Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Dopamine Neurons

 

Science 19 September 2008: Vol. 321. no. 5896, pp. 1690 - 1692

Reward-Predictive Cues Enhance Excitatory Synaptic Strength onto Midbrain Dopamine Neurons

Garret D. Stuber,1 Marianne Klanker,2 Bram de Ridder,1 M. Scott Bowers,1 Ruud N. Joosten,2 Matthijs G. Feenstra,2 Antonello Bonci1,3

¹ Ernest Gallo Clinic and Research Center, Department of Neurology, University of California, San Francisco, Emeryville, CA 94608, USA.
² Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Amsterdam, Netherlands.
³ Wheeler Center for the Neurobiology of Drug Addiction, University of California, San Francisco, San Francisco, CA 94143, USA.

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Using sensory information for the prediction of future events is essential for survival. Midbrain dopamine neurons are activated by environmental cues that predict rewards. We used in vivo voltammetry and in vitro patch-clamp electrophysiology to show that both dopamine release to reward predictive cues and enhanced synaptic strength onto dopamine neurons develop over the course of cue-reward learning. Increased synaptic strength was not observed after stable behavioral responding. Thus, enhanced synaptic strength onto dopamine neurons may act to facilitate the transformation of neutral environmental stimuli to salient reward-predictive cues.

Dopamine (DA) neurons, originating in the ventral tegmental area (VTA) and substantia nigra and projecting to forebrain areas, are essential for the expression of goal-directed behaviors for both natural rewards and drugs of abuse. DA neurons are initially phasically activated by primary rewards such as food but shift their activation to reward-predictive stimuli after extended conditioning. Although DA signaling appears to be plastic, and can be modified by manipulating the contingency between conditioned stimuli and rewards, the cellular mechanisms that underlie this cue-reward learning remain unclear.

Long-term potentiation (LTP) and long-term depression (LTD) are hypothesized cellular mechanisms for learning and memory storage. Glutamatergic synapses onto DA neurons can express LTP, LTD, and short-term plasticity. Furthermore, passive or voluntary exposure to cocaine can lead to long-lasting changes in synaptic function in DA neurons.

VTA extracellular glutamate levels are dramatically increased after exposure to drug-associated cues, suggesting an important role of VTA glutamatergic neurotransmission in modulating goal-directed behavior by conditioned stimuli.

Transient increase in synaptic strength acts to facilitate learning but is not required for the long-term maintenance of cue-reward associations. The persistent storage of cue-reward information may rely on the formation of new synapses or on plasticity in brain regions outside the VTA. These data are in stark contrast to increases in synaptic strength induced by drugs of abuse that can last for weeks after drug exposure and may lead to maladaptive learning in which drug-associated cues are over-valued relative to cues that predict natural reinforcers.

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Science 13 March 2009: Vol. 323. no. 5920, pp. 1496 - 1499

Human Substantia Nigra Neurons Encode Unexpected Financial Rewards

Kareem A. Zaghloul,¹ Justin A. Blanco,² Christoph T. Weidemann,³ Kathryn McGill,¹ Jurg L. Jaggi,¹ Gordon H. Baltuch,¹ Michael J. Kahana³

¹ Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Department of Psychology, University of Pennsylvania, Philadelphia, PA 19104, USA.

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The brain's sensitivity to unexpected outcomes plays a fundamental role in an organism's ability to adapt and learn new behaviors. Emerging research suggests that midbrain dopaminergic neurons encode these unexpected outcomes. We used microelectrode recordings during deep brain stimulation surgery to study neuronal activity in the human substantia nigra (SN) while patients with Parkinson's disease engaged in a probabilistic learning task motivated by virtual financial rewards. Based on a model of the participants' expected reward, we divided trial outcomes into expected and unexpected gains and losses. SN neurons exhibited significantly higher firing rates after unexpected gains than unexpected losses. No such differences were observed after expected gains and losses. This result provides critical support for the hypothesized role of the SN in human reinforcement learning.

Our findings suggest that neurons in the human SN play a central role in reward-based learning, modulating learning based on the discrepancy between the expected and the realized outcome. These findings are consistent with the hypothesized role of the basal ganglia, including the SN, in addiction and other disorders involving reward-seeking behavior. More importantly, these findings are consistent with models of reinforcement learning involving the basal ganglia, and they suggest a neural mechanism underlying reward learning in humans.

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Science 29 February 2008: Vol. 319. no. 5867, pp. 1264 - 1267

BOLD Responses Reflecting Dopaminergic Signals in the Human Ventral Tegmental Area

Kimberlee D'Ardenne,^1,2* Samuel M. McClure,^2,3 Leigh E. Nystrom,^2,3 Jonathan D. Cohen^2,3,4

¹ Department of Chemistry, Princeton University, Princeton, NJ 08544, USA.
² Center for the Study of Brain, Mind, and Behavior, Princeton University, Princeton, NJ 08544, USA.
³ Department of Psychology, Princeton University, Princeton, NJ 08544, USA.
⁴ Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA 15260, USA

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Current theories hypothesize that dopamine neuronal firing encodes reward prediction errors. Although studies in nonhuman species provide direct support for this theory, functional magnetic resonance imaging (fMRI) studies in humans have focused on brain areas targeted by dopamine neurons [ventral striatum (VStr)] rather than on brainstem dopaminergic nuclei [ventral tegmental area (VTA) and substantia nigra]. We used fMRI tailored to directly image the brainstem. When primary rewards were used in an experiment, the VTA blood oxygen level–dependent (BOLD) response reflected a positive reward prediction error, whereas the VStr encoded positive and negative reward prediction errors. When monetary gains and losses were used, VTA BOLD responses reflected positive reward prediction errors modulated by the probability of winning. We detected no significant VTA BOLD response to nonrewarding events.

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Science 23 November 2007: Vol. 318. no. 5854, pp. 1305 - 1308

Social Comparison Affects Reward-Related Brain Activity in the Human Ventral Striatum

K. Fliessbach,¹ B. Weber,¹ P. Trautner,¹ T. Dohmen,² U. Sunde,² C. E. Elger,¹ A. Falk^3*

¹ Life and Brain Center Bonn, Department of NeuroCognition and Clinic of Epileptology, Bonn, Germany.
² Institute for the Study of Labor, Bonn, Germany.
³ University of Bonn, Department of Economics, Bonn, Germany.

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Whether social comparison affects individual well-being is of central importance for understanding behavior in any social environment. Traditional economic theories focus on the role of absolute rewards, whereas behavioral evidence suggests that social comparisons influence well-being and decisions. We investigated the impact of social comparisons on reward-related brain activity using functional magnetic resonance imaging (fMRI). While being scanned in two adjacent MRI scanners, pairs of subjects had to simultaneously perform a simple estimation task that entailed monetary rewards for correct answers. We show that a variation in the comparison subject's payment affects blood oxygenation level–dependent responses in the ventral striatum. Our results provide neurophysiological evidence for the importance of social comparison on reward processing in the human brain.

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Nature 447, 1111-1115 (28 June 2007)

Lateral habenula as a source of negative reward signals in dopamine neurons

Masayuki Matsumoto & Okihide Hikosaka

Laboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892-4435, USA

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Midbrain dopamine neurons are key components of the brain's reward system, which is thought to guide reward-seeking behaviours^. Although recent studies have shown how dopamine neurons respond to rewards and sensory stimuli predicting reward^, it is unclear which parts of the brain provide dopamine neurons with signals necessary for these actions. Here we show that the primate lateral habenula, part of the structure called the epithalamus, is a major candidate for a source of negative reward-related signals in dopamine neurons. We recorded the activity of habenula neurons and dopamine neurons while rhesus monkeys were performing a visually guided saccade task with positionally biased reward outcomes^. Many habenula neurons were excited by a no-reward-predicting target and inhibited by a reward-predicting target. In contrast, dopamine neurons were excited and inhibited by reward-predicting and no-reward-predicting targets, respectively. Each time the rewarded and unrewarded positions were reversed, both habenula and dopamine neurons reversed their responses as the bias in saccade latency reversed. In unrewarded trials, the excitation of habenula neurons started earlier than the inhibition of dopamine neurons. Furthermore, weak electrical stimulation of the lateral habenula elicited strong inhibitions in dopamine neurons. These results suggest that the inhibitory input from the lateral habenula plays an important role in determining the reward-related activity of dopamine neurons.

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