Decoding social rewards via inter-areal coordination frequency in the brain.

Vicarious reward plays a pivotal role in shaping altruism and prosociality. However, neural circuit mechanisms underlying the distinction between vicarious reward and experienced reward are poorly understood. Putnam et al. recently demonstrated that the two types of reward are represented by distinct coordination frequencies within the same cingulate-amygdala pathway.

Chemogenetic dissection of a prefrontal-hypothalamic circuit for socially subjective reward valuation in macaques.

The value of one's own reward is affected by the reward of others, serving as a source for envy. However, it is not known which neural circuits mediate such socially subjective value modulation. Here, we chemogenetically dissected the circuit from the medial prefrontal cortex (MPFC) to the lateral hypothalamus (LH) while male macaques were presented with visual stimuli that concurrently signaled the prospects of one's own and others' rewards. We found that functional disconnection between the MPFC and LH rendered animals significantly less susceptible to others' but not one's own reward prospects. In parallel with this behavioral change, inter-areal coordination, as indexed by coherence and Granger causality, decreased primarily in the delta and theta bands. These findings demonstrate that the MPFC-to-LH circuit plays a crucial role in carrying information about upcoming other-rewards for subjective reward valuation in social contexts.

Tuning in to real-time social interactions in macaques.

Movement synchronization between individuals has been implicated in reinforcing their cohesion. How might such interindividual motor entrainment be controlled by the social brain? The answer remains elusive owing largely to the lack of suitable animal models in which direct neural recordings are available. Here, we show that macaque monkeys exhibit social motor entrainment without human prompting. We found that repetitive arm movements for horizontal bar sliding were phase coherent between two monkeys. The nature of motor entrainment was specific to animal pairs, consistent across days, dependent on visual inputs, and affected by social hierarchy. Notably, the entrainment was diminished when paired with prerecorded movies of a monkey making the same movements or bar motion alone. These findings demonstrate that motor entrainment is facilitated by real-time social exchanges, providing a behavioral platform to study the neural basis of potentially evolutionarily conserved mechanisms that support group cohesion.

Cognitive genomics of learning delay and low level of social performance monitoring in macaque.

Cognitive skills and the underlying neural architecture are under the influence of genetics. Cognitive genomics research explores the triadic relationship between genes, brain, and cognition, with its major strategy being genotype-driven. Here we show that an inverse strategy is feasible to identify novel candidate genes for particular neuro-cognitive phenotypes in macaques. Two monkeys, originally involved in separate psychological studies, exhibited learning delay and low levels of social performance monitoring. In one monkey, mirror neurons were fewer compared to controls and mu suppression was absent in the frontal cortex. The other monkey showed heightened visual responsiveness in both frontal cortex and dopamine-rich midbrain, with a lack of inter-areal synchronization. Exome analyses revealed that the two monkeys were most likely cousins and shared variants in MAP2, APOC1, and potentially HTR2C. This phenotype-driven strategy in cognitive genomics provides a useful means to clarify the genetic basis of phenotypic variation and develop macaque models of neuropsychiatric disorders.

Live agent preference and social action monitoring in the macaque mid-superior temporal sulcus region.

Mentalizing, the ability to infer the mental states of others, is a cornerstone of adaptive social intelligence. While functional brain mapping of human mentalizing has progressed considerably, its evolutionary signature in nonhuman primates remains debated. The discovery that the middle part of the macaque superior temporal sulcus (mid-STS) region has a connectional fingerprint most similar to the human temporoparietal junction (TPJ)-a crucial node in the mentalizing network-raises the possibility that these cortical areas may also share basic functional properties associated with mentalizing. Here, we show that this is the case in aspects of a preference for live social interactions and in a theoretical framework of predictive coding. Macaque monkeys were trained to perform a turn-taking choice task with another real monkey partner sitting directly face-to-face or a filmed partner appearing in prerecorded videos. We found that about three-fourths of task-related mid-STS neurons exhibited agent-dependent activity, most responding selectively or preferentially to the partner's action. At the population level, activities of these partner-type neurons were significantly greater under live-partner compared to video-recorded-partner task conditions. Furthermore, a subset of the partner-type neurons responded proactively when predictions about the partner's action were violated. This prediction error coding was specific to the action domain; almost none of the neurons signaled error in the prediction of reward. The present findings highlight unique roles of the macaque mid-STS at the single-neuron level and further delineate its functional parallels with the human TPJ in social cognitive processes associated with mentalizing.

The Role of the Medial Prefrontal Cortex in Moderating Neural Representations of Self and Other in Primates.

As a frontal node in the primate social brain, the medial prefrontal cortex (MPFC) plays a critical role in coordinating one's own behavior with respect to that of others. Current literature demonstrates that single neurons in the MPFC encode behavior-related variables such as intentions, actions, and rewards, specifically for self and other, and that the MPFC comes into play when reflecting upon oneself and others. The social moderator account of MPFC function can explain maladaptive social cognition in people with autism spectrum disorder, which tips the balance in favor of self-centered perspectives rather than taking into consideration the perspective of others. Several strands of evidence suggest a hypothesis that the MPFC represents different other mental models, depending on the context at hand, to better predict others' emotions and behaviors. This hypothesis also accounts for aberrant MPFC activity in autistic individuals while they are mentalizing others.

Subcortical encoding of agent-relevant associative signals for adaptive social behavior in the macaque.

Primates are group-living creatures that constantly face the challenges posed by complex social demands. To date, the cortical mechanisms underlying social information processing have been the major focus of attention. However, emerging evidence suggests that subcortical regions also mediate the collection and processing of information from other agents. Here, we review the literature supporting the hypothesis that behavioral variables important for decision-making, i.e., stimulus, action, and outcome, are associated with agent information (self and other) in subcortical regions, such as the amygdala, striatum, lateral hypothalamus, and dopaminergic midbrain nuclei. Such self-relevant and other-relevant associative signals are then integrated into a social utility signal, presumably at the level of midbrain dopamine neurons. This social utility signal allows decision makers to organize their optimal behavior in accordance with social demands. Determining how self-relevant and other-relevant signals might be altered in psychiatric and neurodevelopmental disorders will be fundamental to better understand how social behaviors are dysregulated in disease conditions.

Socially relative reward valuation in the primate brain.

Reward valuation in social contexts is by nature relative rather than absolute; it is made in reference to others. This socially relative reward valuation is based on our propensity to conduct comparisons and competitions between self and other. Exploring its neural substrate has been an active area of research in human neuroimaging. More recently, electrophysiological investigation of the macaque brain has enabled us to understand neural mechanisms underlying this valuation process at single-neuron and network levels. Here I show that shared neural networks centered at the medial prefrontal cortex and dopamine-related subcortical regions are involved in this process in humans and nonhuman primates. Thus, socially relative reward valuation is mediated by cortico-subcortically coordinated activity linking social and reward brain networks.

A causal role for frontal cortico-cortical coordination in social action monitoring.

Decision-making via monitoring others' actions is a cornerstone of interpersonal exchanges. Although the ventral premotor cortex (PMv) and the medial prefrontal cortex (MPFC) are cortical nodes in social brain networks, the two areas are rarely concurrently active in neuroimaging, inviting the hypothesis that they are functionally independent. Here we show in macaques that the ability of the MPFC to monitor others' actions depends on input from the PMv. We found that delta-band coherence between the two areas emerged during action execution and action observation. Information flow especially in the delta band increased from the PMv to the MPFC as the biological nature of observed actions increased. Furthermore, selective blockade of the PMv-to-MPFC pathway using a double viral vector infection technique impaired the processing of observed, but not executed, actions. These findings demonstrate that coordinated activity in the PMv-to-MPFC pathway has a causal role in social action monitoring.

Representation of distinct reward variables for self and other in primate lateral hypothalamus.

The lateral hypothalamus (LH) has long been implicated in maintaining behavioral homeostasis essential for the survival of an individual. However, recent evidence suggests its more widespread roles in behavioral coordination, extending to the social domain. The neuronal and circuit mechanisms behind the LH processing of social information are unknown. Here, we show that the LH represents distinct reward variables for "self" and "other" and is causally involved in shaping socially motivated behavior. During a Pavlovian conditioning procedure incorporating ubiquitous social experiences where rewards to others affect one's motivation, LH cells encoded the subjective value of self-rewards, as well as the likelihood of self- or other-rewards. The other-reward coding was not a general consequence of other's existence, but a specific effect of other's reward availability. Coherent activity with and top-down information flow from the medial prefrontal cortex, a hub of social brain networks, contributed to signal encoding in the LH. Furthermore, deactivation of LH cells eliminated the motivational impact of other-rewards. These results indicate that the LH constitutes a subcortical node in social brain networks and shapes one's motivation by integrating cortically derived, agent-specific reward information.

Multiple neuronal circuits for variable object-action choices based on short- and long-term memories.

At each time in our life, we choose one or few behaviors, while suppressing many other behaviors. This is the basic mechanism in the basal ganglia, which is done by tonic inhibition and selective disinhibition. Dysfunctions of the basal ganglia then cause 2 types of disorders (difficulty in initiating necessary actions and difficulty in suppressing unnecessary actions) that occur in Parkinson's disease. The basal ganglia generate such opposite outcomes through parallel circuits: The direct pathway for initiation and indirect pathway for suppression. Importantly, the direct pathway processes good information and the indirect pathway processes bad information, which enables the choice of good behavior and the rejection of bad behavior. This is mainly enabled by dopaminergic inputs to these circuits. However, the value judgment is complex because the world is complex. Sometimes, the value must be based on recent events, thus is based on short-term memories. Or, the value must be based on historical events, thus is based on long-term memories. Such memory-based value judgment is generated by another parallel circuit originating from the caudate head and caudate tail. These circuit-information mechanisms allow other brain areas (e.g., prefrontal cortex) to contribute to decisions by sending information to these basal ganglia circuits. Moreover, the basal ganglia mechanisms (i.e., what to choose) are associated with cerebellum mechanisms (i.e., when to choose). Overall, multiple levels of parallel circuits in and around the basal ganglia are essential for coordinated behaviors. Understanding these circuits is useful for creating clinical treatments of disorders resulting from the failure of these circuits.

Direct and indirect pathways for choosing objects and actions.

A prominent target of the basal ganglia is the superior colliculus (SC) which controls gaze orientation (saccadic eye movement in primates) to an important object. This 'object choice' is crucial for choosing an action on the object. SC is innervated by the substantia nigra pars reticulata (SNr) which is controlled mainly by the caudate nucleus (CD). This CD-SNr-SC circuit is sensitive to the values of individual objects and facilitates saccades to good objects. The object values are processed differently in two parallel circuits: flexibly by the caudate head (CDh) and stably by the caudate tail (CDt). To choose good objects, we need to reject bad objects. In fact, these contrasting functions are accomplished by the circuit originating from CDt: The direct pathway focuses on good objects and facilitates saccades to them; the indirect pathway focuses on bad objects and suppresses saccades to them. Inactivation of CDt deteriorated the object choice, because saccades to bad objects were no longer suppressed. This suggests that the indirect pathway is important for object choice. However, the direct and indirect pathways for 'object choice', which aim at the same action (i.e., saccade), may not work for 'action choice'. One possibility is that circuits controlling different actions are connected through the indirect pathway. Additional connections of the indirect pathway with brain areas outside the basal ganglia may also provide a wider range of behavioral choice. In conclusion, basal ganglia circuits are composed of the basic direct/indirect pathways and additional connections and thus have acquired multiple functions.

Social reward monitoring and valuation in the macaque brain.

Behaviors are influenced by rewards to both oneself and others, but the neurons and neural connections that monitor and evaluate rewards in social contexts are unknown. To address this issue, we devised a social Pavlovian conditioning procedure for pairs of monkeys. Despite being constant in amount and probability, the subjective value of forthcoming self-rewards, as indexed by licking and choice behaviors, decreased as partner-reward probability increased. This value modulation was absent when the conspecific partner was replaced by a physical object. Medial prefrontal cortex neurons selectively monitored self-reward and partner-reward information, whereas midbrain dopaminergic neurons integrated this information into a subjective value. Recordings of local field potentials revealed that responses to reward-predictive stimuli in medial prefrontal cortex started before those in dopaminergic midbrain nuclei and that neural information flowed predominantly in a medial prefrontal cortex-to-midbrain direction. These findings delineate a dedicated pathway for subjective reward evaluation in social environments.

The neuropathological investigation of the brain in a monkey model of autism spectrum disorder with ABCA13 deletion.

The precise biological etiology of autism spectrum disorder (ASD) remains unknown. In this study, we investigated the neuropathology of a monkey model of autism Human ABCA13 is the largest ABC transporter protein, with a length of 5058 amino acids and a predicted molecular weight of >450 kDa. However, the function of this protein remains to be elucidated. This protein is thought to be associated with major psychiatric disease. Using this monkey model of autism with an ABCA13 deletion and a mutation of 5HT2c, we neuropathologically investigated the changes in the neuronal formation in the frontal cortex. As a result, the neuronal formation in the cortex was found to be disorganized with regard to the neuronal size and laminal distribution in the ABCA13 deletion monkey. The catecholaminergic and GABAergic neuronal systems, serotoninergic neuronal formation (5HT2c) were also found to be impaired by an immunohistochemical evaluation. This study suggested that ABCA13 deficit induces the impairment of neuronal maturation or migration, and the function of the neuronal network. This protein might thus play a role in the neurodevelopmental function of the central nervous system and the dysfunction of this protein may be a pathophysiological cause of mental disorders including autism.

Development of social systems neuroscience using macaques.

This paper reviews the literature on social neuroscience studies using macaques in the hope of encouraging as many researchers as possible to participate in this field of research and thereby accelerate the system-level understanding of social cognition and behavior. We describe how different parts of the primate brain are engaged in different aspects of social information processing, with particular emphasis on the use of experimental paradigms involving more than one monkey in laboratory settings. The description begins with how individual neurons are used for evaluating socially relevant information, such as the identity, face, and focus of attention of others in various social contexts. A description of the neural bases of social reward processing and social action monitoring follows. Finally, we provide several perspectives on novel experimental strategies to help clarify the nature of interacting brains under more socially and ecologically plausible conditions.

Performance monitoring in the medial frontal cortex and related neural networks: From monitoring self actions to understanding others' actions.

Action is a key channel for interacting with the outer world. As such, the ability to monitor actions and their consequences - regardless as to whether they are self-generated or other-generated - is of crucial importance for adaptive behavior. The medial frontal cortex (MFC) has long been studied as a critical node for performance monitoring in nonsocial contexts. Accumulating evidence suggests that the MFC is involved in a wide range of functions necessary for one's own performance monitoring, including error detection, and monitoring and resolving response conflicts. Recent studies, however, have also pointed to the importance of the MFC in performance monitoring under social conditions, ranging from monitoring and understanding others' actions to reading others' mental states, such as their beliefs and intentions (i.e., mentalizing). Here we review the functional roles of the MFC and related neural networks in performance monitoring in both nonsocial and social contexts, with an emphasis on the emerging field of a social systems neuroscience approach using macaque monkeys as a model system. Future work should determine the way in which the MFC exerts its monitoring function via interactions with other brain regions, such as the superior temporal sulcus in the mentalizing system and the ventral premotor cortex in the mirror system.

Single-neuron and genetic correlates of autistic behavior in macaque.

Atypical neurodevelopment in autism spectrum disorder is a mystery, defying explanation despite increasing attention. We report on a Japanese macaque that spontaneously exhibited autistic traits, namely, impaired social ability as well as restricted and repetitive behaviors, along with our single-neuron and genomic analyses. Its social ability was measured in a turn-taking task, where two monkeys monitor each other's actions for adaptive behavioral planning. In its brain, the medial frontal neurons responding to others' actions, abundant in the controls, were almost nonexistent. In its genes, whole-exome sequencing and copy number variation analyses identified rare coding variants linked to human neuropsychiatric disorders in 5-hydroxytryptamine (serotonin) receptor 2C (HTR2C) and adenosine triphosphate (ATP)-binding cassette subfamily A13 (ABCA13). This combination of systems neuroscience and cognitive genomics in macaques suggests a new, phenotype-to-genotype approach to studying mental disorders.

Understanding intentional actions from observers' viewpoints: A social neuroscience perspective.

When we see others, we also try to 'see' their unobservable states of minds, such as beliefs, desires, and intentions. We carefully monitor others' actions, as we assume that those actions are outward manifestations of their internal states. Actors and observers can have divergent views on the cause of the same actions. Critically, it is often the observers' view that affects important decisions in social life, from deciding the optimal level of cooperation to judging moral responsibility and court's decisions. Thus, the judgment about intentionality and agency in others' actions determines the way in which the observer deals with the actor. The primate brain has two separate neural systems that function in understanding others' actions and intentions. The mirror system is activated by others' visible actions and predicts their physical consequences in goal terms, whereas the mentalizing system is primarily involved in the prediction of others' intentions and upcoming actions regardless of whether others' actions are directly observable or not. The functional roles of the two systems have sometimes been described as mutually independent or even oppositional. I propose a hypothesis that the two systems may collaborate closely for judging the sense of other-agency.

A Primary Role for Nucleus Accumbens and Related Limbic Network in Vocal Tics.

Inappropriate vocal expressions, e.g., vocal tics in Tourette syndrome, severely impact quality of life. Neural mechanisms underlying vocal tics remain unexplored because no established animal model representing the condition exists. We report that unilateral disinhibition of the nucleus accumbens (NAc) generates vocal tics in monkeys. Whole-brain PET imaging identified prominent, bilateral limbic cortico-subcortical activation. Local field potentials (LFPs) developed abnormal spikes in the NAc and the anterior cingulate cortex (ACC). Vocalization could occur without obvious LFP spikes, however, when phase-phase coupling of alpha oscillations were accentuated between the NAc, ACC, and the primary motor cortex. These findings contrasted with myoclonic motor tics induced by disinhibition of the dorsolateral putamen, where PET activity was confined to the ipsilateral sensorimotor system and LFP spikes always preceded motor tics. We propose that vocal tics emerge as a consequence of dysrhythmic alpha coupling between critical nodes in the limbic and motor networks. VIDEO ABSTRACT.

Common therapeutic mechanisms of pallidal deep brain stimulation for hypo- and hyperkinetic movement disorders.

Abnormalities in cortico-basal ganglia (CBG) networks can cause a variety of movement disorders ranging from hypokinetic disorders, such as Parkinson's disease (PD), to hyperkinetic conditions, such as Tourette syndrome (TS). Each condition is characterized by distinct patterns of abnormal neural discharge (dysrhythmia) at both the local single-neuron level and the global network level. Despite divergent etiologies, behavioral phenotypes, and neurophysiological profiles, high-frequency deep brain stimulation (HF-DBS) in the basal ganglia has been shown to be effective for both hypo- and hyperkinetic disorders. The aim of this review is to compare and contrast the electrophysiological hallmarks of PD and TS phenotypes in nonhuman primates and discuss why the same treatment (HF-DBS targeted to the globus pallidus internus, GPi-DBS) is capable of ameliorating both symptom profiles. Recent studies have shown that therapeutic GPi-DBS entrains the spiking of neurons located in the vicinity of the stimulating electrode, resulting in strong stimulus-locked modulations in firing probability with minimal changes in the population-scale firing rate. This stimulus effect normalizes/suppresses the pathological firing patterns and dysrhythmia that underlie specific phenotypes in both the PD and TS models. We propose that the elimination of pathological states via stimulus-driven entrainment and suppression, while maintaining thalamocortical network excitability within a normal physiological range, provides a common therapeutic mechanism through which HF-DBS permits information transfer for purposive motor behavior through the CBG while ameliorating conditions with widely different symptom profiles.