used to manipulate neuronal excitability. Immunohistochemistry and RNA sequencing were used to investigate molecular mechanisms. Sub-chronic ketamine increased striatal dopamine synthesis capacity (Cohen’s d = 2.5) and locomotor activity. These effects were countered by inhibition of midbrain dopamine neurons, and by activation of PV interneurons in pre-limbic cortex and ventral subiculum of the hippocampus. Sub-chronic ketamine reduced PV expression in these cortical and hippocampal regions. Pharmacological intervention with SEP-363856, a novel psychotropic agent with agonism at trace amine receptor 1 (TAAR1) and 5-HT1A receptors but no appreciable action at dopamine D2 receptors, significantly reduced the ketamine-induced increase in dopamine synthesis capacity. These results show that sub-chronic ketamine treatment in mice mimics the dopaminergic alterations in patients with psychosis, that this requires activation of midbrain dopamine neurons, and can be ameliorated by activating PV interneurons and by a TAAR1/5-HT1A agonist. This identifies novel therapeutic approaches for targeting presynaptic dopamine dysfunction in patients with schizophrenia and effects of ketamine relevant to its therapeutic use for treating major depression.