Eliza Bliss-Moreau - US grants

DESCRIPTION (provided by applicant): Elucidating the components of the socioemotional brain and understanding their contribution to the generation of species typical behavior is germane to understanding and developing effective treatments for a host of mental health and developmental disorders. The proposed work investigates the role of one brain structure, the anterior cingulate cortex (ACC), in normal social and emotional behavior (Specific Aim 1). The ACC has been implicated in a wide array of social and emotional processing in humans and nonhuman animals. Lesion studies in rats and monkeys typically use destructive lesions of the ACC and then test animals in constrained non-naturalistic tasks of social and emotional processing. There are a number of issues with these approaches that are specifically addressed in the proposed projects by using fiber-sparing ibotenic acid lesions and testing animals in semi-naturalistic social and emotional task environments. A cohort of adult rhesus macaques will receive either bilateral, ibotenic acid lesions of the anterior cingulate cortex or sham operations. Animals will complete a battery of semi-naturalistic social and emotional processing tasks during which the frequency and duration of their spontaneously generated behaviors will be captured using a robust behavioral ethogram. A secondary goal of the proposed work is to relate deficiencies in social and emotional process resulting from ACC damage to deficiencies in other ACC-related functions: processing competing or conflicting stimuli (Specific Aim 2) and generating physiological responses (Specific Aim 3). The ACC is widely thought to process competing stimulus inputs in order to execute coherent behavioral responses; this function is likely critical for normal social behavior (e.g., processing affiliative and aggressive signals within a complex social group). The ACC is also thought to be involved in generating and regulating peripheral physiological responses such as changes in heart rate and respiration; this function is likely critical for normal emotional behavior (e.g., experiencing emotional states that are physiologically arousing such as fear or anxiety). Following Specific Aim 1, experimental animals will complete two tasks to address Specific Aims 2 and 3. First, animals will complete a cognitive task during which competing sensory inputs must be resolved to execute the correct behavioral response. Second, animals will complete a task in which they watch socioemotionally provocative videos while their peripheral physiology is measured. Lesioned and control animals' performance on these tasks will be compared and also used as a variable in analyses of social and emotional behavior (from tasks related to Specific Aim 1).

It is well established that social context impacts physical and mental health. People with more social connections experience less illness and recover more quickly and thoroughly when they do. Understanding the mechanism by which social context influences wellbeing will allow for the development of new interventions and treatments for pathology, and in particular psychopathy. Despite accumulating evidence that illustrates a relationship between social relationships and wellbeing, little is known about the biological mechanisms that subserve that relationship. One possible mechanism is that social context influences brain anatomy which in turn influences wellbeing. New evidence collected in people and monkeys illustrates that the more social relationships an individual has, the larger the volume of the amygdala and other brain regions critically important for the generation and regulation of emotions. These data point to a relationship between social network size and the structure and function of brain areas that are important for emotion and wellbeing, although they leave a number of important questions unanswered. First, is it only social network size that matters, or does an individual¿s social role impact neuroanatomy? Second, how does an individual¿s social role early in development influence neuroanatomy across the life span? Third, how does emotional brain neuroanatomy mediate the impact of social life on emotional processing? The goal of the proposed work is to answer these questions. To that end, I will first characterize individual¿s social roles using formal social network analyses. Such analyses provide information about the number of social connections an individual has, but also about what specific role the individual plays in that network. Individuals will then undergo neuroimaging in order to characterize the structure and functional connectivity neuroanatomical regions of interest. They will also complete testing to characterize their emotional processing. I will first examine whether social role influences brain neuroanatomy and emotional processing using a cross sectional study with adult subjects (Specific Aims 1, 3). Next I will examine whether social roles early in development influence neuroanatomy and the capacity for developing new social relationships across a critical developmental period (childhood through young adulthood) using an experimental longitudinal study design (Specific Aim 2, 3). Together, these data will allow for the evaluation of the impact of social roles on emotional processing as mediated by neuroanatomy across the life-span.

? DESCRIPTION (provided by applicant): Why is it that some people float through life in a sea of tranquility while others are constantly riding an emotional roller coaster? Why do some emotionally reactive babies grow up to become calm, centered adults and others remain volatile? Questions about the origins and persistence of variation in emotional life are some of the most important questions for psychiatric and developmental science. The goal of the proposed research is to investigate variation in infants in one system that is important for emotional life-the autonomic nervous system. To that end, we will quantify spontaneous variation in activity of the two branches of the autonomic nervous system (ANS)-the parasympathetic nervous system (PNS) and the sympathetic nervous system (SNS). Activity of the PNS and SNS, which work together to maintain homeostasis is highly variable between people, thought to imbue the stimulus environment with affective meaning, and related to variation in both healthy and pathological affective experience, both healthy and pathological. Variation appears to manifest at least by early childhood but what we do not know is how much variation exists in ANS functioning during infancy, whether early ANS variation relates to other behavioral or biological phenotypes, how stable variation is across development, and what predicts its stability. The proposed research will fill these knowledge gaps. We propose to record ANS activity from infants after they complete a standardized assessment of their behavioral phenotypes and biological profiles as part of the BioBehavioral Assessment program (BBA; OD010962). We will then evaluate whether variation in established behavioral phenotypes (e.g., temperament) and biological markers (e.g., plasma cortisol levels, c-reactive protein levels; serotonin and monoamine oxidase A promoter genotypes) predict ANS activity, and whether variation is stable across the first year of life. The long term goal of the proposed research is to establish rhesus monkeys as a good model for affect development across early development so that we can subsequently identify early biomarkers of and treatments for psychopathology.

Project Summary Pertrubed affective processing is a defining symptom of a host of psychiatric disorders, such as depression where it is a primary symptom, and disorders where affective disturbances are secondary symptoms, for example, schizophrenia. Studies of healthy individuals and those with depressed mood implicate a network of areas centering on ventral anterior cingulate cortex (ACC) and amygdala in the control of long-term changes in affect. Despite this understanding, the neural mechanisms that generate and regulate affective experiences are unclear. One reason for this lack of clarity stems from the fact that studies of affect in animals typically only assess instantaneous and short-lived behavioral and neural responses to discrete aversive or positive stimuli. These stimuli typically last less than a second and generally belonging to a small class (e.g., juice) that are not particularly ecologically relevant. To date, no studies in non-human primates have probed the neural basis of affective states that extend over minutes or hours, durations typical of mood states in humans. Such studies would form the foundation for understanding how mood is controlled at the level of brain circuits and single neurons. The objective of this proposal is to determine how the circuit connecting ventral ACC and amygdala functions before, during, and after the induction of either negative or positive affective states in non-human primates. We hypothesize that negative and positive temporally extended affective states will be associated with unique patterns of local and circuit-level neural activity within ventral ACC and amygdala during affect induction and the selection (or regulation) of affective state. We will test our hypothesis by first determining how local and circuit level activity within ventral ACC and amygdala encodes the valence of dynamic, ecologically relevant stimuli that generate unique affective states (Aim 1). We will record both single neurons and local field potentials in both ventral ACC and amygdala and analyze the timing of the neural responses and LFP coherence among these areas to gain circuit-level understanding. Then, using a translationally- relevant affect induction technique that mirrors affect induction paradigms used in humans, we will establish how affect-related neural activity within the ventral ACC-amygdala circuit is altered when temporally extended changes in affective state, both positive and negative, are induced (Aim 2). The induction of affective state will be confirmed using both behavioral (i.e., response selection) and cardiac correlates of parasympathetic and sympathetic activity, measures of affective state that are well validated in humans. Once the neural mechanisms, the specific patterns of neural activity within the ventral ACC-amygdala circuit that control affective states are known, we anticipate being able to either increase or decrease activity in this circuit to influence affective states. This project marks a significant departure from standard approaches to studying affective non-human primates and has the potential to provide vital knowledge for treating mood disorders.

Project Summary/Abstract While the devastating neural consequences (e.g., microcephaly) of fetal ZIKV infection are clear, the neural mechanisms that create those outcomes are not clear. Accumulating research from human cell lines and mice suggest that ZIKV's ability to infect neural progenitors may be one mechanism, but the extent to which these processes impact neuroanatomy in whole organisms and in primate (including human) brains are unknown. The proposed work takes the first step in understanding how ZIKV disrupts brain structure and function by performing whole-brain neuroanatomical analyses on brains from nonhuman primates infected with or exposed to ZIKV. We capitalize upon an already existing NIH-funded resource ? the brains and other biological samples from rhesus macaques exposed to or infected with ZIKV as part of ongoing work establishing the rhesus macaque as a model for human ZIKV infection and testing vaccines for ZIKV. We will quantify the number, density, and cell size of neurons, glia, and dividing cells in a number of representative cortical and subcortical areas in macaques exposed to or infected with ZIKV at various times of fetal development or in adulthood. The overarching goal of the proposed work is to develop an understanding of how the timing of ZIKV infection relative to development and subsequent manifestation of ZIKV both in terms of clinical symptoms (fever, weight loss) and viremia (magnitude of infection, time of active infection) influence disruption of normal central nervous system neuroanatomy.

Project Summary By 2060, there will be at least 98 million older adults (65 years of age or older) living in the United States (Colby & Ortman, 2014), underscoring the urgency to understand the biological processes that drive healthy, ?successful? aging. While aging is accompanied by a host of negative changes (e.g., deterioration of memory), paradoxically, existing data demonstrate that social and emotional life actually get better with age. Older adults report more positive social experiences, more positive and/or less negative emotional experiences, and have biased attention towards positive and away from negative stimuli (e.g., Birditt et al., 2005; 2009; Luong et al., 2011; Gross et al., 1997; Carstensen et al., 2011; Isaacowitz et al., 2006a,b; Isaacowitz et al., 2008; Isaacowitz, 2012; Mather & Carstensen, 2003). This phenomenon is known as the ?positivity effect? (Mather & Carstensen, 2005; Carstensen & Mikels, 2005). The goal of the proposed research is to take the first step in understanding the biological mechanisms that generate this ?positivity effect? by establishing an animal model of healthy human socioemotional aging with the understanding that we must understand health to treat those who are not healthy. To that end, a suite of tests homologous to those used with humans will be used to evaluate socioemotional processes in rhesus macaques, and the translational relevance of those tests will be determined on a task-by-task basis. The proposed work will evaluate the social behavior of the animals, visual attention to positive and negative stimuli, and features of emotional responding associated with activity in the autonomic nervous system. The goal of the proposed research ? to establish rhesus monkeys as a model for healthy socioemotional aging in humans ? serves the long-term goal of understanding the biological mechanisms that support healthy socioemotional aging, which in turn will enable development of effective treatments and interventions to promote health and well-being in our aging population.

Project Summary At its most extreme, fetal Zika virus infection causes microcephaly ? the significant shrinking of the fetal brain and skull. Accumulating evidence suggests that microcephaly is just one possible outcome of fetal Zika virus infection, however, and that babies born with normal sized heads may have significant central nervous system pathology. The long-term consequences of this pathology are unknown, leaving open the possibility of a secondary epidemic resulting from compromised cognition and socioaffective processing that will occur as babies born during the epidemic age. The proposed work for this supplement augments the Parent Grant by carrying out evaluations of the consequences of this pathology on sensorimotor development of a cohort of nonhuman primates infected with Zika virus as fetuses and a group of procedure matched, non-infected controls. We will evaluate the extent to which maternal and fetal viremia influences behavioral and neural measures of sensorimotor function. Because macaques develop approximately four times faster than humans, we will be able to prospectively model pathology that arises ? that is, we will be able to predict what pathology human babies, infected with Zika virus during the 2015-2016 epidemic, will experience as they grow up. Developmental modeling of this sort is critical for developing effective interventions and treatments to encourage healthy development and ameliorate psychopathology. Funding via this supplement will support the doctoral training of a scholar from a background that is underrepresented in, and typically excluded from, STEM.

Project Summary The vast majority of Alzheimer's disease (AD) cases are late-onset and it ss now widely believed that development of late-onset AD is the consequence of accumulated brain damage over many years. This process begins with the generation of abnormal oligomeric proteins (amyloid beta oligomers, A?Os) from misprocessed amyloid precursor protein. A?Os are toxic to synapses, and over time A?O buildup and synaptic damage lead to deposition of amyloid plaques and hyperphosphorylated tau protein causing neurofibrillary tangles and neuronal loss, the hallmarks of AD neuropathology. Despite tremendous resource investment, the translation of this mechanistic understanding of AD pathogenesis into new therapies for AD remains elusive. We propose the development of a nonhuman primate model of early AD pathogenesis based on exogenous administration of A?Os to middle-aged rhesus monkeys. Our extensive preliminary data show that a month of twice-weekly A?O administration causes synapse loss targeted to highly plastic thin dendritic spines, and neuroinflammation, changes that mirror what is thought to occur in the earliest prodromal phase of human AD. This model therefore addresses a key limitation of existing animal models of AD: it is based on the pathogenetic process thought to lead to the vast majority of human late-onset AD cases. Based on the acute effects of A?O administration on synaptic and glial markers in rhesus monkeys, we hypothesize that deficits in cognition and affect mirroring symptoms of AD in humans will develop over time in rhesus monkeys chronically treated with A?Os and relate to synaptic disease observed in postmortem histology. To test our hypothesis, rhesus monkeys treated with A?Os or a scrambled peptide control will complete cognitive and affective tasks sensitive to cortical and subcortical function. Our design provides detailed assessment of the time course of behavioral changes, and we will determine synaptic, neuronal, and glial markers in the brains of these monkeys concurrently with the emergence of behavioral deficits. Behavior will be tested in repeated cycles so that changes over time with increasing cumulative dose of A?Os can be determined. These experiments will provide a multi-faceted behavioral characterization of how synaptic dysfunction caused by A?O treatment impacts cognitive and affective behaviors dependent on multiple cortical and subcortical structures, and will let us develop A?O administration in rhesus monkeys as a model for testing interventions that may derail the progression of pathological cascades before full-blown AD develops, providing a new setting for developing treatments for an urgent public health problem.

Project Summary Although accumulating evidence in humans points to improvements in emotional life with age, even in the context of physical and cognitive health challenges, the mechanisms that support those improvements are largely unknown. One possibility is that aspects of the social environment and social relationships guard against deleterious aging effects and thus promote wellbeing. Understanding the interplay between social environment and cognitive, affective, and neurobehavioral health outcomes across the lifespan is critical for developing effective interventions for people who suffer from the deleterious effects of aging, including depression and loneliness. Nevertheless, it is not ethical to manipulate humans? social relationships in order to test causal hypotheses. To address this mechanistic question, we capitalize on a robust animal model of human social, cognitive, affective, and neurobehavioral aging ? the rhesus monkey ? in order evaluate whether robust social environments and high-quality relationships promote and protect healthy affective, cognitive, and neurobehavioral aging while restrictions of the social environment compromise it. Additionally, we evaluate whether social interventions, namely increasing access to high quality social partners, may improve cognitive, affective, and neurobehavioral outcomes once they have been compromised by aging processes. We will restrict and then rejuvenate the social environment in both young and aged monkeys, and measure neurobehavioral function (cognition, affect, and neuroimaging measures of brain structure and function) concurrently with these manipulations. In this way, this program of work represents a critical first step in determining the mechanistic impact of social environment on neurobehavioral aging in addition to evaluating a potential intervention that could benefit individuals who have experienced unhealthy aging.