Social Relations and Health
INFLAMMATION-INDUCED DEPRESSED MOOD: THE ROLE OF SOCIAL NEUROCOGNITIVE MECHANISMS
PI: Naomi Eisenberger, PhD
This application is submitted to the NIMH DATR Mood/Sleep Research Program A2-AID. Depressive disorders occur at a high rate in patients with inflammatory disorders, with a point prevalence of 15-29%, which is two to three times greater than that observed in the general population. Substantial evidence has shown that inflammation and increases in proinflammatory cytokine activity play a critical role in the onset and perpetuation of depression and depressive symptoms (e.g. insomnia, fatigue) in those who are co-morbid for inflammatory disorders (Miller et al., 2009). Consistent with this, experimental work has shown that an inflammatory challenge can increase depressed mood in an otherwise healthy sample (Reichenberg et al., 2001). Based on these findings, there has been a growing interest in whether inflammatory processes can contribute to depression in a causal manner and how these effects might occur. Given the observation that inflammatory processes trigger social withdrawal (Dantzer, 2001; Hart, 1988), coupled with evidence that feelings of 'social disconnection' play a critical role in the onset and perpetuation of (non-inflammatory forms of) depression (Heinrich & Gullone, 2006), it is surprising that the social psychological consequences of inflammation and their contribution to depression have not been more fully explored. Here, we suggest that inflammation may increase feelings of social disconnection and that these social psychological changes may be an important contributor to inflammation-associated depression. Indeed, preliminary data demonstrated that an experimentally-induced inflammatory challenge (endotoxin) led to increases in self-reported feelings of social disconnection (e.g., "I feel disconnected from others") in addition to increases in depressed mood (Eisenberger et al., 2009b). Aside from these findings, however, there are no studies that have explored the effect of inflammatory processes on social experience in humans. The over- arching objective of this proposal is to explore the experiential and neural correlates of inflammatory- induced changes in social experience (e.g., feelings of social disconnection), which may provide a critical missing link in understanding the relationship between inflammation and depression. Participants (n=100) will be randomly assigned to receive either endotoxin or placebo and will then be monitored for the next six hours. Blood draws to assess cytokine levels as well as self-reported feelings of social disconnection and depressed mood will be collected hourly. In addition, at the time of peak cytokine response, participants will complete a neuroimaging session to examine the effect of inflammatory challenge on neural sensitivity to social rejection and social acceptance. It is hypothesized that endotoxin will increase feelings of social disconnection over time, and that the underlying neural sensitivities that give rise to these feelings (e.g., increased neural sensitivity to social rejection; decreased neural sensitivity to social acceptance) will contribute to inflammatory-induced depressed mood. PUBLIC HEALTH RELEVANCE: Although substantial evidence has demonstrated links between inflammation and depression, the mechanisms underlying this relationship are poorly understood. Based on the observation that inflammation triggers social withdrawal, coupled with evidence that feelings of social disconnection play a critical role in depression, the proposed research will examine the social psychological consequences of inflammation and their relation to depressive symptoms for the first time. In addition, the proposed research will examine the neural correlates that underlie these social psychological changes to better understand the central mechanisms that contribute to inflammatory-induced depressive symptoms.
USC/UCLA CENTER ON BIODEMOGRAPHY AND POPULATION HEALTH
PI: Eileen Crimmins, PhD, USC PI; Steve Cole, PhD, UCLA Co-I
USC/UCLA Center on Biodemography and Population Health (CBPH) Direct Core D / UCLA Social Genomics Core Laboratory is part of a broader effort to understand biological pathways through which socio-demographic factors affect health risks across the life-course. The Center provides support for research in and the development of the field of Biodemography to clarify how biology mediates between social and economic factors to affect physical and mental health of the population. The integration of biological, epidemiologic and medical risk information into demographic models is fundamental to understanding and projecting demographic trends and population sub group differences in health in order to inform policy. In this application, we request continued funding for the USC/UCLA CBPH in order to: 1) support the development of cutting-edge biodemographic research among CBPH affiliates through support of pilot projects and research infrastructure; 2) to support development of approaches to biodemographic data collection and valdation for demographic research through the use of pilot projects and research infrastructure 3) to further develop an active biodemographic research community both within our two universities and more broadly in the field of popualtion studies; 4) to implement a new External Research Support and Dissemination Core to support development and validation of new research methodologies, including genetic factors, for use in biodemographic research and population surveys more generally; 5) to disseminate broadly information on biodemographic methods. The research supported by the CBPH and the developmnet of infrastructure for measurement and integration of genetic factors will continue to improve our understanding of how individual biological risk factors, combinations of biological risk factors, and interactions of risk factors affect the total length of life, the length of life with health problems, and the population prevalence of specific chronic conditions and disabilities.
SOCIAL REGULATION OF GENE EXPRESSION
PI: Cacioppo / Cole
Research has repeatedly shown that a lack of social ties increases risk for poor health. Recent research has demonstrated that poor mental and physical health outcomes are distally associated with social isolation, are more proximally associated with perceived social isolation, and are not explicable in terms of differences in health behaviors. Recent studies have identified alterations in hypothalamic-pituitary-adrenal (HPA) axis regulation of inflammatory biology in leukocytes as a potential mechanism of isolation-related health risks. Individuals reporting chronically high levels of subjective social isolation have shown a heightened rise in morning cortisol levels (Adams et al. 2006), and alterations in genome-wide transcription of glucocorticoid target genes andNF-:B target genes (Cole et al. 2007). These isolation-related alterations in leukocyte biology might stem from a functional desensitization of the glucocorticoid receptor (GR) in isolated people (Cole 2008), which in turn, is reciprocally related toNF-:B expression, a key factor in regulation of cellular responses to infection, cancer, and inflammation. Impaired transcription of glucocorticoid response genes and increased activity of pro-inflammatory transcription control pathways provide a functional genomic explanation for elevated risk of inflammatory disease in individuals who experience chronically high levels of perceived social isolation. Initial genomics analyses tested a relatively small sample and provided preliminary support for this hypothesis. This revised application seeks to extend those initial findings by (1) expanding the range of genomic analyses, (2) identifying the specific aspect of glucocorticoid-mediated transcriptional control driving those effects, (3) determining the plausibility of a causal role for subjective social isolation in predicting transcriptional control in longitudinal studies, and (4) establishing an animal model of subjective social isolation that can provide a platform for experimental studies. Utilizing participants from the Chicago Health, Aging and social Relations longitudinal study, a population-based sample of middle-aged and older adults, we investigate whether transcriptional alterations occur only in those who show chronically high levels of subjective isolation, or whether similar effects occur even at minimal or variable levels of subjective isolation. Differential expression of GR and/orNF-:B proteins, and/or post-translational modifications of the GR (e.g., GR phosphorylation) will be examined as potential molecular mechanisms of altered glucocorticoid transcriptional control. The plausibility of a causal role for social isolation will be evaluated by examining the extent to which naturally occurring changes in subjective isolation over a two-year period predict changes in transcriptional control. Finally, a non-human primate model will be evaluated by conducting social behavioral assays to distinguish among and determine stability of "sociability" phenotypes in adult male rhesus monkeys, and biological assays will be done to determine relationships between social phenotypes and measures of HPA activity, GR- mediated signal transduction, and genome-wide transcriptional profiles. PUBLIC HEALTH RELEVANCE: Research has repeatedly shown that social isolation increases risk for poor health. We previously found functional genomic differences between individuals high and low in social isolation which could contribute to differences in risk of disease. The proposed research therefore is designed to identify the specific biological mechanisms mediating these genomic effects.
LIFE- SPAN EVOLUTION OF THE CAPABILITIES OF RHESUS MONKEYS
PI: Steve Cole, PhD, UCLA PI
There is substantial interest in understanding the role that early life conditions and subsequent life environments play in determining: adult aging, health, socioeconomic outcomes, personality and cognition. Also of interest is understanding the effects that personality and cognition have on health, aging and socioeconomic outcomes. there is also great interest in understanding possible avenues of compensation, remediation and resilience in these areas. Mechanisms of human development rooted in biology, psychology and the environment are essential to designing policies that promote health, reduce inequality, and develop human potential. A proper study of these mechanisms requires detailed life cycle information on genes, environments and biology. When examined across generations, one can better examine the effects of family influence, and the role of environments in ameliorating or exacerbating initial endowments. Even for a study of humans within a generation, the requisite data are scarce; intergenerational data are even more fragmentary. Experimental evidence for humans is also limited. Rhesus monkeys are genetically and socially similar to humans. Rich data has been collected on rhesus monkeys and their environments, between and across generations, which will be used for this project. Furthermore, this project will generate new data from a variety of interventions. With these data, it is possible to study the evolution of rhesus monkey capabilities and to examine the role of deprivation and remediation in life cycle development. Within limits dictated by animal rights protocols, this project will engineer adverse early and adolescent environments. the project will utilize numerous measures of biology (health), cognition and personality for monkeys sampled over five intervals of the rhesus life cycles and performs a variety of environmental interventions Analyses of these data will reveal new empirical relationships and a deeper, biologically-based understanding of the origins and development of capabilities in an animal species close to humans. Cutting-edge methodology will be used with this data to conduct gene analysis developed for human populations on these rhesus monkey populations. the project will analyze how social factors regulate gene expression in a dynamic setting and in particular which sets of genes are sensitive to social influences, how these influences are transduced into the molecular environment of the cell, and how inherent genetic characteristics might modulate socio-environmental influences. these data will be analyzed using a dynamic econometric model of life cycle skill formation that will guide the formulation of policy analysis for humans. An analysis of rhesus monkeys will serve as a prototype for what is possible in the study of human development. PUBLIC HEALTH RELEVANCE: This proposal seeks support to investigate the origins of inequality in health and other social and economic outcomes and mechanisms to alleviate inequality. Current studies OF inequality in human populations lack firm biological and experimental grounding, but rhesus monkeys share approximately 95% of their genes with humans and possess functionally similar polymorphisms in several genes linked to emotional regulation. Because of these similarities, this project can use experimental research on rhesus monkey populations to investigate the origins of inequality, the mechanisms that foster resilience to adversity, and the efficacy of interventions that compensate or remediate adversity.
RESILIENCE AND HEALTH IN COMMUNITIES AND INDIVIDUALS
PI: Alex Zautra, PhD (ASU PI) / Michael R. Irwin, MD, UCLA PI
The fundamental question asked in this investigation is whether measures of resilience capacity, identified from recent theoretical advances and empirical study, will predict physical and emotional functioning beyond that provided from well-established risk factors for disease and psychological ill-health for community residents from a wide range of backgrounds. A community sample of men and women aged 40 to 65 (total N = 800) will be drawn from 40 census neighborhoods that vary in average income, age, and ethnic composition. Using multi-level methods, participants and their neighborhoods will be evaluated on global indices of risk and resilience. Deeper probing of the underlying bio-behavioral mechanisms of risk and resilience will be conducted through laboratory testing and electronic diary assessments with a sub-sample (N = 200) drawn from the larger pool of participants. Current functioning and precursors of future health status of the mid-aged adults will be taken as outcomes. For those mid-aged adults with children, the outcome measures will also be assessed in one their children approaching adult life (aged 16 to 24 years; N = 160) to probe the transmission of resilience across generations.
DAILY EXPERIENCE IN ADOLESCENCE AND BIOMARKERS OF EARLY RISK FOR ADULT HEALTH
PI: Andrew Fuligni, PhD / Michael R. Irwin, MD, Co-I
Despite calls for the identification of early risk factors for the development of chronic health conditions, there has been little longitudinal research on biomarkers of health that has been conducted in persons younger than 25 years of age. In addition, there is only a minimal understanding of how biological indices of early risk for adult health develop among adolescents with Latin American and Asian backgrounds, the two fastest rising ethnic groups in theUnited States, who are at differential risk for adverse health outcomes as compared to European Americans. An understanding of these processes is necessary for the development of ethnically and culturally relevant prevention efforts. We propose a 3-wave longitudinal study of adolescents and their caregivers from Mexican, Chinese and European backgrounds in order to assess the impact of daily experience on biological indicators of early risk for adult health. Our focus on daily experience stems from the need to identify the mechanisms by which global social factors identified in demographic surveys, such as lower education and income, play themselves out in individuals' daily lives. Daily experiences such as social conflict, excessive demands, emotional distress, threat, and sleep behaviors have been shown to be linked to both global risk factors and multiple biological indices of health risk among adults. The project will include both intensive behavioral assessments and detailed biological markers of health risk from both adolescents and their parents in order to address the following specific aims: (1) describe the development during adolescence of biological indices of early risk for adult health; (2) assess the role of daily experience in the development of early health risk; (3) examine the existence of ethnic disparities in early health risk; and (4) explore the role of potential protective factors in the development of early health risk. Approximately 540 pairs of adolescents and primary caregivers (180 from each ethnic group) will be assessed when the adolescents are approximately 15-16, 17-18, and 19-20 years of age. Each year, both adolescents and caregivers will participate in interviews that include measures of global social factors such as socioeconomic background and potential protective factors such as social connectedness. Participants will report daily experiences using a nightly diary checklist for 9 consecutive days. Salivary cortisol will be obtained at 4 time points each day for 4 of these days in order to analyze HPA activity, and participants will wear wrist actigraphs for the same 4 days to measure objective sleep behaviors. Blood pressure, BMI, and waist/hip ratio will be assessed, and dried blood spots will be obtained for the assessment of c-reactive-protein (CRP), cholesterol, and high density lipoproteins (HDL). Finally, peripheral blood samples will be provided by a subsample of 120 families for the assessment of plasma interleukin-6 (IL-6), a pro-inflammatory cytokine, and for gene expression analyses of molecular signaling pathways driving inflammatory biology. PUBLIC HEALTH RELEVANCE: There is only a minimal understanding of how biological indices of early risk for adult health develop among adolescents with Latin American and Asian backgrounds, the two fastest rising ethnic groups in theUnited States, who are at differential risk for adverse health outcomes as compared to European American. More in-depth examinations of the daily lives of adolescents from these populations could identify both the sources of these disparities as well as unique risk and protective factors. An understanding of these processes is necessary for the development of ethnically and culturally relevant prevention efforts.
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Antagonistic pleiotropy at the human IL6 promoter confers genetic resilience to the pro-inflammatory effects of adverse social conditions in adolescence.  Cole SW, Arevalo JM, Manu K, Telzer EH, Kiang L, Bower JE, Irwin MR, Fuligni AJ. Dev Psychol. 2011 Jul;47(4):1173-80. PMID: 21639625
Transcript origin analysis identifies antigen-presenting cells as primary targets of socially regulated gene expression in leukocytes.  Cole SW, Hawkley LC, Arevalo JM, Cacioppo JT. Proc Natl Acad Sci U S A. 2011 Feb 15;108(7):3080-5. Epub 2011 Feb 7. PMID: 21300872 Free PMC Article