Activity-dependent organization of prefrontal hub-networks for associative learning and signal transformation.

Associative learning is crucial for adapting to environmental changes. Interactions among neuronal populations involving the dorso-medial prefrontal cortex (dmPFC) are proposed to regulate associative learning, but how these neuronal populations store and process information about the association remains unclear. Here we developed a pipeline for longitudinal two-photon imaging and computational dissection of neural population activities in male mouse dmPFC during fear-conditioning procedures, enabling us to detect learning-dependent changes in the dmPFC network topology. Using regularized regression methods and graphical modeling, we found that fear conditioning drove dmPFC reorganization to generate a neuronal ensemble encoding conditioned responses (CR) characterized by enhanced internal coactivity, functional connectivity, and association with conditioned stimuli (CS). Importantly, neurons strongly responding to unconditioned stimuli during conditioning subsequently became hubs of this novel associative network for the CS-to-CR transformation. Altogether, we demonstrate learning-dependent dynamic modulation of population coding structured on the activity-dependent formation of the hub network within the dmPFC.

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.

Rewarding-unrewarding prediction signals under a bivalent context in the primate lateral hypothalamus.

Animals can expect rewards under equivocal situations. The lateral hypothalamus (LH) is thought to process motivational information by producing valence signals of reward and punishment. Despite rich studies using rodents and non-human primates, these signals have been assessed separately in appetitive and aversive contexts; therefore, it remains unclear what information the LH encodes in equivocal situations. To address this issue, macaque monkeys were conditioned under a bivalent context in which reward and punishment were probabilistically delivered, in addition to appetitive and aversive contexts. The monkeys increased approaching behavior similarly in the bivalent and appetitive contexts as the reward probability increased. They increased avoiding behavior under the bivalent and aversive contexts as the punishment probability increased, but the mean frequency was lower under the bivalent context than under the aversive context. The population activity correlated with these mean behaviors. Moreover, the LH produced fine prediction signals of reward expectation, uncertainty, and predictability consistently in the bivalent and appetitive contexts by recruiting context-independent and context-dependent subpopulations of neurons, while it less produced punishment signals in the aversive and bivalent contexts. Further, neural ensembles encoded context information and "rewarding-unrewarding" and "reward-punishment" valence. These signals may motivate individuals robustly in equivocal environments.

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.

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.

Eye gaze differences in school scenes between preschool children and adolescents with high-functioning autism spectrum disorder and those with typical development.

BACKGROUND: Children with autism spectrum disorder (ASD) may experience difficulty adapting to daily life in a preschool or school settings and are likely to develop psychosomatic symptoms. For a better understanding of the difficulties experienced daily by preschool children and adolescents with ASD, this study investigated differences in eye gaze behavior in the classroom environment between children with ASD and those with typical development (TD). METHODS: The study evaluated 30 children with ASD and 49 children with TD. Participants were presented with images of a human face and a classroom scene. While they gazed at specific regions of visual stimuli, eye tracking with an iView X system was used to evaluate and compare the duration of gaze time between the two groups. RESULTS: Compared with preschool children with TD, preschool children with ASD spent less time gazing at the eyes of the human face and the object at which the teacher pointed in the classroom image. Preschool children with TD who had no classroom experience tended to look at the object the teacher pointed at in the classroom image. CONCLUSION: Children with ASD did not look at the human eyes in the facial image or the object pointed at in the classroom image, which may indicate their inability to analyze situations, understand instruction in a classroom, or act appropriately in a group. This suggests that this gaze behavior of children with ASD causes social maladaptation and psychosomatic symptoms. A therapeutic approach that focuses on joint attention is desirable for improving the ability of children with ASD to adapt to their social environment.

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.

Encoding prediction signals during appetitive and aversive Pavlovian conditioning in the primate lateral hypothalamus.

The lateral hypothalamus (LH), which plays a role in homeostatic functions such as appetite regulation, is also linked to arousal and motivational behavior. However, little is known about how these components are encoded in the LH. Thus cynomolgus monkeys were conditioned with two distinct contexts, i.e., an appetitive context with available rewards and an aversive context with predicted air puffs. Different LH neuron groups encoded different degrees of expectation, predictability, and risks of rewards in a specific manner. A nearly equal number of one-third of the recorded LH neurons showed a positive or negative correlation between their response to visual conditioned stimuli (CS) that predicted the probabilistic delivery of rewards (0%, 50%, and 100%) and the associative values. For another one-third of recorded neurons, a nearly equal number showed a positive or negative correlation between their responses to rewards [appetitive unconditioned stimulus (US)] and reward predictability. Some neurons exhibited their highest or lowest trace-period responses in the 50% reward trials. These response modulations were represented independently and overlaid on a consistent excitatory or inhibitory response across the conditioning events. LH neurons also showed consistent responses in the aversive context. However, the responses to aversive conditioning events depending on the air puff value and predictability were less common. The multifaceted modulation of consistent activity related to outcome predictions may reflect motivational and arousal signals. Furthermore, it may underlie the role the LH plays in the integration and relay of signals to cortices for adaptive and goal-directed physiological and behavioral responses to environmental changes. NEW & NOTEWORTHY The lateral hypothalamus (LH) is implicated in motivational and arousal behavior; however, the detailed information carried by single LH neurons remains unclear. We demonstrate that primate LH neurons encode multiple combinations of signals concerning different degrees of expectation, appreciation, and uncertainty of rewards in consistent responses across conditioning events and between different contexts. This multifaceted modulation of activity may underlie the role of the LH as a critical node integrating motivational signals with arousal signals.

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.

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.

Distinct Functions of the Primate Putamen Direct and Indirect Pathways in Adaptive Outcome-Based Action Selection.

Cortico-basal ganglia circuits are critical regulators of reward-based decision making. Reinforcement learning models posit that action reward value is encoded by the firing activity of striatal medium spiny neurons (MSNs) and updated upon changing reinforcement contingencies by dopamine (DA) signaling to these neurons. However, it remains unclear how the anatomically distinct direct and indirect pathways through the basal ganglia are involved in updating action reward value under changing contingencies. MSNs of the direct pathway predominantly express DA D1 receptors and those of the indirect pathway predominantly D2 receptors, so we tested for distinct functions in behavioral adaptation by injecting D1 and D2 receptor antagonists into the putamen of two macaque monkeys performing a free choice task for probabilistic reward. In this task, monkeys turned a handle toward either a left or right target depending on an asymmetrically assigned probability of large reward. Reward probabilities of left and right targets changed after 30-150 trials, so the monkeys were required to learn the higher-value target choice based on action-outcome history. In the control condition, the monkeys showed stable selection of the higher-value target (that more likely to yield large reward) and kept choosing the higher-value target regardless of less frequent small reward outcomes. The monkeys also made flexible changes of selection away from the high-value target when two or three small reward outcomes occurred randomly in succession. DA D1 antagonist injection significantly increased the probability of the monkey switching to the alternate target in response to successive small reward outcomes. Conversely, D2 antagonist injection significantly decreased the switching probability. These results suggest distinct functions of D1 and D2 receptor-mediated signaling processes in action selection based on action-outcome history, with D1 receptor-mediated signaling promoting the stable choice of higher-value targets and D2 receptor-mediated signaling promoting a switch in action away from small reward outcomes. Therefore, direct and indirect pathways appear to have complementary functions in maintaining optimal goal-directed action selection and updating action value, which are dependent on D1 and D2 DA receptor signaling.

Spatiotemporal characteristics of gaze of children with autism spectrum disorders while looking at classroom scenes.

Children with autism spectrum disorders (ASD) who have neurodevelopmental impairments in social communication often refuse to go to school because of difficulties in learning in class. The exact cause of maladaptation to school in such children is unknown. We hypothesized that these children have difficulty in paying attention to objects at which teachers are pointing. We performed gaze behavior analysis of children with ASD to understand their difficulties in the classroom. The subjects were 26 children with ASD (19 boys and 7 girls; mean age, 8.6 years) and 27 age-matched children with typical development (TD) (14 boys and 13 girls; mean age, 8.2 years). We measured eye movements of the children while they performed free viewing of two movies depicting actual classes: a Japanese class in which a teacher pointed at cartoon characters and an arithmetic class in which the teacher pointed at geometric figures. In the analysis, we defined the regions of interest (ROIs) as the teacher's face and finger, the cartoon characters and geometric figures at which the teacher pointed, and the classroom wall that contained no objects. We then compared total gaze time for each ROI between the children with ASD and TD by two-way ANOVA. Children with ASD spent less gaze time on the cartoon characters pointed at by the teacher; they spent more gaze time on the wall in both classroom scenes. We could differentiate children with ASD from those with TD almost perfectly by the proportion of total gaze time that children with ASD spent looking at the wall. These results suggest that children with ASD do not follow the teacher's instructions in class and persist in gazing at inappropriate visual areas such as walls. Thus, they may have difficulties in understanding content in class, leading to maladaptation to school.

What makes the dorsomedial frontal cortex active during reading the mental states of others?

The dorsomedial frontal part of the cerebral cortex is consistently activated when people read the mental states of others, such as their beliefs, desires, and intentions, the ability known as having a theory of mind (ToM) or mentalizing. This ubiquitous finding has led many researchers to conclude that the dorsomedial frontal cortex (DMFC) constitutes a core component in mentalizing networks. Despite this, it remains unclear why the DMFC becomes active during ToM tasks. We argue that key psychological and behavioral aspects in mentalizing are closely associated with DMFC functions. These include executive inhibition, distinction between self and others, prediction under uncertainty, and perception of intentions, all of which are important for predicting others' intention and behavior. We review the literature supporting this claim, ranging in fields from developmental psychology to human neuroimaging and macaque electrophysiology. Because perceiving intentions in others' actions initiates mentalizing and forms the basis of virtually all types of social interaction, the fundamental issue in social neuroscience is to determine the aspects of physical entities that make an observer perceive that they are intentional beings and to clarify the neurobiological underpinnings of the perception of intentionality in others' actions.

Saccadic compression of rectangle and Kanizsa figures: now you see it, now you don't.

BACKGROUND: Observers misperceive the location of points within a scene as compressed towards the goal of a saccade. However, recent studies suggest that saccadic compression does not occur for discrete elements such as dots when they are perceived as unified objects like a rectangle. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the magnitude of horizontal vs. vertical compression for Kanizsa figure (a collection of discrete elements unified into single perceptual objects by illusory contours) and control rectangle figures. Participants were presented with Kanizsa and control figures and had to decide whether the horizontal or vertical length of stimulus was longer using the two-alternative force choice method. Our findings show that large but not small Kanizsa figures are perceived as compressed, that such compression is large in the horizontal dimension and small or nil in the vertical dimension. In contrast to recent findings, we found no saccadic compression for control rectangles. CONCLUSIONS: Our data suggest that compression of Kanizsa figure has been overestimated in previous research due to methodological artifacts, and highlight the importance of studying perceptual phenomena by multiple methods.

A continuously lit stimulus is perceived to be shorter than a flickering stimulus during a saccade.

When subjects made a saccade across a single-flashed dot, a flickering dot or a continuous dot, they perceived a dot, an array (phantom array), or a line (phantom line), respectively. We asked subjects to localize both endpoints of the phantom array or line and calculated the perceived lengths. Based on the findings of Matsumiya and Uchikawa (2001), we predicted that the apparent length of the phantom line would be larger than that of the phantom array. In Experiment 1 of the current study, contrary to the prediction, the phantom line was found to be shorter than the phantom array. In Experiment 2, we investigated whether the function underlying the filled-unfilled space illusion (Lewis, 1912) instead of the function underlying the saccadic compression could explain the results. Subjects were asked to localize both endpoints of a line or an array while keeping their eyes fixated. Although the results of Experiment 2 showed that the perceived length of a line was shorter than that of an array, the function underlying the filled-unfilled illusion could not fully account for the results of Experiment 1. To explain the present results, we proposed a model for the localization process and discussed its validity.

Perisaccadic perception of continuous flickers.

To realize perceptual space constancy, the visual system compensates for the retinal displacement caused by eye movements. It has been reported that the compensation process does not function perfectly around the time of a saccade--a perisaccadic flash is systematically mislocalized. However, observations made with transient flash stimuli do not necessarily indicate a general perisaccadic failure of space constancy. To investigate how the visual system realizes perisaccadic space constancy for continuous stimuli, we examined the time course of localization for a perisaccadic 500 Hz flicker with systematic variation of the onset timing, the offset timing and the duration. If each flash in the flicker is localized individually in the same way as a single flash, the apparent position and length of the flicker should be predicted from the time course of mislocalization of a perisaccadic flash. However, the results did not support this prediction in many respects. A dot array (of half the length of the retinal image) was perceived when the flicker was presented during a saccade, while only a single dot was perceived when the flicker was presented only before or after the saccade. A flash in a flicker was localized at a different position, depending on the onset timing, the offset timing and the duration of the flicker, even if the flash was presented at the same timing to the saccade. In general, our results support a two-stage localization in which the local geometrical configuration is first generated primarily based on the retinal information, and then localized as a whole in the egocentric or exocentric space. The localization is based on the eye position signal sampled at a time temporally distant from the saccade, which enables precise localization and space constancy for continuous stimuli.