Disentangling perceptual awareness from nonconscious processing in rhesus monkeys (Macaca mulatta).

Scholars have long debated whether animals, which display impressive intelligent behaviors, are consciously aware or not. Yet, because many complex human behaviors and high-level functions can be performed without conscious awareness, it was long considered impossible to untangle whether animals are aware or just conditionally or nonconsciously behaving. Here, we developed an empirical approach to address this question. We harnessed a well-established cross-over double dissociation between nonconscious and conscious processing, in which people perform in completely opposite ways when they are aware of stimuli versus when they are not. To date, no one has explored if similar performance dissociations exist in a nonhuman species. In a series of seven experiments, we first established these signatures in humans using both known and newly developed nonverbal double-dissociation tasks and then identified similar signatures in rhesus monkeys (Macaca mulatta). These results provide robust evidence for two distinct modes of processing in nonhuman primates. This empirical approach makes it feasible to disentangle conscious visual awareness from nonconscious processing in nonhuman species; hence, it can be used to strip away ambiguity when exploring the processes governing intelligent behavior across the animal kingdom. Taken together, these results strongly support the existence of both nonconscious processing as well as functional human-like visual awareness in nonhuman animals.

Increasing Central Serotonin with 5-hydroxytryptophan Disrupts the Inhibition of Social Gaze in Nonhuman Primates.

To competently navigate the world, individuals must flexibly balance distinct aspects of social gaze, orienting toward others and inhibiting orienting responses, depending on the context. These behaviors are often disrupted amongst patient populations treated with serotonergic drugs. However, those in the field lack a clear understanding of how the serotonergic system mediates social orienting and inhibiting behaviors. Here, we tested how increasing central concentrations of serotonin with the direct precursor 5-hydroxytryptophan (5-HTP) would modulate the ability of rhesus macaques (both sexes) to use eye movements to flexibly orient to, or inhibit orienting to, faces. Systemic administrations of 5-HTP effectively increased central serotonin levels and impaired flexible orientation and inhibition. Critically, 5-HTP selectively impaired the ability of monkeys to inhibit orienting to face images, whereas it similarly impaired orienting to face and control images. 5-HTP also caused monkeys to perseverate on their gaze responses, making them worse at flexibly switching between orienting and inhibiting behaviors. Furthermore, the effects of 5-HTP on performance correlated with a constriction of the pupil, an increased time to initiate trials, and an increased reaction time, suggesting that the disruptive effects of 5-HTP on social gaze behaviors are likely driven by a downregulation of arousal and motivational states. Together, these findings provide causal evidence for a modulatory relationship between 5-HTP and social gaze behaviors in nonhuman primates and offer translational insights for the role of the serotonergic system in social gaze.SIGNIFICANCE STATEMENT Behavioral changes arising from pharmacological agents that target serotonergic functions are complex and difficult to predict. Here, we examined the causal impacts of administering the direct precursor of serotonin, 5-HTP, on orienting and inhibiting social gaze in nonhuman primates. 5-HTP increased central concentrations of serotonin and selectively impaired the ability of monkeys to inhibit orienting to faces while similarly impairing the ability of monkeys to orient to face and control images. These behavioral gaze impairments were systematically associated with a downregulation of arousal and motivational states, indexed by pupil constriction, increased time to initiate trials, and increased reaction time. These findings provide a causal link between 5-HTP and social gaze behaviors in nonhuman primates and provide translational insights about serotonergic interventions.

The orbitofrontal cortex: A goal-directed cognitive map framework for social and non-social behaviors.

The orbitofrontal cortex (OFC) is regarded as one of the core brain areas in a variety of value-based behaviors. Over the past two decades, tremendous knowledge about the OFC function was gained from studying the behaviors of single subjects. As a result, our previous understanding of the OFC's function of encoding decision variables, such as the value and identity of choices, has evolved to the idea that the OFC encodes a more complex representation of the task space as a cognitive map. Accumulating evidence also indicates that the OFC importantly contributes to behaviors in social contexts, especially those involved in cooperative interactions. However, it remains elusive how exactly OFC neurons contribute to social functions and how non-social and social behaviors are related to one another in the computations performed by OFC neurons. In this review, we aim to provide an integrated view of the OFC function across both social and non-social behavioral contexts. We propose that seemingly complex functions of the OFC may be explained by its role in providing a goal-directed cognitive map to guide a wide array of adaptive reward-based behaviors in both social and non-social domains.

The anterior cingulate cortex is necessary for forming prosocial preferences from vicarious reinforcement in monkeys.

A key feature of most social relationships is that we like seeing good things happen to others. Research has implicated the anterior cingulate cortex (ACC) in attaching value to social outcomes. For example, single neurons in macaque ACC selectively code reward delivery to the self, a partner, both monkeys, or neither monkey. Here, we assessed whether the ACC's contribution to social cognition is causal by testing rhesus monkeys (Macaca mulatta) on a vicarious reinforcement task before and after they sustained ACC lesions. Prior to surgery, actors learned that 3 different visual cues mapped onto 3 distinct reward outcomes: to self ("Self"), to the other monkey ("Other"), or to neither monkey ("Neither"). On each trial, actors saw a cue that predicted one of the 3 juice offers and could accept the offer by making a saccade to a peripheral target or reject the offer by breaking fixation. Preoperatively, all 6 actors displayed prosocial preferences, indicated by their greater tendency to give reward to Other relative to Neither. Half then received selective, bilateral, excitotoxic lesions of the ACC, and the other half served as unoperated controls. After surgery, all monkeys retained the social preferences they had demonstrated with the preoperatively learned cues, but this preference was reduced in the monkeys with ACC lesions. Critically, none of the monkeys in the ACC lesion group acquired social preferences with a new set of cues introduced after surgery. These data indicate that the primate ACC is necessary for acquisition of prosocial preferences from vicarious reinforcement.

Oxytocin under opioid antagonism leads to supralinear enhancement of social attention.

To provide new preclinical evidence toward improving the efficacy of oxytocin (OT) in treating social dysfunction, we tested the benefit of administering OT under simultaneously induced opioid antagonism during dyadic gaze interactions in monkeys. OT coadministered with a µ-opioid receptor antagonist, naloxone, invoked a supralinear enhancement of prolonged and selective social attention, producing a stronger effect than the summed effects of each administered separately. These effects were consistently observed when averaging over entire sessions, as well as specifically following events of particular social importance, including mutual eye contact and mutual reward receipt. Furthermore, attention to various facial regions was differentially modulated depending on social context. Using the Allen Institute's transcriptional atlas, we further established the colocalization of µ-opioid and κ-opioid receptor genes and OT genes at the OT-releasing sites in the human brain. These data across monkeys and humans support a regulatory relationship between the OT and opioid systems and suggest that administering OT under opioid antagonism may boost the therapeutic efficacy of OT for enhancing social cognition.

An integrated framework for the role of oxytocin in multistage social decision-making.

Interest in the effects of oxytocin on social behavior has persisted even as an overarching theory describing these effects has remained largely elusive. Some of the earliest studies on the effects of oxytocin on social decision-making indicated that oxytocin might enhance prosocial actions directed toward others. This led to development of the prosocial hypothesis, which stipulates that oxytocin specifically enhances prosocial choices. However, further work indicated that oxytocin administration could elicit antisocial behaviors as well in certain social situations, highlighting the importance of context-dependent effects. At least two prominent hypotheses have been used to explain these seemingly contradictory findings. The social salience hypothesis indicates that the effects of oxytocin can be conceptualized as a general increase in the salience of social stimuli in the environment. Distinctly, the approach/withdrawal hypothesis stipulates that oxytocin enhances approach behaviors and decreases withdrawal behaviors. These phenomenologically motivated hypotheses regarding the effects of oxytocin on social behavior have created controversies in the field. In this review, we present a multistage framework of social decision-making designed to unify these disparate theories in a process common to all social decisions. We conceptualize this process as involving multiple distinct computational steps, including sensory input, sensory perception, valuation, decision formulation, and behavioral output. Iteratively, these steps generate social behaviors, and oxytocin could be acting on any of these steps to exert its effects. In support of this framework, we examine both behavioral and neural evidence across rodents, non-human primates, and humans, determining at what point in our multistage framework oxytocin could be eliciting its socially relevant effects. Finally, we postulate based on our framework that the prosocial, social salience, and approach/withdrawal hypotheses may not be mutually exclusive and could explain the influence of oxytocin on social behavior to different extents depending on context.

Neural mechanisms of social decision-making in the primate amygdala.

Social decisions require evaluation of costs and benefits to oneself and others. Long associated with emotion and vigilance, the amygdala has recently been implicated in both decision-making and social behavior. The amygdala signals reward and punishment, as well as facial expressions and the gaze of others. Amygdala damage impairs social interactions, and the social neuropeptide oxytocin (OT) influences human social decisions, in part, by altering amygdala function. Here we show in monkeys playing a modified dictator game, in which one individual can donate or withhold rewards from another, that basolateral amygdala (BLA) neurons signaled social preferences both across trials and across days. BLA neurons mirrored the value of rewards delivered to self and others when monkeys were free to choose but not when the computer made choices for them. We also found that focal infusion of OT unilaterally into BLA weakly but significantly increased both the frequency of prosocial decisions and attention to recipients for context-specific prosocial decisions, endorsing the hypothesis that OT regulates social behavior, in part, via amygdala neuromodulation. Our findings demonstrate both neurophysiological and neuroendocrinological connections between primate amygdala and social decisions.

Region-Specific Summation Patterns Inform the Role of Cortical Areas in Selecting Motor Plans.

Given an instruction regarding which effector to move and what location to move to, simply adding the effector and spatial signals together will not lead to movement selection. For this, a nonlinearity is required. Thresholds, for example, can be used to select a particular response and reject others. Here we consider another useful nonlinearity, a supralinear multiplicative interaction. To help select a motor plan, spatial and effector signals could multiply and thereby amplify each other. Such an amplification could constitute one step within a distributed network involved in response selection, effectively boosting one response while suppressing others. We therefore asked whether effector and spatial signals sum supralinearly for planning eye versus arm movements from the parietal reach region (PRR), the lateral intraparietal area (LIP), the frontal eye field (FEF), and a portion of area 5 (A5) lying just anterior to PRR. Unlike LIP neurons, PRR, FEF, and, to a lesser extent, A5 neurons show a supralinear interaction. Our results suggest that selecting visually guided eye versus arm movements is likely to be mediated by PRR and FEF but not LIP.

Live interaction distinctively shapes social gaze dynamics in rhesus macaques.

The dynamic interaction of gaze between individuals is a hallmark of social cognition. However, very few studies have examined social gaze dynamics after mutual eye contact during real-time interactions. We used a highly quantifiable paradigm to assess social gaze dynamics between pairs of monkeys and modeled these dynamics using an exponential decay function to investigate sustained attention after mutual eye contact. When monkeys were interacting with real partners compared with static images and movies of the same monkeys, we found a significant increase in the proportion of fixations to the eyes and a smaller dispersion of fixations around the eyes, indicating enhanced focal attention to the eye region. Notably, dominance and familiarity between the interacting pairs induced separable components of gaze dynamics that were unique to live interactions. Gaze dynamics of dominant monkeys after mutual eye contact were associated with a greater number of fixations to the eyes, whereas those of familiar pairs were associated with a faster rate of decrease in this eye-directed attention. Our findings endorse the notion that certain key aspects of social cognition are only captured during interactive social contexts and dependent on the elapsed time relative to socially meaningful events.

Neuroethology of primate social behavior.

A neuroethological approach to human and nonhuman primate behavior and cognition predicts biological specializations for social life. Evidence reviewed here indicates that ancestral mechanisms are often duplicated, repurposed, and differentially regulated to support social behavior. Focusing on recent research from nonhuman primates, we describe how the primate brain might implement social functions by coopting and extending preexisting mechanisms that previously supported nonsocial functions. This approach reveals that highly specialized mechanisms have evolved to decipher the immediate social context, and parallel circuits have evolved to translate social perceptual signals and nonsocial perceptual signals into partially integrated social and nonsocial motivational signals, which together inform general-purpose mechanisms that command behavior. Differences in social behavior between species, as well as between individuals within a species, result in part from neuromodulatory regulation of these neural circuits, which itself appears to be under partial genetic control. Ultimately, intraspecific variation in social behavior has differential fitness consequences, providing fundamental building blocks of natural selection. Our review suggests that the neuroethological approach to primate behavior may provide unique insights into human psychopathology.

Inhaled oxytocin amplifies both vicarious reinforcement and self reinforcement in rhesus macaques (Macaca mulatta).

People attend not only to their own experiences, but also to the experiences of those around them. Such social awareness profoundly influences human behavior by enabling observational learning, as well as by motivating cooperation, charity, empathy, and spite. Oxytocin (OT), a neurosecretory hormone synthesized by hypothalamic neurons in the mammalian brain, can enhance affiliation or boost exclusion in different species in distinct contexts, belying any simple mechanistic neural model. Here we show that inhaled OT penetrates the CNS and subsequently enhances the sensitivity of rhesus macaques to rewards occurring to others as well as themselves. Roughly 2 h after inhaling OT, monkeys increased the frequency of prosocial choices associated with reward to another monkey when the alternative was to reward no one. OT also increased attention to the recipient monkey as well as the time it took to render such a decision. In contrast, within the first 2 h following inhalation, OT increased selfish choices associated with delivery of reward to self over a reward to the other monkey, without affecting attention or decision latency. Despite the differences in species typical social behavior, exogenous, inhaled OT causally promotes social donation behavior in rhesus monkeys, as it does in more egalitarian and monogamous ones, like prairie voles and humans, when there is no perceived cost to self. These findings potentially implicate shared neural mechanisms.

Automated 3D analysis of social head-gaze behaviors in freely moving marmosets.

Social communication relies on the ability to perceive and interpret the direction of others' attention, which is commonly conveyed through head orientation and gaze direction in both humans and non-human primates. However, traditional social gaze experiments in non-human primates require restraining head movements, which significantly limit their natural behavioral repertoire. Here, we developed a novel framework for accurately tracking facial features and three-dimensional head gaze orientations of multiple freely moving common marmosets (Callithrix jacchus). To accurately track the facial features of marmoset dyads in an arena, we adapted computer vision tools using deep learning networks combined with triangulation algorithms applied to the detected facial features to generate dynamic geometric facial frames in 3D space, overcoming common occlusion challenges. Furthermore, we constructed a virtual cone, oriented perpendicular to the facial frame, to model the head gaze directions. Using this framework, we were able to detect different types of interactive social gaze events, including partner-directed gaze and jointly-directed gaze to a shared spatial location. We observed clear effects of sex and familiarity on both interpersonal distance and gaze dynamics in marmoset dyads. Unfamiliar pairs exhibited more stereotyped patterns of arena occupancy, more sustained levels of social gaze across inter-animal distance, and increased gaze monitoring. On the other hand, familiar pairs exhibited higher levels of joint gazes. Moreover, males displayed significantly elevated levels of gazes toward females' faces and the surrounding regions irrespective of familiarity. Our study lays the groundwork for a rigorous quantification of primate behaviors in naturalistic settings.

Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention.

Neurons from multiple prefrontal areas encode several key variables of social gaze interaction. To explore the causal roles of the primate prefrontal cortex in real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events. Microstimulations of the orbitofrontal cortex, but not the dorsomedial prefrontal cortex or the anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing the distance of fixations relative to a partner's eyes and in the temporal dimension by reducing the inter-looking interval and the latency to reciprocate the other's directed gaze. By contrast, on a longer timescale, microstimulations of the dorsomedial prefrontal cortex modulated inter-individual gaze dynamics relative to one's own gaze positions. These findings demonstrate that multiple regions in the primate prefrontal cortex may serve as functionally accessible nodes in controlling different aspects of dynamic social attention and suggest their potential for a therapeutic brain interface.

Development of a Marmoset Apparatus for Automated Pulling (MarmoAAP) to Study Cooperative Behaviors.

In recent years, the field of neuroscience has increasingly recognized the importance of studying animal behaviors in naturalistic environments to gain deeper insights into ethologically relevant behavioral processes and neural mechanisms. The common marmoset (Callithrix jacchus), due to its small size, prosocial nature, and genetic proximity to humans, has emerged as a pivotal model toward this effort. However, traditional research methodologies often fail to fully capture the nuances of marmoset social interactions and cooperative behaviors. To address this critical gap, we developed the Marmoset Apparatus for Automated Pulling (MarmoAAP), a novel behavioral apparatus designed for studying cooperative behaviors in common marmosets. MarmoAAP addresses the limitations of traditional behavioral research methods by enabling high-throughput, detailed behavior outputs that can be integrated with video and audio recordings, allowing for more nuanced and comprehensive analyses even in a naturalistic setting. We also highlight the flexibility of MarmoAAP in task parameter manipulation which accommodates a wide range of behaviors and individual animal capabilities. Furthermore, MarmoAAP provides a platform to perform investigations of neural activity underlying naturalistic social behaviors. MarmoAAP is a versatile and robust tool for advancing our understanding of primate behavior and related cognitive processes. This new apparatus bridges the gap between ethologically relevant animal behavior studies and neural investigations, paving the way for future research in cognitive and social neuroscience using marmosets as a model organism.

Lesions to the mediodorsal thalamus, but not orbitofrontal cortex, enhance volatility beliefs linked to paranoia.

Beliefs-attitudes toward some state of the environment-guide action selection and should be robust to variability but sensitive to meaningful change. Beliefs about volatility (expectation of change) are associated with paranoia in humans, but the brain regions responsible for volatility beliefs remain unknown. The orbitofrontal cortex (OFC) is central to adaptive behavior, whereas the magnocellular mediodorsal thalamus (MDmc) is essential for arbitrating between perceptions and action policies. We assessed belief updating in a three-choice probabilistic reversal learning task following excitotoxic lesions of the MDmc (n = 3) or OFC (n = 3) and compared performance with that of unoperated monkeys (n = 14). Computational analyses indicated a double dissociation: MDmc, but not OFC, lesions were associated with erratic switching behavior and heightened volatility belief (as in paranoia in humans), whereas OFC, but not MDmc, lesions were associated with increased lose-stay behavior and reward learning rates. Given the consilience across species and models, these results have implications for understanding paranoia.

Idiosyncratic and systematic aspects of spatial representations in the macaque parietal cortex.

The sensorimotor transformations for visually guided reaching were originally thought to take place in a series of discrete transitions from one systematic frame of reference to the next with neurons coding location relative to the fixation position (gaze-centered) in occipital and posterior parietal areas, relative to the shoulder in dorsal premotor cortex, and in muscle- or joint-based coordinates in motor output neurons. Recent empirical and theoretical work has suggested that spatial encodings that use a range of idiosyncratic representations may increase computational power and flexibility. We now show that neurons in the parietal reach region use nonuniform and idiosyncratic frames of reference. We also show that these nonsystematic reference frames coexist with a systematic compound gain field that modulates activity proportional to the distance between the eyes and the hand. Thus, systematic and idiosyncratic signals may coexist within individual neurons.

Brain games: toward a neuroecology of social behavior.

In the target article, Schilbach et al. defend a "second-person neuroscience" perspective that focuses on the neural basis of social cognition during live, ongoing interactions between individuals. We argue that a second-person neuroscience would benefit from formal approaches borrowed from economics and behavioral ecology and that it should be extended to social interactions in nonhuman animals.

Beyond cortex: The evolution of the human brain.

Human evolution has been marked by a striking increase in total brain volume relative to body size. While a prominent and characteristic feature of this volumetric shift has been the disproportionate expansion of association cortex across our evolutionary lineage, descent with modification is apparent throughout all neural systems in both human and nonhuman primates. However, despite evidence for the ubiquitous and complex influence of evolutionary forces on brain biology, within the psychological sciences the vast majority of the literature on human brain evolution is entirely corticocentric. This selective focus has contributed to a flawed theoretical framework in which the evolution of association cortex is viewed as an isolated process, removed from the rest of the brain. Here, we review our current understanding of how evolutionary pressures have acted across anatomically and functionally coupled networks, highlighting the diverse set of rules and principles that govern human brain development. In doing so we challenge the systemic mischaracterization of human cognition and behavior as a competition that pits phylogenetically recent cortical territories against evolutionarily ancient subcortical and cerebellar systems. Rather, we propose a comprehensive view of human brain evolution with critical importance for the use of animal models, theory development, and network-focused approaches in the study of behavior across health and disease. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Closed-loop microstimulations of the orbitofrontal cortex during real-life gaze interaction enhance dynamic social attention.

The prefrontal cortex is extensively involved in social exchange. During dyadic gaze interaction, multiple prefrontal areas exhibit neuronal encoding of social gaze events and context-specific mutual eye contact, supported by a widespread neural mechanism of social gaze monitoring. To explore causal manipulation of real-life gaze interaction, we applied weak closed-loop microstimulations that were precisely triggered by specific social gaze events to three prefrontal areas in monkeys. Microstimulations of orbitofrontal cortex (OFC), but not dorsomedial prefrontal or anterior cingulate cortex, enhanced momentary dynamic social attention in the spatial dimension by decreasing distance of one's gaze fixations relative to partner monkey's eyes. In the temporal dimension, microstimulations of OFC reduced the inter-looking interval for attending to another agent and the latency to reciprocate other's directed gaze. These findings demonstrate that primate OFC serves as a functionally accessible node in controlling dynamic social attention and suggest its potential for a therapeutic brain interface.

Dissociation of vicarious and experienced rewards by coupling frequency within the same neural pathway.

Vicarious reward, essential to social learning and decision making, is theorized to engage select brain regions similarly to experienced reward to generate a shared experience. However, it is just as important for neural systems to also differentiate vicarious from experienced rewards for social interaction. Here, we investigated the neuronal interaction between the primate anterior cingulate cortex gyrus (ACCg) and the basolateral amygdala (BLA) when social choices made by monkeys led to either vicarious or experienced reward. Coherence between ACCg spikes and BLA local field potential (LFP) selectively increased in gamma frequencies for vicarious reward, whereas it selectively increased in alpha/beta frequencies for experienced reward. These respectively enhanced couplings for vicarious and experienced rewards were uniquely observed following voluntary choices. Moreover, reward outcomes had consistently strong directional influences from ACCg to BLA. Our findings support a mechanism of vicarious reward where social agency is tagged by interareal coordination frequency within the same shared pathway.