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Recent studies have suggested that the basal ganglia, the center of stimulus-reward associative learning, are involved in social behavior. However, the role of the basal ganglia in social information processing remains unclear. Here, we demonstrate that the striatum tail (STRt) in macaque monkeys, which is sensitive to visual objects with long-term reward history (i.e., stable object value), is also sensitive to socially familiar persons. Many STRt neurons responded to face images of persons, especially those who took daily care of the subject monkeys. These face-responsive neurons also encoded stable object value. The strength of the neuronal modulation of social familiarity and stable object value biases were positively correlated. These results suggest that both social familiarity and stable object value information are mediated by a common neuronal mechanism. Thus, the representation of social information is linked to reward information in the STRt, not in the dedicated social information circuit., Competing Interests: The authors declare no competing financial interests., (© 2024 The Author(s).)

In real life, multiple objects of different values are mixed in a variety of environments. To survive, animals need to find rewarding objects that may be located but hidden in particular contexts (e.g., environments) with bad objects that are unassociated with reward. Then, animals and humans pay attention to the enriched environment so that they can find the rewarding object vigorously. How can the brain initiate such behavior based on the context? We thus created a behavioral task for monkeys in which multiple contextual events (environment, action cue) sequentially occurred before objects appeared. We then studied the lateral habenula (LHb), which inhibit dopamine neurons (Matsumoto and Hikosaka, 2007). LHb neurons showed phasic responses in each event step-by-step across the sequential events, whose direction (excitation or inhibition) corresponded to the immediate change of the predicted value. Moreover, LHb neurons sequentially compared detailed prediction errors based on their significance in multiple contexts., Competing Interests: The authors declare no competing interests., (© 2022 The Author(s).)

Optogenetics has revolutionized neuroscience in small laboratory animals, but its effect on animal models more closely related to humans, such as non-human primates (NHPs), has been mixed. To make evidence-based decisions in primate optogenetics, the scientific community would benefit from a centralized database listing all attempts, successful and unsuccessful, of using optogenetics in the primate brain. We contacted members of the community to ask for their contributions to an open science initiative. As of this writing, 45 laboratories around the world contributed more than 1,000 injection experiments, including precise details regarding their methods and outcomes. Of those entries, more than half had not been published. The resource is free for everyone to consult and contribute to on the Open Science Framework website. Here we review some of the insights from this initial release of the database and discuss methodological considerations to improve the success of optogenetic experiments in NHPs., Competing Interests: Declaration of Interests S. Palfi received consulting honorarium from OxfordBiomedica. K.V.S. is a consultant for Neuralink and is on the scientific advisory board for CTRL-Labs, MIND-X, Inscopix, and Heal. These entities did not support this work. P.N.S. has financial interests in Neuralink, a company developing clinical therapies using brain stimulation., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The thalamus is known to process information from various brain regions and relay it to other brain regions, serving an essential role in sensory perception and motor execution. The thalamus also receives inputs from basal ganglia nuclei (BG) involved in value-based decision making, suggesting a role in the value process. We found that neurons in a particular area of the rhesus macaque posterior thalamus encoded the historical value memory of visual objects. Many of these value-coding neurons were located in the suprageniculate nucleus (SGN). This thalamic area directly received anatomical input from the superior colliculus (SC), and the neurons showed visual responses with contralateral preferences. Notably, the value discrimination activity of these thalamic neurons increased during learning, with the learned values stably retained even more than 200 days after learning. Our data indicate that single neurons in the posterior thalamus not only processed simple visual information but also represented historical values. Furthermore, our data suggest an SC-posterior thalamus-BG-SC subcortical loop circuit that encodes the historical value, enabling a quick automatic gaze by bypassing the visual cortex., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A primary function of the primate amygdala is to modulate behavior based on emotional cues. To study the underlying neural mechanism, we first inactivated the amygdala locally and temporarily by injecting a GABA agonist. Then, saccadic eye movements and gaze were suppressed only on the contralateral side. Next, we performed optogenetic activation after injecting a viral vector into the amygdala. Optical stimulation in the amygdala excited amygdala neurons, whereas optical stimulation of axon terminals in the substantia nigra pars reticulata inhibited nigra neurons. Optical stimulation in either structure facilitated saccades to the contralateral side. These data suggest that the amygdala controls saccades and gaze through the basal ganglia output to the superior colliculus. Importantly, this amygdala-derived circuit mediates emotional context information, whereas the internal basal ganglia circuit mediates object value information. This finding demonstrates a basic mechanism whereby basal ganglia output can be modulated by other areas conveying distinct information., Competing Interests: Declaration of Interests The authors declare no competing financial interests., (Published by Elsevier Inc.)

As a central hub for cognitive control, prefrontal cortex (PFC) is thought to utilize memories. However, unlike working or short-term memory, the neuronal representation of long-term memory in PFC has not been systematically investigated. Using single-unit recordings in macaques, we show that PFC neurons rapidly update and maintain responses to objects based on short-term reward history. Interestingly, after repeated object-reward association, PFC neurons continue to show value-biased responses to objects even in the absence of reward. This value-biased response is retained for several months after training and is resistant to extinction and to interference from new object-reward learning for many complex objects (>90). Accordingly, the monkeys remember the values of the learned objects for several months in separate testing. These findings reveal that in addition to flexible short-term and low-capacity memories, primate PFC represents stable long-term and high-capacity memories, which could prioritize valuable objects far into the future., (Published by Elsevier Ltd.)

The striatum controls behavior in two ways: facilitation and suppression through the direct and indirect pathways, respectively. However, it is still unclear what information is processed in these pathways. To address this question, we studied two pathways originating from the primate caudate tail (CDt). We found that the CDt innervated the caudal-dorsal-lateral part of the substantia nigra pars reticulata (cdlSNr), directly or indirectly through the caudal-ventral part of the globus pallidus externus (cvGPe). Notably, cvGPe neurons receiving inputs from the CDt were mostly visual neurons that encoded stable reward values of visual objects based on long-past experiences. Their dominant response was inhibition by valueless objects, which generated disinhibition of cdlSNr neurons and inhibition of superior colliculus neurons. Our data suggest that low-value signals are sent by the CDt-indirect pathway to suppress saccades to valueless objects, whereas high-value signals are sent by the CDt-direct pathway to facilitate saccades to valuable objects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Dopamine neurons promote learning by processing recent changes in reward values, such that reward may be maximized. However, such a flexible signal is not suitable for habitual behaviors that are sustained regardless of recent changes in reward outcome. We discovered a type of dopamine neuron in the monkey substantia nigra pars compacta (SNc) that retains past learned reward values stably. After reward values of visual objects are learned, these neurons continue to respond differentially to the objects, even when reward is not expected. Responses are strengthened by repeated learning and are evoked upon presentation of the objects long after learning is completed. These "sustain-type" dopamine neurons are confined to the caudal-lateral SNc and project to the caudate tail, which encodes long-term value memories of visual objects and guides gaze automatically to stably valued objects. This population of dopamine neurons thus selectively promotes learning and retention of habitual behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Choosing valuable objects is critical for survival, but their values may change flexibly or remain stable. Therefore, animals should be able to update the object values flexibly by recent experiences and retain them stably by long-term experiences. However, it is unclear how the brain encodes the two conflicting forms of values and controls behavior accordingly. We found that distinct circuits of the primate caudate nucleus control behavior selectively in the flexible and stable value conditions. Single caudate neurons encoded the values of visual objects in a regionally distinct manner: flexible value coding in the caudate head and stable value coding in the caudate tail. Monkeys adapted in both conditions by looking at objects with higher values. Importantly, inactivation of each caudate subregion disrupted the high-low value discrimination selectively in the flexible or stable context. This parallel complementary mechanism enables animals to choose valuable objects in both flexible and stable conditions., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Motor actions are facilitated when expected reward value is high. It is hypothesized that there are neurons that encode expected reward values to modulate impending actions and potentially represent motivation signals. Here, we present evidence suggesting that the ventral pallidum (VP) may participate in this process. We recorded single neuronal activity in the monkey VP using a saccade task with a direction-dependent reward bias. Depending on the amount of the expected reward, VP neurons increased or decreased their activity tonically until the reward was delivered, for both ipsiversive and contraversive saccades. Changes in expected reward values were also associated with changes in saccade performance (latency and velocity). Furthermore, bilateral muscimol-induced inactivation of the VP abolished the reward-dependent changes in saccade latencies. These data suggest that the VP provides expected reward value signals that are used to facilitate or inhibit motor actions., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but nonrewarding experiences such as aversive and alerting events. Here we review recent advances in understanding the reward and nonreward functions of dopamine. Based on this data, we propose that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control. Some dopamine neurons encode motivational value, supporting brain networks for seeking, evaluation, and value learning. Others encode motivational salience, supporting brain networks for orienting, cognition, and general motivation. Both types of dopamine neurons are augmented by an alerting signal involved in rapid detection of potentially important sensory cues. We hypothesize that these dopaminergic pathways for value, salience, and alerting cooperate to support adaptive behavior., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Midbrain dopamine neurons are thought to signal predictions about future rewards based on the memory of past rewarding experience. Little is known about the source of their reward memory and the factors that control its timescale. Here we recorded from dopamine neurons, as well as one of their sources of input, the lateral habenula, while animals predicted upcoming rewards based on the past reward history. We found that lateral habenula and dopamine neurons accessed two distinct reward memories: a short-timescale memory expressed at the start of the task and a near-optimal long-timescale memory expressed when a future reward outcome was revealed. The short- and long-timescale memories were expressed in different forms of reward-oriented eye movements. Our data show that the habenula-dopamine pathway contains multiple timescales of memory and provide evidence for their role in motivated behavior., ((c) 2010 Elsevier Inc. All rights reserved.)

Dopamine has a crucial role in anticipation of motivational events. To investigate the underlying mechanisms of this process, we analyzed the activity of dopamine neurons and one of their major sources of input, neurons in the lateral habenula, while animals anticipated upcoming behavioral tasks. We found that lateral habenula and dopamine neurons anticipated tasks in two distinct manners. First, neurons encoded the timing distribution of upcoming tasks through gradual changes in their tonic activity. This tonic signal encoded rewarding tasks in preference to punishing tasks and was correlated with classic phasic coding of motivational value. Second, neurons transmitted a phasic signal marking the time when a task began. This phasic signal encoded rewarding and punishing tasks in similar manners, as though reflecting motivational salience. Our data suggest that the habenula-dopamine pathway motivates anticipation through a combination of tonic reward-related and phasic salience-related signals.

The desire to know what the future holds is a powerful motivator in everyday life, but it is unknown how this desire is created by neurons in the brain. Here we show that when macaque monkeys are offered a water reward of variable magnitude, they seek advance information about its size. Furthermore, the same midbrain dopamine neurons that signal the expected amount of water also signal the expectation of information, in a manner that is correlated with the strength of the animal's preference. Our data show that single dopamine neurons process both primitive and cognitive rewards, and suggest that current theories of reward-seeking must be revised to include information-seeking.

As a major output station of the basal ganglia, the globus pallidus internal segment (GPi) projects to the thalamus and brainstem nuclei thereby controlling motor behavior. A less well known fact is that the GPi also projects to the lateral habenula (LHb) which is often associated with the limbic system. Using the monkey performing a saccade task with positionally biased reward outcomes, we found that antidromically identified LHb-projecting neurons were distributed mainly in the dorsal and ventral borders of the GPi and that their activity was strongly modulated by expected reward outcomes. A majority of them were excited by the no-reward-predicting target and inhibited by the reward-predicting target. These reward-dependent modulations were similar to those in LHb neurons but started earlier than those in LHb neurons. These results suggest that GPi may initiate reward-related signals through its effects on the LHb, which then influences the dopaminergic and serotonergic systems.

Both appetitive and aversive outcomes can reinforce animal behavior. It is not clear, however, whether the opposing kinds of reinforcers are processed by specific or common neural mechanisms. To investigate this issue, we studied macaque monkeys that performed a memory-guided saccade task for three different outcomes, namely delivery of liquid reward, avoidance of air puff, and feedback sound only. Animals performed the task best in rewarded trials, intermediately in aversive trials, and worst in sound-only trials. Most task-related activity in lateral prefrontal cortex was differentially influenced by the reinforcers. Aversive avoidance had clear effects on some prefrontal neurons, although the effects of rewards were more common. We also observed neurons modulated by both positive and negative reinforcers, reflecting reinforcement or attentional processes. Our results demonstrate that information about positive and negative reinforcers is processed differentially in prefrontal cortex, which could contribute to the role of this structure in goal-directed behavior.

Midbrain dopamine (DA) neurons are thought to encode reward prediction error. Reward prediction can be improved if any relevant context is taken into account. We found that monkey DA neurons can encode a context-dependent prediction error. In the first noncontextual task, a light stimulus was randomly followed by reward, with a fixed equal probability. The response of DA neurons was positively correlated with the number of preceding unrewarded trials and could be simulated by a conventional temporal difference (TD) model. In the second contextual task, a reward-indicating light stimulus was presented with the probability that, while fixed overall, was incremented as a function of the number of preceding unrewarded trials. The DA neuronal response then was negatively correlated with this number. This history effect corresponded to the prediction error based on the conditional probability of reward and could be simulated only by implementing the relevant context into the TD model.

Eye movements are often influenced by expectation of reward. Using a memory-guided saccade task with an asymmetric reward schedule, we show that visual responses of monkey SC neurons increase when the visual stimulus indicates an upcoming reward. The increase occurred in two distinct manners: (1) reactively, as an increase in the gain of the visual response when the stimulus indicated an upcoming reward; (2) proactively, as an increase in anticipatory activity when reward was expected in the neuron's response field. These effects were observed mostly in saccade-related SC neurons in the deeper layer which would receive inputs from the cortical eye fields and the basal ganglia. These results, together with recent findings, suggest that the gain modulation may be determined by the inputs from both the cortical eye fields and the basal ganglia, whereas the anticipatory bias may be derived mainly from the basal ganglia.

Complex learned motor sequences can be composed of a combination of a small number of elementary actions. To investigate how the brain represents such sequences, we devised an oculomotor sequence task in which the monkey had to choose the target solely by the sequential context, not by the current stimulus combination. We found that many neurons in the supplementary eye field (SEF) became active with a specific target direction (D neuron) or a specific target/distractor combination (C neuron). Furthermore, such activity was often selective for one among several sequences that included the combination (S neuron). These results suggest that the SEF contributes to the generation of saccades in many learned sequences.

A subset of caudate neurons fires before cues that instruct the monkey what he should do. To test the hypothesis that the anticipatory activity of such neurons depends on the context of stimulus-reward mapping, we examined their activity while the monkeys performed a memory-guided saccade task in which either the position or the color of a cue indicated presence or absence of reward. Some neurons showed anticipatory activity only when a particular position was associated with reward, while others fired selectively for color-reward associations. The functional segregation suggests that caudate neurons participate in feature-based anticipation of visual information that predicts reward. This neuronal code influences the general activity level in response to visual features without improving the quality of visual discrimination.