EARLY LIFE ADVERSITY, INFLAMMATORY BURDEN, AND VULNERABILITY: A TRANSLATIONAL APPROACH

Chairs & Presenters:

Michael B. Hennessy (Co-Chair and Presenter)
Joanne Weinberg (Co-Chair and Discussant)
Katherine Ehrlich
Charlis Raineki
Tamara Bodnar

Details of Research Subjects: Models of Neurodevelopmental Disorders, Physiological Processes including hormonal modulation, Socio-emotional including attachment & temperament, Neurodevelopment and Plasticity including imaging work, Stress, Adversity

Ages of Research Subjects: prenatal, infancy, adolescence, adult

Topics: Models of Neurodevelopmental Disorders, Physiological Processes including hormonal modulation, Socio-emotional including attachment & temperament, Neurodevelopment and Plasticity including imaging work, Stress, Adversity

Description:

EARLY LIFE ADVERSITY, INFLAMMATORY BURDEN, AND VULNERABILITY: A TRANSLATIONAL APPROACH

Risk for diseases and disorders over the life course is influenced by prenatal and early life adversities, including psychosocial and physical stress, undernutrition, and alcohol and drug exposure. This symposium will explore how two forms of early adversity—early social stress and fetal alcohol exposure—alter neuroimmune and inflammatory processes to increase risk for adverse mental and physical health outcomes in later life. Utilizing a translational approach, speakers will address effects of early social stress and fetal alcohol exposure in animal models and humans. Dr. Hennessy’s research with rodent and nonhuman primate models examines how early attachment disruption and social separation can sensitize neuroinflammatory processes to promote depressive outcomes. Dr. Ehrlich’s studies investigate how stress in parent-child relationships “gets under the skin” to alter innate and adaptive immunity and so shape risk for an assortment of physical disorders. Dr. Raineki’s studies examining individual and interactive developmental effects of prenatal alcohol exposure and early life adversity in his rat model demonstrate associations between anxiety-like behavior and changes in peripheral and central cytokine levels. Dr. Bodnar’s work on human adults with fetal alcohol spectrum disorder demonstrates elevated white blood cell counts, greater anxiety, and early symptoms of autoimmune diseases, and suggests that adversity may be a modulator of immune and emotional dysregulation. Together, these findings point to a number of specific processes by which early life adversity may shape the developmental trajectory, resulting in neuroimmune sensitization and a proinflammatory bias, to increase vulnerability to physical and mental health disorders in later life.

Ruth E. Grunau (Chair and Presenter)

Livio Provenzi

Mia McLean

Susanne Brummelte

Martha G. Welch 

RODENT AND NONHUMAN PRIMATE MODELS OF ATTACHMENT DISRUPTION AND INFLAMMATORY-MEDIATED DEPRESSION

Michael Hennessy, Wright State University, Yellow Springs, OH, United States (Primary Presenter)

Patricia A. Schiml, Terrence Deak, John Capitanio, and Erin Kinnally

Disruption of filial attachment in children is associated with lasting neuroinflammatory burden that appears to increase vulnerability to depression and other stress-related psychological and physical disorders when individuals are challenged again in adolescence and beyond. Comparative experiments can confirm causality inferred from correlative human studies and are necessary for establishing underlying mechanisms. Rodent models are efficient for establishing mechanisms while complementary findings in nonhuman primates increase confidence in generalizability to humans. Guinea pig pups show many similarities in filial attachment to primate infants, including a 2-stage reaction to separation: initial distress followed by depressive-like passive responses. We have shown that these depressive-like responses of guinea pig pups are mediated by inflammatory mechanisms as evidenced by accompanying fever and increased cytokine gene expression, as well as by partial reversibility with anti-inflammatory treatment. Importantly, early separation increases depressive-like behavioral and febrile responses to a further separation in adolescence. This sensitization supports the interpretation that disruption of early attachment produces neuroinflammatory burden that increases vulnerability to depression following a “second hit” in later life. Findings that a COX inhibitor attenuates the sensitized response, and that earlier separation alters expression of prostaglandin-synthesizing enzyme genes, implicates a prostaglandin (PGE-2) mechanism. In parallel studies with rhesus macaques, we showed that isolation in adulthood also produces a depressive-like behavioral response that is associated with increased markers of inflammation and is subject to sensitization following repeated separation. As in humans, this depressive-like response was enhanced in monkeys who received poor quality maternal care in infancy.

LINKING THE SOCIAL WORLD TO PHYSICAL HEALTH: INSIGHTS AND NEW DIRECTIONS

Katherine B. Ehrlich, University of Georgia, Athens, GA, United States (Primary Presenter)

Kelsey L. Corallo and Sarah M. Lyle

Social stressors (e.g., early adversity, chronic interpersonal stress, loneliness) have long been recognized as risk factors for a diverse set of poor outcomes across development, including poor physical health in adulthood. But how do these experiences “get under the skin” to shape risk for infection or disease? And how can we study these phenomena in childhood and adolescence—a developmental window during which most youth have exceptionally good health? Conceptual models point to the important role of the immune system in shaping risk for chronic diseases of aging, including heart disease and diabetes. In this talk, I will provide an overview of my research program, which focuses on links between social experiences and physical health across development. Highlights will include recent evidence documenting associations between (a) parent-child relationship experiences and children’s asthma morbidity and cytokine regulation, (b) children’s exposure to parental depression and future risk for metabolic dysregulation, and (c) maltreatment exposure and low-grade inflammation in childhood. I will conclude with a road map for the next chapter of our lab’s work, which is focused on how social and environmental stressors relate to children’s response to vaccination. These ongoing studies leverage standard vaccinations as a tool to evaluate children’s adaptive immunity—a branch of the immune system that plays an important role in fighting off infectious disease. Collectively, our work suggests that social experiences are associated with both the innate and adaptive branches of the immune system, and these links may have long-term implications for physical health.

ASSESSING THE IMPACT OF EARLY-LIFE ADVERSITY ON EMOTIONALITY AND NEUROIMMUNE FUNCTION OF ANIMALS PRENATALLY EXPOSED TO ALCOHOL

Charlis Raineki, University of British Columbia, Vancouver, BC Canada (Primary Presenter)

Tamara S. Bodnar, Parker J. Holman, and Joanne Weinberg

Prenatal alcohol exposure (PAE) impacts immune system development. Importantly, altered immune function can impact overall emotional regulation. Not surprisingly, PAE is associated with increased vulnerability to psychopathologies. Moreover, PAE carries an increased risk of being exposed to early-life adversity (ELA), which also impacts immune function and emotional regulation. Nevertheless, few studies have investigated how ELA contributes to the pervasive and long-lasting effects of PAE. Here, we evaluated whether ELA further exacerbates the vulnerability to emotional dysregulation and immune dysfunction observed following PAE. PAE and control rat litters were exposed either to limited bedding [postnatal day (PN) 8-12] to model ELA or to normal bedding. During early (PN30) or late (PN45) adolescence, male and female offspring were tested in the open field (OF) and elevated plus maze (EPM), and exposed to swim stress; blood and brains were collected following swim stress to evaluate cytokine levels. In adulthood, we evaluated peripheral and central immune system responses to immune challenge (LPS). Our results indicate that in females, PAE resulted in anxiety-like behaviors in the OF at both ages, whereas in males, PAE combined with ELA increased anxiety-like behaviors in the EPM at both ages. The behavioral alterations were associated with age-specific changes in peripheral and central cytokine levels. Moreover, different from PAE females, PAE males exposed to ELA failed to mount appropriate immune responses to LPS in adulthood. Taken together, our results suggest that altered immune function may underlie, at least in part, the emotional dysregulation observed following PAE and/or ELA.

LONG-LASTING CHANGES IN HEALTH AND IMMUNE OUTCOMES IN ADULTS WITH FETAL ALCOHOL SPECTRUM DISORDER

Tamara S. Bodnar, University of British Columbia, Vancouver, BC Canada (Primary Presenter)

Charlis Raineki, Amanda Chao, Christine Loock, Tim Oberlander, Joanne Weinberg, and the Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD)

Deficits in cognitive and executive function are well documented in children with Fetal Alcohol Spectrum Disorders (FASD); however, few studieshave followed children with FASD into adulthood and almost none have investigated health outcomes. To address this gap, the current study was designed to evaluate health outcomes in adults with FASD.Study participants include adults with FASD and unexp­­osed controls. Participants complete health questionnaires examining domains including rates of early-life adversity (ELA) and physical and mental health status. As well, blood samples are collected for a complete blood count and cytokine measurements. Preliminary results indicate that adults with FASD have elevated white blood cell counts compared to unexposed controls, and this is driven by increased neutrophils and lymphocytes. In addition, while there were no differences in autoimmune disease rates, adults with FASD report higher rates of early general symptoms of autoimmune diseases. With regards to mental health, adults with FASD have higher rates of anxiety, compared to unexposed controls. Finally, evaluation of the relationship between ELA, immune function, and mental health status indicated that adversity is a key modulator of immune and emotional dysregulation in adults with FASD. These data indicate that prenatal alcohol exposure results in life long changes in immune-related outcomes. Moreover, as inflammatory responses have been shown to play an important role in the pathophysiology of mental health problems, ongoing work aims to explore whether immune-related changes could be a driver of mental health disorders in FASD.