Explore the vast range of titles available.

Dopamine neurons are thought to encode novelty in addition to reward prediction error (the discrepancy between actual and predicted values). In this study, we compared dopamine activity across the striatum using fiber fluorometry in mice. During classical conditioning, we observed opposite dynamics in dopamine axon signals in the ventral striatum (‘VS dopamine’) and the posterior tail of the striatum (‘TS dopamine’). TS dopamine showed strong excitation to novel cues, whereas VS dopamine showed no responses to novel cues until they had been paired with a reward. TS dopamine cue responses decreased over time, depending on what the cue predicted. Additionally, TS dopamine showed excitation to several types of stimuli including rewarding, aversive, and neutral stimuli whereas VS dopamine showed excitation only to reward or reward-predicting cues. Together, these results demonstrate that dopamine novelty signals are localized in TS along with general salience signals, while VS dopamine reliably encodes reward prediction error. New experiences trigger a variety of responses in animals. We are surprised by, move towards, and often explore new objects. But how does the brain control these responses? Dopamine is a molecule that controls many processes in the brain and plays critical roles in various mental disorders, diseases that affect movement, and addiction. Rewarding experiences (like a glass of cold water on a hot day) can trigger dopamine neurons and studies have also shown that dopamine neurons respond to new experiences. This suggested that novelty may be rewarding in itself, or that novelty may signal the potential for future reward. On the other hand, it may be that different groups of dopamine neurons play different roles in responding to new or rewarding experiences. In 2015, it was reported that dopamine neurons connected to the rear part of an area in the brain called the striatum receive signals from different parts of the brain than most other dopamine neurons. The dopamine neurons connected to this “tail” of the striatum preferentially received inputs from regions involved in arousal rather than reward, suggesting that they may have a unique role and transmit a different type of information. Now, Menegas et al. have shown that dopamine signals in different areas of the striatum separate reward from novelty and other signals in mice. The results demonstrate that new odors activate dopamine neurons projecting to the tail of the striatum, but that this activity fades as the novelty wears off (as the mice learn to associate the odor with a particular outcome). By contrast, dopamine neurons projecting to the front of the striatum do not respond to novelty, but rather become more active as mice learn which odors accompany rewards (only responding to odors that predict reward). The experiments also show that dopamine neurons in the tail of the striatum encode information about the importance of a stimulus. Together, these findings indicate that some of the roles dopamine plays in the brain may not be related to reward, but are instead linked to the novelty and importance of the stimulus. The next challenge will be to find out how the separate reward and novelty signals in dopamine neurons relate to the animals’ behavior. This may help us to better understand dopamine-related psychiatric conditions, such as depression and addiction.

Dopamine is thought to regulate learning from appetitive and aversive events. Here we examined how optogenetically-identified dopamine neurons in the lateral ventral tegmental area of mice respond to aversive events in different conditions. In low reward contexts, most dopamine neurons were exclusively inhibited by aversive events, and expectation reduced dopamine neurons’ responses to reward and punishment. When a single odor predicted both reward and punishment, dopamine neurons’ responses to that odor reflected the integrated value of both outcomes. Thus, in low reward contexts, dopamine neurons signal value prediction errors (VPEs) integrating information about both reward and aversion in a common currency. In contrast, in high reward contexts, dopamine neurons acquired a short-latency excitation to aversive events that masked their VPE signaling. Our results demonstrate the importance of considering the contexts to examine the representation in dopamine neurons and uncover different modes of dopamine signaling, each of which may be adaptive for different environments. There are many types of learning; one type of learning means that rewards and punishments can shape future behavior. Dopamine is a molecule that allows neurons in the brain to communicate with one another, and it is released in response to unexpected rewards. Most neuroscientists believe that dopamine is important to learn from the reward; however, there are different opinions about whether dopamine is important to learn from punishments or not. Previous studies that tried to examine how dopamine activities change in response to punishment have reported different results. One of the likely reasons for the controversy is that it was difficult to measure only the activity of dopamine-releasing neurons. To overcome this issue, Matsumoto et al. used genetically engineered mice in which shining a blue light into their brain would activate their dopamine neurons but not any other neurons. Tiny electrodes were inserted into the brains of these mice, and a blue light was used to confirm that these electrodes were recording from the dopamine-producing neurons. Specifically if the electrode detected an electrical impulse when blue light was beamed into the brain, then the recorded neuron was confirmed to be a dopamine-producing neuron. Measuring the activities of these dopamine neurons revealed that they were indeed activated by reward but inhibited by punishment. In other words, dopamine neurons indeed can signal punishments as negative and rewards as positive on a single axis. Further experiments showed that, if the mice predicted both a reward and a punishment, the dopamine neurons could integrate information from both to direct learning. Matsumoto et al. also saw that when mice received rewards too often, their dopamine neurons did not signal punishment correctly. These results suggest that how we feel about punishment may depend on how often we experience rewards. In addition to learning, dopamine has also been linked to many psychiatric symptoms such as addiction and depression. The next challenge will be to examine how the frequency of rewards changes an animal’s state and responses to punishment in more detail, and how this relates to normal and abnormal behaviors.

Midbrain dopamine neurons are well known for their role in reward-based reinforcement learning. We found that the activity of dopamine axons in the posterior tail of the striatum (TS) scaled with the novelty and intensity of external stimuli, but did not encode reward value. We demonstrated that the ablation of TS-projecting dopamine neurons specifically inhibited avoidance of novel or high-intensity stimuli without affecting animals’ initial avoidance responses, suggesting a role in reinforcement rather than simply in avoidance itself. Furthermore, we found that animals avoided optogenetic activation of dopamine axons in TS during a choice task and that this stimulation could partially reinstate avoidance of a familiar object. These results suggest that TS-projecting dopamine neurons reinforce avoidance of threatening stimuli. More generally, our results indicate that there are at least two axes of reinforcement learning using dopamine in the striatum: one based on value and one based on external threat.

A large body of evidence has indicated that the phasic responses of midbrain dopamine neurons show a remarkable similarity to a type of teaching signal (temporal difference (TD) error) used in machine learning. However, previous studies failed to observe a key prediction of this algorithm: that when an agent associates a cue and a reward that are separated in time, the timing of dopamine signals should gradually move backward in time from the time of the reward to the time of the cue over multiple trials. Here we demonstrate that such a gradual shift occurs both at the level of dopaminergic cellular activity and dopamine release in the ventral striatum in mice. Our results establish a long-sought link between dopaminergic activity and the TD learning algorithm, providing fundamental insights into how the brain associates cues and rewards that are separated in time.The authors found that dopamine signals move gradually from time of reward to time of cue through intermediate timepoints, similarly to the evaluation signals used in temporal difference learning. These findings thereby fill a gap between computational theories and the brain.

Dopamine (DA) plays multiple roles in a wide range of physiological and pathological processes via a large network of dopaminergic projections. To dissect the spatiotemporal dynamics of DA release in both dense and sparsely innervated brain regions, we developed a series of green and red fluorescent G-protein-coupled receptor activation-based DA (GRAB DA ) sensors using a variety of DA receptor subtypes. These sensors have high sensitivity, selectivity and signal-to-noise ratio with subsecond response kinetics and the ability to detect a wide range of DA concentrations. We then used these sensors in mice to measure both optogenetically evoked and behaviorally relevant DA release while measuring neurochemical signaling in the nucleus accumbens, amygdala and cortex. Using these sensors, we also detected spatially resolved heterogeneous cortical DA release in mice performing various behaviors. These next-generation GRAB DA sensors provide a robust set of tools for imaging dopaminergic activity under a variety of physiological and pathological conditions. Next-generation red and green G-protein-coupled receptor-based dopamine sensors with improved properties have been developed. Their performance is demonstrated in cell culture, in brain slices and in vivo in the mouse.

Different regions of the striatum regulate different types of behavior. However, how dopamine signals differ across striatal regions and how dopamine regulates different behaviors remain unclear. Here, we compared dopamine axon activity in the ventral, dorsomedial, and dorsolateral striatum, while mice performed a perceptual and value-based decision task. Surprisingly, dopamine axon activity was similar across all three areas. At a glance, the activity multiplexed different variables such as stimulus-associated values, confidence, and reward feedback at different phases of the task. Our modeling demonstrates, however, that these modulations can be inclusively explained by moment-by-moment changes in the expected reward, that is the temporal difference error. A major difference between areas was the overall activity level of reward responses: reward responses in dorsolateral striatum were positively shifted, lacking inhibitory responses to negative prediction errors. The differences in dopamine signals put specific constraints on the properties of behaviors controlled by dopamine in these regions.

Combining rabies-virus tracing, optical clearing (CLARITY), and whole-brain light-sheet imaging, we mapped the monosynaptic inputs to midbrain dopamine neurons projecting to different targets (different parts of the striatum, cortex, amygdala, etc) in mice. We found that most populations of dopamine neurons receive a similar set of inputs rather than forming strong reciprocal connections with their target areas. A common feature among most populations of dopamine neurons was the existence of dense ‘clusters’ of inputs within the ventral striatum. However, we found that dopamine neurons projecting to the posterior striatum were outliers, receiving relatively few inputs from the ventral striatum and instead receiving more inputs from the globus pallidus, subthalamic nucleus, and zona incerta. These results lay a foundation for understanding the input/output structure of the midbrain dopamine circuit and demonstrate that dopamine neurons projecting to the posterior striatum constitute a unique class of dopamine neurons regulated by different inputs. Most neurons send their messages to recipient neurons by releasing a substance called a ‘neurotransmitter’ that binds to receptors on the target cell. The sites of this type of signal transmission are called synapses. Some small populations of neurons modulate the activity of hundreds or thousands of these synapses all across the brain by releasing ‘neuromodulators’ that affect how they work. These neuromodulators are essential because they broadcast information that is likely to be useful to many brain regions, like a ‘news channel’ for the brain. One important neuromodulator in the mammalian brain is dopamine, which contributes to motivation, learning, and the control of movement. Clusters of cells deep in the brain release dopamine, and people with Parkinson's disease gradually lose these cells. This makes it increasingly difficult for their brains to produce the correct amount of dopamine, and results in symptoms such as tremors and stiff muscles. Individual dopamine neurons typically send information to a single part of the brain. This suggests that dopamine neurons with different targets might have different roles. To explore this possibility, Menegas et al. classified dopamine neurons in the mouse brain into eight types based on the areas to which they project, and then mapped which neurons send input signals to each type. These inputs are likely to shape the activity of each type (that is, their ‘message’ to the rest of the brain). The mapping revealed that most dopamine neurons do not receive substantial input from the area to which they project (i.e., they do not form ‘closed loops’). Instead, most of their input comes from a common set of brain regions, including a particularly large number of inputs from the ventral striatum. However, Menegas et al. found one exception. Dopamine neurons that target part of the brain called the posterior striatum receive relatively little input from the ventral striatum. Their input comes instead from a set of other brain structures, and in particular from a region called the subthalamic nucleus. Electrical stimulation of the subthalamic nucleus can help to relieve the symptoms of Parkinson's disease. Therefore, the results presented by Menegas et al. suggest that this population of dopamine neurons might be particularly relevant to Parkinson's disease and that focusing future studies on them could ultimately be beneficial for patients.

Dopamine (DA) neurons in the ventral tegmental area bidirectionally regulate the activity of serotonin neurons in the dorsal raphe nucleus. Low-strength activity causes inhibition via dopamine receptor D2, whereas high- strength activity causes activation via dopamine receptor D1, and this circuit contributes to anorexia nervosa-like behaviors in mice.

Mice display robust, stereotyped behaviours towards pups: virgin males typically attack pups, whereas virgin females and sexually experienced males and females display parental care. Here we show that virgin males genetically impaired in vomeronasal sensing do not attack pups and are parental. Furthermore, we uncover a subset of galanin-expressing neurons in the medial preoptic area (MPOA) that are specifically activated during male and female parenting, and a different subpopulation that is activated during mating. Genetic ablation of MPOA galanin neurons results in marked impairment of parental responses in males and females and affects male mating. Optogenetic activation of these neurons in virgin males suppresses inter-male and pup-directed aggression and induces pup grooming. Thus, MPOA galanin neurons emerge as an essential regulatory node of male and female parenting behaviour and other social responses. These results provide an entry point to a circuit-level dissection of parental behaviour and its modulation by social experience. Sexual experience brings radical changes in how male mice behave with pups—virgin males attack them whereas mature fathers display parental care; here the authors identify a subset of hypothalamic neurons whose ablation leads to parental deficits in both males and females, and whose activation in virgin males suppresses aggression and induces pup grooming. Neuronal control of parental behaviour Sexual experience brings radical change in how male mice behave with pups — virgin males attack them whereas experienced fathers display parental care. Now Catherine Dulac and colleagues show that virgin males with impaired pheromone sensing do not attack pups. Even more spectacularly, the authors identify a subset of hypothalamic neurons expressing the neuropeptide galanin whose activation in virgin males suppresses aggression and induces pup grooming. Genetic ablation of galanin-expressing neurons results in dramatic impairment of both maternal and paternal responses to pups. The molecular identification of a neuronal population controlling parental behaviour in both males and females is likely to attract wide interest from both neuroscientists and ethologists.