Steve W C Chang, Ph.D. - US grants

DESCRIPTION (provided by applicant): Neuropeptides are critical for social cognition, and are actively being pursued as a therapeutic agent for treating diseases with marked social deficits, such as autism spectrum disorders (ASD), schizophrenia, and psychopathy. Oxytocin (OT) is an evolutionarily conserved neuropeptide involved in social processing in multiple species. Despite numerous demonstrations of OT-induced social behavior, it remains unclear how OT modulates networks of neurons involved in social decision-making. Using the reward donation task involving donor and recipient monkeys, we reported that inhaled OT enhances vicarious reinforcement of the donor when the choice is between rewarding another and no one, whereas it amplifies self reinforcement when the choice is between rewarding himself and another. OT in this task also enhances the looking behavior at the recipient following reward donations. Empathy-related processing might be mediated by a cohort of networks involving amygdala, anterior cingulate (ACC), and orbitofrontal cortices (OFC). In the reward donation task, we also found that ACC neurons predominantly represent rewards delivered to another, whereas OFC neurons predominantly represent rewards delivered to self. Amygdala contains a high number of OT receptors, and mediates affective and social processing. Amygdala, especially the basolateral portion, is reciprocally connected with ACC and OFC, and is involved in evaluating both positive and negative rewards. OT directly gates information processing in amygdala with other structures, and influences amygdala activations during social evaluations in humans. Critically, OT receptor risk allele carriers for ASD show altered amygdala activations in social emotional tasks. Given these observations, we seek to elucidate the following by capitalizing upon the reward donation task: 1) activity of single amygdala neurons during reward allocation decisions; 2) neural mechanisms of OT-induced responses in amygdala neurons; and 3) specific modulations of ACC and OFC neurons due to OT-mediated processes by amygdala. We hypothesize that amygdala contains both vicarious and self reinforcement signals, and these are both amplified by inhaled OT. We further hypothesize that local OT delivery to amygdala neurons enhances self reward signals in OFC and vicarious reward signals in ACC. Our results have a potential to advance our knowledge on neuropsychiatric diseases with social deficits, and our understanding of OT-based therapeutics. PUBLIC HEALTH RELEVANCE: Despite a broad continuum of phenotypic variation in behavior, individuals with autism spectrum disorders (ASD) share core deficits in social interaction. Here we propose that social dysfunction in ASD results, in part, from problems in deriving vicarious reward from others, and that this process may depend on neuropeptide oxytocin, which is implicated in various social processes. We will use our animal model of vicarious reward to discover how oxytocin, a potential therapy for ASD, mediates social processing in the brain, and discover its role in brain dysfunction.

? DESCRIPTION (provided by applicant): The Golden Rule transcends time and culture. Social reciprocity, as implied by the Golden Rule, is a crucial component of normal social interactions. Individuals with psychiatric disorders marked by social deficits often fail to reciprocate normally with others. Although various types of reciprocity have been observed in humans and non-humans, the underlying neural mechanisms remain unknown. An animal model of complex social cognition that could be explored with single-unit recording and pharmacological manipulations of specific groups of neurons will help uncover the neural mechanisms underlying social reciprocity. Here we propose to develop a new social game in interacting dyads of rhesus monkeys. We have previously shown that rhesus monkeys prefer to donate juice rewards to other monkeys when the alternative is to reward neither monkey, but prefer to reward just themselves when the alternative is to share the rewards with others. In the new social game proposed here, the reward-donating (prosocial) and reward-withholding (antisocial) preferences displayed by one monkey could be subsequently reciprocated by the other monkey in a turn-taking fashion. This game will be used to investigate how neurons in the primate prefrontal cortex are involved in the computation of reciprocity during social interactions. We will record neuronal spiking activity from a brain structure in the medial prefrontal cortex called the anterio cingulate gyrus (ACCg), as it contains neurons that signal both the rewards received by oneself and another individual. In particular, we will investigate whether, how, and at what points in time the reciprocity-induced changes in social preferences are reflected in the activity of ACCg neurons. We hypothesize that ACCg activity associated with rewards received by self and others is gain modulated by the reciprocity level across two interacting monkeys. Furthermore, we will examine how the activity in one monkey's brain is dynamically modulated with respect to the neuronal activity in the other's brain during these reciprocal reward exchanges. We hypothesize that the reward outcome signaling by the ACCg is central to reciprocity, endorsing the notion that ACCg belongs to the core circuits mediating normal social behaviors.

Project Summary Our proposal will investigate how neuronal coordination between the medial frontal cortex (MFC) and the basolateral amygdala (BLA) is causally involved in complex social interactions. We will capitalize on our newly developed social gaze interaction paradigm in pairs of rhesus macaques to understand the neurobiological mechanisms of MFC-BLA coupling, with a goal of working toward generating a macaque model of social dysfunction. We will first determine whether and how the two regions are coordinated during various social gaze events (e.g., looking at the eyes or mutual eye contact). We will then stimulate MFC, BLA or both in order to disrupt the MFC-BLA coordination to induce social gaze deficits. Finally, we will examine whether these disruptions are generalizable to other social domains by testing the impact of perturbing MFC-BLA coordination in a complex social decision-making game. Informed by these results, we hope to investigate in the future how pharmacological (systemic or focal drug manipulations) and behavioral (social interaction manipulations) interventions could effectively restore the inducible social deficits.

Project Summary Several clinical trials have found that intranasal oxytocin (OT) treatment is not practically viable in its current form for improving core social symptoms in autism spectrum disorders (ASD). The current intranasal OT treatment has been criticized for its often weak and inconsistent effects, demanding an important need to explore new ways to improve its efficacy and reliability in modulating the OT system. While much less studied, the central opioid system has also been implicated in ASD based on the opioid dysregulation found in certain cases of ASD, as well as the well-known modulatory effects of opioid agonists, such as morphine, and its receptor antagonists, such as naloxone (NAL), in regulating social behaviors. In this translational non-human primate proposal, we will investigate a new alternative therapeutic option in improving core social functions by exploiting the robust regulatory relationship between the central OT and opioid systems. Our pharmacological study in non-human primates recently provided a proof of concept of this combined pharmacological approach in more effectively modulating social attention. The combined intranasal administration of OT and NAL (OTNAL) enhanced spontaneous social attention and contingent gaze dynamics following interactive eye contact over and beyond the summed effects from administering OT alone and NAL alone, indicating a combinatorial benefit of OTNAL. Capitalizing on this finding, we now propose to determine the optimal doses of OT and NAL in the combined OTNAL format, its corresponding cerebrospinal fluid markers of successful OTNAL interventions, as well as the neurophysiological markers underlying the combinatorial benefits in the domain of social attention. We will first obtain comprehensive dose-response functions for the OTNAL intervention during spontaneously occurring real- life social gaze interactions and assess the corresponding changes in cerebrospinal fluid OT levels due to OTNAL compared to other conditions (Aim 1A, 1B). We will then study how neural activity patterns within and across two key brain nodes in social processing, the amygdala and the anterior cingulate cortex, are impacted by OTNAL (Aim 2). Finally, we will test causal contributions of these two regions for the OTNAL effects by blocking OT-binding receptor types focally in these areas (Aim 3). The results from this work will offer novel mechanistic insights into the combined pharmacological approach using OTNAL to more vigorously promote social engagements in the primate brain. Such results will help set the stage for translating the combinatorial benefit of using intranasal OTNAL for more effectively and reliably reducing core social symptoms in ASD.