Michael L. Platt - US grants

DESCRIPTION (provided by applicant): This project seeks to understand the role of the limbic system in choosing movements for execution. Anatomical and physiological evidence suggest that, within the limbic system, posterior cingulate cortex (CGp) may integrate the sensory motor, and reward signals that guide the oculomotor system to shift gaze to a particular visual stimulus. The purpose of the proposed study is to determine whether CGp encodes the motivational significance of visually-guided saccades, or merely their spatial coordinates. This study has 3 goals. The first goal is to quantify the representation of the timing and spatial coordinates of visual and oculomotor events in CGp. To do this, both initial fixation position and target position will be varied while animal subjects perform reaction-time and delayed saccade tasks. Pilot data suggest that different subpopulations of CGp neurons signal the spatial coordinates of either sensory or motor events, and that these spatial representations are encoded in retinotopic and head-centered coordinates, respectively. The second goal is to determine whether CGp neurons encode the reward outcome of eye movements. Single CGp neurons will be studied while animal subjects either shift gaze to a single target while reward size is varied, or choose between gaze shifts of different reward value. Pilot data suggest the new finding that some CGp neurons encode the amount of reward delivered after a particular saccade. These data suggest that CGp neurons may assign motivational valence to visually-guided saccades based on the outcome of those movements. The third goal is to determine whether CGp activation signals the valence of sensory and motor events or the spatial coordinates of those events. Stimulation will be applied to CGp during fixation trials, and the choices animal subjects make on subsequent choice trials examined. If CGp activation assigns motivational valence to particular movements, then stimulation should bias future choices. Overall, this project may reveal important interactions between the limbic system and visuo-motor planning areas during behavioral guidance, and promises to yield data that may clarify the mechanisms underlying the emotional, cognitive, and motor deficits characterizing individuals with limbic system disorders.

DESCRIPTION: (provided by applicant) Mobile animals orient to salient features of their environment. In some animals, such as primates, covert orienting of attention has evolved as a flexible mechanism for monitoring potentially important locations or stimuli in the absence of overt orienting. Psychophysical and neurophysiological studies conducted in the laboratory have extensively probed these attentional mechanisms in primates trained to discriminate simple stimuli whose salience or behavioral significance is arbitrarily assigned. Observational studies of primates conducted in field settings, however, suggest that particular stimuli, such as visual images of conspecifics, are intrinsically salient and elicit overt orienting of attention. It remains unknown whether these stimuli also evoke covert shifts of attention under naturalistic behavioral conditions, although these are presumably the ecological conditions in which covert attentional mechanisms evolved. Just how the attentional mechanisms so extensively studied by psychologists and neuro-biologists function in animals performing naturalistic behaviors, which do not require extensive training, remains obscure. These lacunae suggest that a unified approach combining ethological, psychological, and neurobiological techniques would provide a powerful new paradigm for understanding mechanisms of attention in both human and non-human primates. The goal of the proposed research project is to develop a neuro-ethology of primate attention. Psychophysical techniques will be used to quantify the intrinsic salience or motivational value of visual images of familiar conspecifics for both covert and overt orienting of attention in particular behavioral contexts. Concurrently, neurophysiological techniques will be used to study the representation of the intrinsic motivational salience of socially meaningful images in parietal cortex, an area of the brain known to play a critical role in both overt and covert orienting of attention. The synergistic approach developed in this proposal offers the promise of an integrated neuroethology that may reveal unique insights into the evolution of attentional mechanisms in primates, including humans.

DESCRIPTION (PROVIDED BY APPLICANT): Anatomical, neurophysiological, and neuroimaging evidence suggest that posterior cingulate cortex (CGp) contributes to both motivational and visuospatial processing (Mesulam 1999;Maddock 1999). New neurophysiological data indicate that CGp neurons not only report the spatial coordinates of visually-guided gaze shifts, but also represent their motivational value (McCoy et al. 2003). The timing arid reward-sensitivity of CGp responses, coupled with the observation that CGp dysfunction in humans is associated with both spatial disorientation and mood/anxiety disorders, invite the hypothesis that this limbic area binds motivational salience to visuospatial locations (Mesulam 1999;McCoy and Platt 2004). Furthermore, neurophysiological evidence suggests that motivational and visuospatial information may be computationally bound by CGp in a manner consistent with attention-based models in learning theory (cf. Pearce and hall 1980). This hypothesis raises several important questions. First, do CGp neurons encode the motivational value of visual targets independent of overt orienting? Second, are motivational signals in CGp referenced spatially to the eyes, head, world, or objects? Third, do motivational modulations of neuronal activity in CGp reflect external rewards or the subjective salience of visuospatial targets? And fourth, does activation of CGp functionally bind motivational salience to visuospatial locations? We propose to answer these questions through a combination of behavioral, neurophysiological, and microstimulation studies. Preliminary data suggest that CGp neurons signal the conditional motivational value of visual targets independent of saccades;CGp signals are referenced allocentrically to objects in the world;CGp responses are correlated with subjective preferences for a particular visual target location, rather than the history of rewards associated with that target;and microstimulation in CGp systematically biases orienting towards contralateral space. These data are consistent with the proposed hypothesis that CGp binds motivational salience to locations in visual space. Further microstimulation experiments will be aimed at determining whether the timing with which microstimulation is delivered to CGp systematically influences orienting choices as predicted by reinforcement learning theory. The proposed research is an important step in achieving the broader goal of understanding low the limbic system helps guide visuospatial processing areas to adapt attention dynamically to changing contexts and evolving behavioral goals.

[unreadable] DESCRIPTION (provided by applicant): Mobile animals orient to salient features of the environment. In primates, covert orienting of attention has also evolved as a flexible mechanism for monitoring potentially important locations or stimuli in the absence of overt orienting. While prior laboratory studies have extensively probed attention in both human and nonhuman primates trained to discriminate simple stimuli whose behavioral significance has been arbitrarily assigned, observational studies conducted in natural settings suggest that social stimuli are intrinsically salient and attract attention. Moreover, recent laboratory studies indicate that social cues, such as the direction of gaze of other individuals, access a privileged information channel that reflexively guides attention in both human and nonhuman primates. These studies suggest that mechanisms of attention have evolved that are sensitive to cues predicting the goals and intentions of other individuals, but exactly what these cues are and how they guide attention remain obscure, despite the fact that breakdown of these mechanisms is associated with severely debilitating mental disorders such as autism and schizophrenia. Although neurophysiological studies have revealed that social stimuli such as faces, their identity, emotional state, and direction of gaze, are processed in ventral stream visual areas of temporal cortex, these areas are not known to be important for orienting attention. In contrast, parietal cortex is thought to play a crucial role in both overt and covert allocation of visuo-spatial attention, but neurons in this area are not known to be particularly sensitive to stimulus attributes such as facial identity or the direction of gaze in a face. These observations strongly suggest that visual social signals arising in the temporal lobe are somehow transformed into orienting commands in parietal cortex, but the mechanisms supporting these transformations remain unknown. The objective of our research is to decipher how visual social signals are transformed into attentional orienting, using a combination of ethological, psychophysical, and neurophysiological techniques in monkeys. First, psychophysical techniques will be used to quantify the intrinsic motivational value of social stimuli for both covertly and overtly orienting attention. Second, neurophysiological techniques will be used to study the neural correlates of socially-motivated attention in parietal cortex, a principal structure controlling attention. Finally, the role of orbitofrontal cortex in socially-cued and socially-motivated attention will be determined using the same techniques. Achieving these aims will constrain models of the transformation of visual social signals arising in the ventral visual processing stream into socially appropriate orienting. [unreadable] [unreadable]

Current evidence identifies two inter-related systems for representing and manipulating quantities in humans: 1) a symbolically-mediated exact numerical system used in precise mathematical operations; 2) a nonverbal approximate sense of numerosity that is evolutionarily primitive and which is present early in human ontogeny. Neurobiological and behavioral data strongly suggest that the symbolically-mediated exact numerical system taps into the approximate numerosity sense. Sensitivity to numerosity, a fuzzy sense of the number of objects or events, predicts numerical and mathematical performance throughout development. Moreover, brain imaging and lesion studies in humans implicate parietal cortex in both exact numerical processing and the approximate numerosity sense. Single neurons in the primate ventral intraparietal area (VIP), as well as in prefrontal cortex (dlPFC), respond selectively to a specific number of elements in a visual array. By contrast, neurons in the lateral intraparietal area (LIP) respond in a monotonic fashion to the number of elements in a visual array located within the neuronal receptive field. These observations suggest the hypothesis that LIP neurons integrate visual information to form a representation of accumulated numerosity, which is read out by neurons in VIP and dlPFC to signal a specific numerical value. This hypothesis is consistent with several computational models of numerical representation, in which numerosity units representing a specific cardinal value, such as 3 or 5, receive input from summation units encoding the quantity of elements within their receptive fields. Despite the attractiveness of this hypothesis, several important questions remain. First, neurons representing cardinal numerosity were described in monkeys trained to make explicit same/different judgments, while neurons representing accumulated numerical magnitude were described in monkeys that were not trained to make any explicit numerosity judgments. Thus, the neuronal coding scheme used to represent number may reflect training or task demands, rather than the intrinsic numerical coding properties of neurons in number-sensitive areas. Since math performance can be improved by training on simple numerosity and spatial manipulation tasks, understanding the effects of explicit training on numerosity encoding by neurons in parietal cortex is particularly important. Second, the assumption that summation units in LIP provide inputs to numerosity units in VIP (or dlPFC), and that these connections are functionally relevant for numerosity discrimination, remains to be tested. The goal of the proposed project is to address these questions using behavioral, neurophysiological, pharmacological, and computational techniques. Understanding the neural mechanisms that relate visuospatial information-processing to representations of numerosity may suggest important improvements in early childhood mathematical education and remediation that will benefit all children, particularly those suffering from impaired quantitative abilities.

DESCRIPTION (provided by applicant): This is an application for support from the Recovery Act Limited Competition for NIH Grants: Research to Address the Heterogeneity in Autism Spectrum Disorders (R01) RFA-MH-09-170. We propose to leverage ongoing collaboration among faculty at Duke University, Yale University, and the University of Puerto Rico to develop a model of heterogeneity in social behavior in a nonhuman primate model in an ethologically natural context, identify genetic variation associated with this variability in social behavior, and determine the underlying mechanism using a combination of genetic, behavioral, and pharmacological techniques in the laboratory. One of the hallmark features of autism spectrum disorders (ASD) is dysfunction in social perception, attention, and interaction. Nonetheless, significant individual variation in these features frustrates diagnosis and challenges the development of effective treatments. Evidence suggests that individual variation in social behavior in ASD arises from a combination of genetic predispositions and individual experience, yet the underlying biological mechanisms remain poorly understood, in part due to the lack of a suitable animal model in which natural variation in both underlying genetics and individual experience generates heterogeneity in social behavior that is qualitatively similar, if not homologous, to that seen in humans. To address this gap, we propose to develop a model for studying the genetic, contextual, and neurobiological contributions to social behavior phenotype in rhesus macaques. We have previously demonstrated that these animals show hallmark social perception, attention, and reward behaviors that are qualitatively similar to those shown by typically developing humans;that individual variation in key genes impairs these behaviors in humans and rhesus in similar ways;and the same underlying neural pathways mediate the extraction of social information from the environment, translation of that information into reward and punishment signals, and ultimate expression of this information in attention to others that promotes or inhibits further interaction. Our proposed research will first characterize variability in social reward, social attention, and social aggression in a natural population of rhesus macaques living in large groups on Cayo Santiago Island in Puerto Rico, then assay key genes thought to contribute to social behavior and its dysfunction in humans including ASD, a finally test the impact of potential therapeutic interventions in the laboratory in macaques of known genotype. Our start-up has been catalyzed by support from the Duke University Institute for Brain Sciences, which has been renewed through the end of 2009, as well as support from the Duke Primate Genomics Initiative, in order to provide a seamless transition to ARRA stimulus grant support. Our project can be scaled up NOW by hiring new staff, paying extra technician and bench fees, and purchasing supplies and minor equipment with ARRA funds. Specifically, we will generate 7 new jobs and support salary for 7 faculty. Notably, we already have the research architecture in place to do high-throughput phenotyping and genetic analyses in monkeys, with targeted pharmacological studies in genetically-identified subgroups of animals. By integrating these methods we will develop a biologically predictive model of heterogeneity in primate social behavior that will inform our understanding of the basic genetic, developmental, and neurobiological causes of phenotypic heterogeneity in autism. PUBLIC HEALTH RELEVANCE: One of the hallmark features of autism spectrum disorders (ASD) is dysfunction in social perception, attention, and interaction. Nonetheless, significant individual variation in these features frustrates diagnosis and challenges the development of effective treatments. To address this gap, we will determine the genetic, developmental, and neurobiological contributions to social behavior phenotype in rhesus macaques.

Social contexts are rife with uncertainty. Consequently, much of our sensory apparatus and cognitive skill is applied to reducing this volatility by acquiring information about others. The brain mechanisms that evaluate social information and translate it into decisions, however, remain poorly understood-despite clear dysfunction of these mechanisms in neurological disorders such as autism, social anxiety, and anorexia which are characterized by dysfunctional social motivation and decision making. We hypothesize that social signals are first decoded by several distinct brain areas, including superior temporal sulcus (STS) and amygdala, translated into value signals in the ventral striatum (VS), and transformed into a common currency for comparison and exchange with other types of rewards in the orbital (OFC) and medial prefrontal cortex (mPFC). We propose to use complementary fMRI techniques in human subjects and electrophysiological techniques in macaques to test this hypothesis. Critically, we will use the same psychophysical technique to estimate reward functions for social stimuli in humans and monkeys, thus validating our comparison. Crucially, temporary inactivation of nodes in this network in monkeys and comparison with fMRI results in a high-functioning clinical population with social dysfunction will be used to functionally evaluate our model.

DESCRIPTION (provided by applicant): The nascent interdisciplinary field of Neuroeconomics harnesses the computational rigor of economics and the technological advances of modern biology to advance discovery in the decision sciences. Since pathologies of decision making are endemic to addiction-they serve a causal role in its development, they exacerbate the biological and social consequences of the disorder, and they impair remediation and treatment ~ the National Institutes of Health has recognized Neuroeconomics as fundamental to solving this important societal problem. Here we propose a National Institute of Drug Abuse (NIDA) P30 Core Center uniting two areas of institutional strength at Duke, Neuroeconomics/Cognitive Neuroscience and Interdisciplinary Addiction Research, to support hiring two new faculty, each in partnership with the Duke Institute for Brain Sciences (DIBS) and an academic department: Duke is an internationally recognized leader in both of these fields, yet their collective strengths have not yet been brought to bear on core problems of decision making in addiction. There are several areas of existing institutional strength in these areas that include the Center for Neuroeconomic Studies (CNS), the Center for Cognitive Neuroscience (CCN), the NIDA-supported Translational Prevention Research Center (TPRC), the Duke Center for Nicotine and Smoking Cessation Research (CNSCR), The Fuqua School of Business, and the strong behavioral neuroscience groups within the Departments of Neurobiology, Psychiatry, and Psychology and Neuroscience. Despite these strengths, fundamental gaps remain. The proposed Core Center will fill important gaps in the Duke decision-making research community, will bring important and cutting-edge research competencies, and will strengthen Duke's position as one of the leading institutions in this important research area. It will bring new teaching capabilities to the undergraduate neuroscience major and to graduate training more broadly. Finally, it will provide an important new link for DIBS to socially relevant applications for neuroscience, consistent with Duke's strategic goal of "Knowledge in the Sen/ice of Society". A NIDA P30 Core Center will give Duke the leverage to immediately fill these gaps and catalyze integration of these disparate groups by hiring two new faculties that each brings new expertise bridging current Neuroeconomics and Addiction research at Duke.

DESCRIPTION (provided by applicant): Autism spectrum disorder (ASD) handicaps the social and communicative abilities of 1 out of every 110 children in the United States. Evidence suggests that individual variation in social behavior in ASD, as well as within the typically developing human population, arises from a combination of genetic predispositions and individual experience, yet the underlying biological mechanisms remain poorly understood. Progress lags due to the lack of a suitable animal model in which natural variation in both underlying genetics and individual experience generates heterogeneity in social behavior that is qualitatively similar, if not homologous, to that in humans. Development of an animal model with natural social variation homologous to that of humans will permit us to more effectively target interventions that directly impact the neural circuits mediating behaviors impaired in ASD. To address this gap, we will develop a fully-realized biological model of the genetic contributions to social behavior phenotype by characterizing social behavior and cognition and their genetic foundations in a large population of animals living in naturalistic circumstances with minimal external intervention. We will use observational techniques and field experiments to quantitatively define heterogeneity in social temperament and social cognition phenotypes in males and females. In our stratified approach, we will assess social temperament using intensive observation of natural behavior and social cognition using analogs of standard laboratory tasks. We will also assay genetic variation using a stratified approach. We will first use an a priori approach that assays gene polymorphisms previously implicated in social behavior, as well as polymorphisms in the same or related pathways that have yet to be assessed in macaques. Genetic variation will include repeat length polymorphisms (VNTRs) as well as single nucleotide polymorphisms (SNPs) and will be used to identify genetic biomarkers for social phenotypes. In parallel, we will use a data-driven, bottom-up approach to identify new genomic variants linked to social behavior and cognition, by conducting full genome sequencing on 50 key individuals identified by pedigree and social temperament. Variants identified by whole-genome sequencing of selected individuals then will be assayed across the entire population to assess statistical correlations with social behaviors. Computational techniques will be used to develop biologically-meaningful measures of the relationships between phenotypic and genotypic variation. Bioinformatics software and infrastructure, previously developed and extensively validated by our group for analysis of genomic variants in human populations, will be adapted to identify and annotate genomic variations in the macaque population, and to identify variants correlated with specific measures of social behavior. These data will be combined with life history and pedigree data to generate predictive models of the impact of genotype and social phenotype on biological success.

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 impairments in deriving vicarious reinforcement from others. Observing what happens to others powerfully shapes normal human learning and behavior. Such other-regarding outcomes can drive observational learning, and motivate behaviors such as cooperation, as well as envy. Empathic responses associated with vicarious reward appear early in ontogeny, and their impairment in neuropsychiatric disorders like ASD can have devastating consequences. Understanding and treating social dysfunction in ASD will be advanced by discovering and manipulating the neural mechanisms that derive vicarious reward and punishment from what happens to others. Although brain-imaging studies have revealed some of the neural circuitry mediating social interactions, the neuronal mechanisms underlying vicarious reward remain unknown. We will use our new behavioral model of vicarious reward to determine the underlying neuronal mechanisms, delineate the impacts of network dysfunction due to reversible inactivation of ACC or OFC on vicarious reward and other-regarding behavior, and define the effects of oxytocin (OT), a potential therapeutic intervention for ASD, on behavior and neural function.

? DESCRIPTION (provided by applicant): Developing safe and effective new treatments for impaired social cognition in neuropsychiatric disorders, including autism spectrum disorders (ASD), borderline personality, schizophrenia, and social anxiety, is an important priority. Here we propose to evaluate and refine new treatments for impaired social cognition by determining how pharmacological and magnetic manipulations affect neurophysiological dynamics in the putative social brain network. Intranasal oxytocin (OT) and transcranial magnetic stimulation (TMS) hold great promise as therapies for impaired social cognition, yet their neuronal bases, as well as safety and effectiveness, are poorly understood. We will address these questions by assessing the impact of focal repetitive TMS (rTMS) and inhaled OT on joint attention, social reward/empathy, and strategic social cognition, while monitoring concurrent neuronal activity in a circuit functionally implicated in social cognition. In humans, social cognition is mediated, in part, by a circuit including the temporal parietal junction (TPJ) and anterior cingulate cortex gyrus (ACCg). Nevertheless, it is difficult to determine noninvasively the precise neurophysiological dynamics mediating social cognition in this circuit in humans, as well as the impact of rTMS and OT on neuronal activity locally or across the circuit. To address this challenge, we will use new primate models of complex social cognition permitting direct, simultaneous investigation of the effects of OT and rTMS on neural circuit dynamics, and a new TMS stimulator designed by our group that permits simultaneous neuromodulation and recording in monkeys. Rhesus macaques display social cognition similar to that of humans and these functions are linked to neuronal activity in putative homologs of human TPJ and ACCg in the superior temporal sulcus (STS) and ACCg. First, we will record neural activity in STS and ACCg to determine the relationships between local neuronal spiking, local field potentials, oscillatory neural dynamics and social cognition. We will specifically probe neural activity patterns associated with social attention, social reward/empathy, and strategic social cognition. Next, we will determine how inhaled OT affects social attention, social reward/empathy, and strategic social cognition as well as concurrent neuronal spiking, local field potentials, and oscillatory neural dynamics in STS and ACCg. Third, we will assess the effects of rTMS to STS on social attention, social reward/empathy, and strategic social cognition and neuronal spiking, local field potentials, and oscillatory neural dynamics recorded concurrently in STS and in ACCg. Our proposed studies promise new knowledge that may transform how we understand and treat impaired social cognition.

? DESCRIPTION (provided by applicant): Appropriate social behavior often demands self-control. Both neuropsychiatric disorders (e.g., schizophrenia, addiction) as well as disease states (e.g., HIV positivity, brain lesions) can lead to changes in the neural mechanisms involved in self-control - often with effects most strongly manifested in social contexts. Understanding how the brain identifies social contexts, evaluates potential outcomes, and guides selection of appropriate behavior would provide insight into these disorders and the development of new treatments. Recent work - including from our group - demonstrates that neural activity in temporo-parietal junction (TPJ) signals information relevant for identifying social context, that these social signals influence valuation processes in orbitofrontal cortex (OFC) and ventral striatum (VS), and that social value signals inform reward comparison processes in ventromedial prefrontal cortex (vmPFC). Yet, this now-standard model for social decision making leaves unanswered key questions about brain function and dysfunction, especially how social contexts can potentiate maladaptive decision making observed in disorders. We propose and empirically test a novel two-stage neural circuit model of social decisions. The first stage involves identification of a social context, which we hypothesize relies on computations in TPJ that shape subsequent valuation and decision processes elsewhere. In a second stage, control processes shape ongoing behavior toward social goals (e.g., maximizing the acquisition of information about others, shaping interpersonal reputations), which we refer to as social control. We propose to evaluate this model using an integrated set of experiments conducted in humans and monkeys. We will use similar tasks that manipulate the nature and quality of social contexts (e.g., cooperative or competitive) for decision making, involve both social and non-social reward outcomes, and provide complementary information from functional magnetic resonance imaging (fMRI) in humans, neurophysiological recordings in monkeys, and repetitive transcranial magnetic stimulation (rTMS) in both species (including simultaneous neural recordings in monkeys).

There is substantial evidence that social factors can affect physiological well-being and evolutionary fitness, but the molecular mechanisms underlying these relationships are not well understood. This dissertation project examines patterns of change in gene expression as they are distributed through the social networks of free-ranging rhesus monkeys, to understand how chronic social isolation might translate into physiological effects. The project will result in comparative data on sociality and epigenetic change that can inform research on human well-being and social isolation. Findings from the project will be made accessible to the global scientific community, and the project will support undergraduate and graduate student training in STEM research, as well as public science outreach activities.

Although we know much about the health and fitness benefits of investing in social bonds, we know little about the molecular mechanisms that actually translate these effects. This project will test the hypothesis that DNA methylation is a coordinated response to the social environment, by comparing methylation patterns for those in chronic social isolation and those heavily involved in a group's social life, and assessing methylation patterns in genetic pathways of known consequence for physiological well-being. The investigators will use a multi-year, multi-group behavioral data set to quantify the social networks of 80 monkeys (M. mulatta) of the Cayo Santiago colony using the tool-kit of Social Network Analysis (SNA). Reduced Representation Bisulfite Sequencing with whole blood DNA will be used to calculate genome-wide methylation levels and The investigators will also determine if there is over-representation of DNA methylation in a behaviorally- and health-implicated serotonergic system. Past and pilot research indicates that serotonergic genetics might be differentially adaptive based on variance in the social environment, and this study will provide empirical data to better understand the role of the serotonergic system signaling pathway in phenotypic plasticity.

The emergence of high-throughput and cost-efficient sequencing technologies has led to dramatic recent progress in identifying genetic correlates of mental health syndromes. Despite this progress, the underlying biological mechanisms remain poorly understood. Critical challenges include determining which variants are causally related to disease etiology, how this variation is associated with variation in social behavior and cognition, and how this variation interacts with the environment to produce dysfunction. The standard approach to address these challenges is to study small animal models like mice and flies, but such models are limited by their simple behavioral and cognitive repertoire and potential differences in the underlying neural circuitry, compared with humans. A promising alternative is to define the multi-omic architecture and neuroanatomy associated with complex social behavior in nonhuman primates, which share core neural and genetic pathways with humans adapted to social life. The goal of the proposed research is to identify how the brain processes social experiences to produce a greater understanding of vulnerability and resilience to life events that ultimately affect health and well-being. Specifically, we will quantitatively define social support and social vulnerability in the free-ranging rhesus macaque population of Cayo Santiago Island (Puerto Rico) and will assess the associations between these factors and the multi-omic architecture and neuroanatomy of the primate brain. We will do so under typical environmental conditions but will also take advantage of the occurrence of an extreme environmental event, a major hurricane, to evaluate social resilience in multiple conditions. First, we will describe the neurogenomic and regulatory landscape in the primate social brain and its associated anatomical implications under baseline chronic stress conditions. We will generate region specific transcriptomes and epigenomes for brain areas associated with social information processing and implicated in mental health genetic models. We will combine these genomic data with detailed measures of structural connectivity and receptor densities collected using brain imaging and histology techniques. The combination of these approaches will help us develop a fully-realized biological model that recapitulates the genetic and environmental contributions to social phenotypes as well as their molecular, structural, and functional correlates. Finally, we will delineate how social support buffers the impact of a traumatic life event and the resulting severe and sudden stressful experiences of Hurricane Maria and its aftermath. Development of this type of animal model will permit us to more effectively target interventions that directly impact the neural circuits mediating behaviors impaired in a variety of mental health syndromes.

ABSTRACT / SUMMARY New technologies are enabling molecular profiling of single brain cells at remarkable throughput. However, these new methods have yet to be extensively applied to the brains of model organisms that bridge the evolutionary distance between mouse and human, including the most common nonhuman primate model system - the rhesus macaque. Here we propose to generate an anatomically resolved, single cell atlas of the epigenome (5.5 million cells) and transcriptome (11 million cells) of the rhesus macaque brain. We will apply two methods, recently developed in our labs, that rely on ?combinatorial indexing? to cost-effectively profile the epigenomes (sci-ATAC-seq) and transcriptomes (sci-RNA-seq) of large numbers of cells or nuclei. As our first aim, we will generate high resolution, single cell epigenetic and transcriptional atlases of one male and one female rhesus macaque brain. Specifically, we will profile chromatin accessibility in 750,000 nuclei (sci-ATAC- seq) and transcription in 1,500,000 nuclei (sci-RNA-seq) from each of two macaque brains (for a total of 4.5 million cells). These will be obtained from 25 anatomically dissected brain regions (30,000 sci-ATAC-seq and 60,000 sci-RNA-seq profiles per region per brain). As our second aim, we will extend these atlases to span the primate lifespan. Specifically, we will perform single cell epigenetic and transcriptional profiling of the brains of 50 additional rhesus macaques (25 regions per brain; 3,200 sci-ATAC-seq and 6,400 sci-RNA-seq profiles per individual/region, for a total of 12 million molecularly profiled cells). This large sample size will allow us to characterize natural variation in chromatin accessibility and transcription within each cell type, between individuals, sexes, and across the natural lifespan of rhesus macaques. At 16.5 million cells, our rhesus macaque brain atlas will comprise the largest transcriptional and epigenomic single cell dataset of any primate organ to date. Our data will be rapidly shared with BICCN and the broader community. We anticipate it will be an essential resource, complementary to other efforts, for identifying the distribution and function of key cell types across the primate brain, allowing for the development of cell type- and region-specific molecular interventions that will help us understand brain function and the etiology, and potentially the treatment, of brain disorders.

Project Summary This project focuses on the development of noninvasive therapeutic interventions in humans to improve spatial cognition due to declines seen during healthy and pathological aging. Both normal and pathophysiological processes that occur in aging result in difficulties navigating. These challenges can be profoundly debilitating. A central capacity in navigation is the ability to plan routes to goals. While the brain circuits for navigation are increasingly well-characterized, the nature of neural representations of goals for goal-directed navigation remain less so. We aim to describe neural representations for goal locations for navigation. In order to fully describe these representations and how they change in aging, both young and old nonhuman primates will run mazes in virtual reality while wireless neural recordings are performed in the prefrontal cortex. An important tool to explore computations for goal-directed navigation in humans is the use of virtual reality. But there are important differences between virtual reality and real life navigation, and the generalization of findings in virtual reality to the real world must be explored. To aid in understanding how such findings can be extended to the real world, we aim to directly compare neural activity in both contexts by building real world mazes that match virtual ones. Monkeys will learn to navigate a maze for rewards in virtual reality and then assessed in real world analogues. This novel experimental design will allow the direct comparison of neuronal activity and learning in virtual mazes to activity and behavior in real world mazes. Finally, in order to spur the development of therapies to address the scourge of age-related declines in spatial cognition, we will utilize noninvasive repetitive transcranial magnetic stimulation, already approved to treat major depression disorder, to stimulate activity in the prefrontal cortex in both young and old monkeys. We will examine how this intervention changes the neural activity and the behavior as monkeys run mazes. We anticipate that we will be able to rescue observed deficits in navigation in older monkeys using such intervention and hence potentially advance a new path of treatment for declines in spatial cognition in the elderly.