Sensory stimuli alter discharge rate of dopamine (DA) neurons: evidence for two functional types of DA cells in the substantia nigra

Dopamine neurons have long been thought to facilitate learning by broadcasting reward prediction error (RPE), a teaching signal used in machine learning, but more recent work has advanced alternative models of dopamine’s computational role. Here, I revisit this critical issue and review new experimental evidences that tighten the link between dopamine activity and RPE. First, I introduce the recent observation of a gradual backward shift of dopamine activity that had eluded researchers for over a decade. I also discuss several other findings, such as dopamine ramping, that were initially interpreted to conflict but later found to be consistent with RPE. These findings improve our understanding of neural computation in dopamine neurons.

Morphine has a strong analgesic effect and is suitable for various types of pain, so it is widely used. But long-term usage of morphine can lead to drug tolerance, which limits its clinical application. The complex mechanisms underlying the development of morphine analgesia into tolerance involve multiple nuclei in the brain. Recent studies reveal the signaling at the cellular and molecular levels as well as neural circuits contributing to morphine analgesia and tolerance in the ventral tegmental area (VTA), which is traditionally considered a critical center of opioid reward and addiction. Existing studies show that dopamine receptors and μ-opioid receptors participate in morphine tolerance through the altered activities of dopaminergic and/or non-dopaminergic neurons in the VTA. Several neural circuits related to the VTA are also involved in the regulation of morphine analgesia and the development of drug tolerance. Reviewing specific cellular and molecular targets and related neural circuits may provide novel precautionary strategies for morphine tolerance.

Midbrain dopamine neurons play critical roles in reward- and aversion-driven associative learning. However, it is not clear whether they do this by a common mechanism or by separate mechanisms that can be dissociated. In the present study we addressed this question by testing whether a partial lesion of the dopamine neurons of the rat SNc has comparable effects on conditioned place preference (CPP) learning and conditioned place aversion (CPA) learning. Partial lesions of dopamine neurons in the rat substantia nigra pars compacta (SNc) induced by bilateral intranigral infusion of 6-hydroxydopamine (6-OHDA, 3 μg/side) or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 200 μg/side) impaired learning of conditioned place aversion (CPA) without affecting conditioned place preference (CPP) learning. Control experiments demonstrated that these lesions did not impair motor performance and did not alter the hedonic value of the sucrose and quinine. The number of dopamine neurons in the caudal part of the SNc positively correlated with the CPP scores of the 6-OHDA rats and negatively correlated with CPA scores of the SHAM rats. In addition, the CPA scores of the 6-OHDA rats positively correlated with the tissue content of striatal dopamine. Insomuch as reward-driven learning depends on an increase in dopamine release by nigral neurons, these findings show that this mechanism is functional even in rats with a partial lesion of the SNc. On the other hand, if aversion-driven learning depends on a reduction of extracellular dopamine in the striatum, the present study suggests that this mechanism is no longer functional after the partial SNc lesion.

The phasic dopamine reward prediction error response is a major brain signal underlying learning, approach and decision making. This dopamine response consists of two components that reflect, initially, stimulus detection from physical impact and, subsequenttly, reward valuation; dopamine activations by punishers reflect physical impact rather than aversiveness. The dopamine reward signal is distinct from earlier reported and recently confirmed phasic changes with behavioural activation. Optogenetic activation of dopamine neurones in monkeys causes value learning and biases economic choices. The dopamine reward signal conforms to formal economic utility and thus constitutes a utility prediction error signal. In these combined ways, the dopamine reward prediction error signal constitutes a potential neuronal substrate for the crucial economic decision variable of utility.

Animals behave differently in response to visual cues with distinct ethological meaning, a process usually thought to be achieved through differential visual processing. Using a defined zebrafish escape circuit as a model, we found that behavior selection can be implemented at the visuomotor transformation stage through a visually responsive dopaminergic-inhibitory circuit module. In response to non-threatening visual stimuli, hypothalamic dopaminergic neurons and their positively regulated hindbrain inhibitory interneurons increase activity, suppressing synaptic transmission from the visual center to the escape circuit. By contrast, threatening visual stimuli inactivate some of these neurons, resulting in dis-inhibition of the visuomotor transformation and escape generation. The distinct patterns of dopaminergic-inhibitory neural module’s visual responses account for this stimulus-specific visuomotor transformation and behavioral control. Thus, our study identifies a behavioral relevance-dependent mechanism that controls visuomotor transformation and behavior selection and reveals that neuromodulation can be tuned by visual cues to help animals generate appropriate responses.

Dopaminergic neurons in a range of species are responsive to sensory stimuli. In the anesthetized preparation, responses to non-noxious and noxious sensory stimuli are usually tonic in nature, although long-duration changes in activity have been reported in the awake preparation as well. However, in the awake preparation, short-latency, phasic changes in activity are most common. These phasic responses can occur to unconditioned aversive and non-aversive stimuli, as well as to the stimuli which predict them. In both the anesthetized and awake preparations, not all dopaminergic neurons are responsive to sensory stimuli, however responsive neurons tend to respond to more than a single stimulus modality. Evidence suggests that short-latency sensory information is provided to dopaminergic neurons by relatively primitive subcortical structures – including the midbrain superior colliculus for vision and the mesopontine parabrachial nucleus for pain and possibly gustation. Although short-latency visual information is provided to dopaminergic neurons by the relatively primitive colliculus, dopaminergic neurons can discriminate between complex visual stimuli, an apparent paradox which can be resolved by the recently discovered route of information flow through to dopaminergic neurons from the cerebral cortex, via a relay in the colliculus. Given that projections from the cortex to the colliculus are extensive, such a relay potentially allows the activity of dopaminergic neurons to report the results of complex stimulus processing from widespread areas of the cortex. Furthermore, dopaminergic neurons could acquire their ability to reflect stimulus value by virtue of reward-related modification of sensory processing in the cortex. At the forebrain level, sensory-related changes in the tonic activity of dopaminergic neurons may regulate the impact of the cortex on forebrain structures such as the nucleus accumbens. In contrast, the short latency of the phasic responses to sensory stimuli in dopaminergic neurons, coupled with the activation of these neurons by non-rewarding stimuli, suggests that phasic responses of dopaminergic neurons may provide a signal to the forebrain which indicates that a salient event has occurred (and possibly an estimate of how salient that event is). A stimulus-related salience signal could be used by downstream systems to reinforce behavioral choices.