Discrete coding of reward probability and uncertainty by dopamine neurons

Uncertainty is critical in the measure of information and in assessing the accuracy of predictions. It is determined by probability P, being maximal at P = 0.5 and decreasing at higher and lower probabilities. Using distinct stimuli to indicate the probability of reward, we found that the phasic activation of dopamine neurons varied monotonically across the full range of probabilities, supporting past claims that this response codes the discrepancy between predicted and actual reward. In contrast, a previously unobserved response covaried with uncertainty and consisted of a gradual increase in activity until the potential time of reward. The coding of uncertainty suggests a possible role for dopamine signals in attention-based learning and risk-taking behavior.     

Temporal summation and refractoriness in hypothalamic reward neurons as measured by self-stimulation behavior

A neurophysiological technique of double-pulse stimulation has been applied to freely moving rats with chronic indwelling electrodes in the hypothalamic reward area. Self-stimulation thresholds, measured as a function of the interpulse interval, generated curves with time constants characteristic of refractory periods and temporal synaptic summation. The results indicate a way of studying central neuronal processes for which the overt behavior of the animal is the dependent variable.     

Uniform inhibition of dopamine neurons in the ventral tegmental area by aversive stimuli

Dopamine neurons play a key role in reward-related behaviors. Reward coding theories predict that dopamine neurons will be inhibited by or will not respond to aversive stimuli. Paradoxically, between 3 and 49% of presumed dopamine neurons are excited by aversive stimuli. We found that, in the ventral tegmental area of anesthetized rats, the population of presumed dopamine neurons that are excited by aversive stimuli is actually not dopaminergic. The identified dopamine neurons were inhibited by the aversive stimulus. These findings suggest that dopamine neurons are specifically excited by reward and that a population of nondopamine neurons is excited by aversive stimuli.     

Encoding predictive reward value in human amygdala and orbitofrontal cortex

Adaptive behavior is optimized in organisms that maintain flexible representations of the value of sensory-predictive cues. To identify central representations of predictive reward value in humans, we used reinforcer devaluation while measuring neural activity with functional magnetic resonance imaging. We presented two arbitrary visual stimuli, both before and after olfactory devaluation, in a paradigm of appetitive conditioning. In amygdala and orbitofrontal cortex, responses evoked by a predictive target stimulus were decreased after devaluation, whereas responses to the nondevalued stimulus were maintained. Thus, differential activity in amygdala and orbitofrontal cortex encodes the current value of reward representations accessible to predictive cues.     

Neuronal activity related to reward value and motivation in primate frontal cortex

In several areas of the macaque brain, neurons fire during delayed-response tasks at a rate determined by the value of the reward expected at the end of the trial. The activity of these neurons might be related to the value of the expected reward or to the degree of motivation induced by expectation of the reward. We describe results indicating that the nature of reward-dependent activity varies across areas. Neuronal activity in orbitofrontal cortex represents the value of the expected reward, whereas neuronal activity in premotor cortex reflects the degree of motivation.     

Modulation of brain reward circuitry by leptin

Leptin, a hormone secreted by fat cells, suppresses food intake and promotes weight loss. To assess the action of this hormone on brain reward circuitry, changes in the rewarding effect of lateral hypothalamic stimulation were measured after leptin administration. At five stimulation sites near the fornix, the effectiveness of the rewarding electrical stimulation was enhanced by chronic food restriction and attenuated by intracerebroventricular infusion of leptin. In contrast, the rewarding effect of stimulating neighboring sites was insensitive to chronic food restriction and was enhanced by leptin in three of four cases. These opposing effects of leptin may mirror complementary changes in the rewarding effects of feeding and of competing behaviors.     

Reward-predictive cues enhance excitatory synaptic strength onto midbrain dopamine neurons

Using sensory information for the prediction of future events is essential for survival. Midbrain dopamine neurons are activated by environmental cues that predict rewards, but the cellular mechanisms that underlie this phenomenon remain elusive. 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.     

Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease

Neural transplantation can restore striatal dopaminergic neurotransmission in animal models of Parkinson's disease. It has now been shown that mesencephalic dopamine neurons, obtained from human fetuses of 8 to 9 weeks gestational age, can survive in the human brain and produce marked and sustained symptomatic relief in a patient severely affected with idiopathic Parkinson's disease. The grafts, which were implanted unilaterally into the putamen by stereotactic surgery, restored dopamine synthesis and storage in the grafted area, as assessed by positron emission tomography with 6-L-[18F]fluorodopa. This neurochemical change was accompanied by a therapeutically significant reduction in the patient's severe rigidity and bradykinesia and a marked diminuation of the fluctuations in the patient's condition during optimum medication (the "on-off" phenomenon). The clinical improvement was most marked on the side contralateral to the transplant.     

Discrimination by rats of conspecific odors of reward and nonreward

The hypothesis that, after receiving reward and nonreward, rats excrete differential odors perceptible to other rats was tested by making the correct turn in a T-maze contingent on discrimination of any such odors. Clear evidence for an "odor of nonreward or frustration" was obtained, and there was the suggestion of a transistory odor after early reward trials.     

D1 and D2 dopamine receptor-regulated gene expression of striatonigral and striatopallidal neurons

The striatum, which is the major component of the basal ganglia in the brain, is regulated in part by dopaminergic input from the substantia nigra. Severe movement disorders result from the loss of striatal dopamine in patients with Parkinson's disease. Rats with lesions of the nigrostriatal dopamine pathway caused by 6-hydroxydopamine (6-OHDA) serve as a model for Parkinson's disease and show alterations in gene expression in the two major output systems of the striatum to the globus pallidus and substantia nigra. Striatopallidal neurons show a 6-OHDA-induced elevation in their specific expression of messenger RNAs (mRNAs) encoding the D2 dopamine receptor and enkephalin, which is reversed by subsequent continuous treatment with the D2 agonist quinpirole. Conversely, striatonigral neurons show a 6-OHDA-induced reduction in their specific expression of mRNAs encoding the D1 dopamine receptor and substance P, which is reversed by subsequent daily injections of the D1 agonist SKF-38393. This treatment also increases dynorphin mRNA in striatonigral neurons. Thus, the differential effects of dopamine on striatonigral and striatopallidal neurons are mediated by their specific expression of D1 and D2 dopamine receptor subtypes, respectively.     

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine destroys dopamine neurons in explants of rat embryo mesencephalon

Explants of embryonic rat mesencephalon were grown in organotypic culture. Addition of 10 microM 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to the culture medium for 4 to 7 days resulted in loss of dopamine cell bodies and fiber outgrowths, as observed by fluorescence histochemistry. At the same time, the cultures showed decreased uptake of tritium-labeled dopamine. However, no signs of generalized toxicity were evident when the explant cultures were viewed by light and phase-contrast microscopy. These results show that MPTP exerts a relatively selective destructive action in dopamine neurons in vitro, similar to the action observed in humans and monkeys in vivo. Pargyline (10 microM), a monoamine oxidase inhibitor, protected the dopamine neurons in the explants. Organotypic cultures provide an experimental model for the study of the properties of MPTP in vitro.     

Differential effects of classical and atypical antipsychotic drugs on A9 and A10 dopamine neurons

Prolonged treatment with classical antipsychotic drugs decreased the number of spontaneously active dopamine neurons in both the substantia nigra (A9) and the ventral tegmental area (A10) of the rat brain. In contrast, treatment with atypical antipsychotic drugs selectively decreased the number of A10 dopamine neurons. Related drugs lacking antipsychotic efficacy failed to decrease dopamine activity. These findings suggest that the inability of atypical antipsychotic drugs to decrease A9 dopamine neuronal activity may be related to their lower potential for causing tardive dyskinesia and that the inactivation of A10 neurons may be involved in the delayed onset of therapeutic effects during treatment.     

Role of noradrenergic signaling by the nucleus tractus solitarius in mediating opiate reward

Norepinephrine (NE) is widely implicated in opiate withdrawal, but much less is known about its role in opiate-induced locomotion and reward. In mice lacking dopamine beta-hydroxylase (DBH), an enzyme critical for NE synthesis, we found that NE was necessary for morphine-induced conditioned place preference (CPP; a measure of reward) and locomotion. These deficits were rescued by systemic NE restoration. Viral restoration of DBH expression in the nucleus tractus solitarius, but not in the locus coeruleus, restored CPP for morphine. Morphine-induced locomotion was partially restored by DBH expression in either brain region. These data suggest that NE signaling by the nucleus tractus solitarius is necessary for morphine reward.     

Adaptive recognition by nucleic acid aptamers

Nucleic acid molecules play crucial roles in diverse biological processes including the storage, transport, processing, and expression of the genetic information. Nucleic acid aptamers are selected in vitro from libraries containing random sequences of up to a few hundred nucleotides. Selection is based on the ability to bind ligand molecules with high affinity and specificity. Three-dimensional structures have been determined at high resolution for a number of aptamers in complex with their cognate ligands. Structures of aptamer complexes reveal the key molecular interactions conferring specificity to the aptamer-ligand association, including the precise stacking of flat moieties, specific hydrogen bonding, and molecular shape complementarity. These basic principles of discriminatory molecular interactions in aptamer complexes parallel recognition events central to many cellular processes involving nucleic acids.     

Identification of presynaptic neurons by laser photostimulation

An optical method involving the use of a laser and a novel fluorescent dye as a photostimulation probe has been developed to identify presynaptic neurons in a large ensemble of cells. Illumination of an extracellularly stained neuron by the laser microbeam evokes action potentials. With this technique an interneuron connecting identified leech neurons was quickly located. The method speeds up the elucidation of neuronal networks, especially when small cells are involved.     

Transmitter sensitivity of neurons assayed by autoradiography

Ionic conductance channels that are opened by activating nicotinic acetylcholine receptors at synapses of sympathetic neurons are permeable to small organic amines. Uptake of a tritium-labeled amine through these channels can be measured by autoradiography. This provides a simple and direct way to assess the sensitivity of individual neurons to acetylcholine without using microelectrodes.