The authors present a unified account of 2 neural systems concerned with the development and expression of adaptive behaviors: a mesencephalic dopamine system for reinforcement learning and a “generic” error-processing system associated with the anterior cingulate cortex The existence of the error-processing system has been inferred from the error-related negativity (ERN), a component of the event-related brain potential elicited when human participants commit errors in reaction-time tasks The authors propose that the ERN is generated when a negative reinforcement learning signal is conveyed to the anterior cingulate cortex via the mesencephalic dopamine system and that this signal is used by the anterior cingulate cortex to modify performance on the task at hand They provide support for this proposal using both computational modeling and psychophysiological experimentation

/pdf/the-neural-basis-of-human-error-processing-reinforcement-246y7vy4ka.pdf

The neural basis of human error processing: Reinforcement learning, dopamine, and the error-related negativity.

http://www.columbia.edu/itc/gsas/g9600/2003/JavitchReadings/Schultz(Sulzer).pdf

Getting Formal with Dopamine and Reward

The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

/pdf/the-dopamine-hypothesis-of-schizophrenia-version-iii-the-3pqlczm8om.pdf

The Dopamine Hypothesis of Schizophrenia: Version III—The Final Common Pathway

Positive affect systematically influences performance on many cognitive tasks. A new neuropsychological theory is proposed that accounts for many of these effects by assuming that positive affect is associated with increased brain dopamine levels. The theory predicts or accounts for influences of positive affect on olfaction, the consolidation of long-term (i.e., episodic) memories, working memory, and creative problem solving. For example, the theory assumes that creative problem solving is improved, in part, because increased dopamine release in the anterior cingulate improves cognitive flexibility and facilitates the selection of cognitive perspective.

/pdf/a-neuropsychological-theory-of-positive-affect-and-its-1m5h32sghh.pdf

A neuropsychological theory of positive affect and its influence on cognition.

https://homepages.inf.ed.ac.uk/pseries/Neuroinformatics/Uhlhaas&Singer2006.pdf

Neural Synchrony in Brain Disorders: Relevance for Cognitive Dysfunctions and Pathophysiology

The principal features and mechanisms of dopamine modulation in the prefrontal cortex

The ionic mechanisms by which dopamine (DA) regulates the excitability of layers V-VI prefrontal cortex (PFC) output neurons (including those that project to the nucleus accumbens) were investigated in rat brain slices using in vitro intracellular recording techniques. DA or the D1 receptor agonist SKF38393, but not the D2 agonist quinpirole, reduced the first spike latency and lowered the firing threshold of the PFC neurons in response to depolarizing current pulses. This was accomplished by enhancing the duration of a tetradotoxinsensitive, slowly inactivating Na+ current and attenuating a slowly inactivating, outwardly rectifying, dendrotoxin-sensitive K+ current. Furthermore, D1 receptor stimulation attenuated high-threshold Ca2+ spike(s) (HTS) evoked primarily from the apical dendrites of these PFC neurons. Taken together, these data suggest that D1 receptor stimulation on layers V-VI pyramidal PFC neurons: (1) restricts the effects of inputs to the apical dendrites of these neurons by attenuating the dendritic HTS-mediated amplification of such inputs; and (2) potentiates the influence of local inputs from neighboring deep layers V-VI neurons by enhancing the slowly inactivating Na+ current and attenuating the slowly inactivating K+ current. By influencing the input/output characteristics of PFC-->NAc neurons, DA may play an important role in the processes through which PFC signals are translated into action.

https://www.jneurosci.org/content/jneuro/16/5/1922.full.pdf

Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro: modulation of dendritic-somatic signal integration

This study examined the electrophysiological and morphological characteristics of layers V-VI pyramidal prefrontal cortex (PFC) neurons. In vitro intracellular recordings coupled with biocytin injections that preserved some of the PFC efferents to the nucleus accumbens (NAc) were made in brain slices. Four principal pyramidal cell types were identified and classified as regular spiking (RS) (19%), intrinsic bursting (IB) (64%), repetitive oscillatory bursting (ROB) (13%), and intermediate (IM) (4%) types. All PFC cells exhibited either subthreshold oscillation in membrane voltage or pacemaker-like rhythmic firing. IB neurons were demonstrated electrophysiologically and cytochemically to be PFC-->NAc neurons. In all IB and some RS neurons, a tetrodotoxin-sensitive, slowly inactivating Na+ current and a transient Ni(2+)-sensitive, low-threshold Ca2+ current mediated subthreshold inward rectification. During sustained membrane depolarization, the Na+ current was opposed by a 4-aminopyridine- sensitive, outwardly rectifying, slowly inactivating K+ current. Together, these three currents controlled the firing threshold of the PFC neurons. All IB and ROB cells also had postspike Ca(2+)-mediated depolarizing afterpotentials, postburst Ca(2+)-dependent after hyperpolarizations, and low- and high-threshold Ca2+ spikes. In addition, ROB cells had a hyperpolarizing “sag” mediated by the cationic conductance, Ih. IB and ROB neurons had extensive dendritic trees and radially ascending or tangentially projecting axon collaterals. RS and IM cells had comparatively simpler morphological profiles. These electrophysiological and morphological properties of the four principal pyramidal PFC cell types have provided valuable details for understanding further how PFC processes input and transmit outputs to regions such as the NAc.

https://www.jneurosci.org/content/jneuro/16/5/1904.full.pdf

Electrophysiological and morphological properties of layers V-VI principal pyramidal cells in rat prefrontal cortex in vitro

The effects of electrical stimulation of the ventral subiculum/CA1 region of the hippocampus on changes in dopamine oxidation current (corresponding to dopamine efflux) in the nucleus accumbens were examined using in vivo chronoamperometry with stearate-graphite paste electrodes in urethane-anaesthetized rats. Burst-patterned monophasic pulses (10-100 Hz/burst delivered at 0.8-4 Hz) evoked a three-component change in dopamine efflux in the nucleus accumbens with an initial transient increase in the dopamine signal above baseline, followed by an immediate decrease below baseline, and thereafter by a prolonged increase in the dopamine signal above baseline. 6-Hydroxydopamine lesions of the mesoaccumbens dopamine pathway or transection of the fimbria-fornix blocked all of the evoked changes in the dopamine signal. Both the first and third components of enhanced dopamine efflux were blocked by microinfusion into the nucleus accumbens of the ionotropic glutamate receptor antagonists (+/-)-2-amino-5-phosphonopentanoic acid, 6,7-dinitroquinoxaline-2,3-dione and kynurenate. Burst stimulation-evoked decreases in the dopamine signal were abolished following microinfusions into the nucleus accumbens of the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine. These results suggest that ventral subiculum/CA1 glutamatergic inputs to the nucleus accumbens may presynaptically modulate dopamine efflux by synaptic activation of both ionotropic and metabotropic glutamate receptors in the nucleus accumbens. These glutamate-dopamine interactions may constitute part of the mechanisms by which hippocampal signals are integrated through selective modulation of dopamine release in the nucleus accumbens in both physiological and pathological conditions.

Stimulation of the Ventral Subiculum of the Hippocampus Evokes Glutamate Receptor‐mediated Changes in Dopamine Efflux in the Rat Nucleus Accumbens

Afferents from the basolateral amygdala and dopamine projections from the ventral tegmental area to the nucleus accumbens have both been implicated in reward-related processes. The present study used in vivo chronoamperometry with stearate-graphite paste electrodes in urethane-anaesthetized rats to determine how basolateral amygdala efferents to the nucleus accumbens synaptically regulate dopamine efflux. Repetitive-pulse (20 Hz for 10 s) electrical stimulation of the basolateral amygdala evoked a complex pattern of changes in monitored dopamine oxidation currents in the nucleus accumbens related to dopamine efflux. These changes were characterized by an initial increase that was time-locked to stimulation, a secondary decrease below baseline, followed by a prolonged increase in the dopamine signal above baseline. The effects of burst-patterned stimulation (100 Hz, 5 pulses/burst, 1-s interburst interval, 40 s) of the basolateral amygdala on the basal accumbens dopamine signal were similar to those evoked by 20 Hz stimulation, with the lack of a secondary suppressive component. Infusions of the ionotropic glutamate receptor antagonists (+/-)-2-amino-5-phosphonopentanoic acid (APV) or 6,7-dinitroquinoxaline-2,3-dione (DNQX) into the nucleus accumbens dose-dependently blocked or attenuated the initial and prolonged increases in the dopamine signal following 20 Hz or burst-patterned basolateral amygdala stimulation. Infusions of the metabotropic glutamate receptor antagonist (+)-alpha-methyl-4-carboxyphenylglycine selectively blocked the intermediate suppressive effect of 20 Hz basolateral amygdala stimulation on dopamine oxidation currents. Blockade of glutamate receptors or inhibition of dopamine neuronal activity via infusions of either APV + DNQX, lidocaine or gamma-hydroxybutyric acid, respectively, into the ventral tegmental area did not effect the pattern of changes in the accumbens dopamine signal evoked by basolateral amygdala stimulation. These data suggest that the glutamatergic basolateral amygdala inputs to nucleus accumbens dopamine terminals synaptically facilitate or depress dopamine efflux, and these effects are independent of dopamine neuronal firing activity. Moreover, these results imply that changes in nucleus accumbens dopamine levels following presentation of reward-related stimuli may be mediated, in part, by the basolateral amygdala.

Charles R. Yang

Papers

The principal features and mechanisms of dopamine modulation in the prefrontal cortex

Dopamine D1 receptor actions in layers V-VI rat prefrontal cortex neurons in vitro: modulation of dendritic-somatic signal integration

Electrophysiological and morphological properties of layers V-VI principal pyramidal cells in rat prefrontal cortex in vitro

Stimulation of the Ventral Subiculum of the Hippocampus Evokes Glutamate Receptor‐mediated Changes in Dopamine Efflux in the Rat Nucleus Accumbens

Basolateral amygdala stimulation evokes glutamate receptor-dependent dopamine efflux in the nucleus accumbens of the anaesthetized rat.