Erin L Kinnally - US grants

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The experience of early life stress puts individuals at greater risk for psychopathology later in life. Multiple neural pathways contribute to this risk, but the serotonin transporter (5-HTT) is among the foremost of these. The target of the most effective antidepressants, neural 5-HTT expression is lower in depressed patients and in victims of early life stress. Identifying the mechanism(s) of plasticity in 5-HTT gene function or of its transcription factors following early stress may therefore inform intervention strategies to improve mental health following trauma. The PI will investigate whether a well-characterized experimental early life stressor leads to dysregulation of 5-HTT and one of its major transcriptional enhancers(glucocorticoid receptor, NR3C1 or GR) in infant rhesus macaques, and whether this dysregulation is epigenetically mediated.

DESCRIPTION (provided by applicant): Early life stress is the most potent predictor of disadvantageous neurobehavioral development in human children. The validation of experimental translational animal models of early life stress will be essential to understanding how early experience affects infant development in positive and negative ways. The development of these strategies will be our best experimental avenue to develop informed intervention and prevention strategies for improving the lives of children that experience early trauma. Some well-characterized experimental animal models of early stress (e.g., maternal deprivation) are difficult to translate to the human experience. Many other manipulations exert their effects by reducing parental investment (e.g., variable foraging demand, repeated maternal separation). These manipulations work well because there are few more potent stressors for the developing infant than poor parental care (e.g., neglect or abuse). A related strategy is to observe the range of care individuals receive and determine its effects on variation in individual development. This is a powerful approach, as it allows us to determine the effects of moderate maltreatment, in addition to more extreme influences, on infant development. A significant drawback to this approach is that shared genes and environment between the mother and infant confound the investigation. Because of the potential for this gene- environment correlation, it i impossible to know, for example, whether the experience of neglect and abuse leads to adverse neurobehavioral traits, or whether shared genes between parent and offspring are associated with both poor parenting and enhanced stress reactivity. Therefore, studies of the effects of early environment must include appropriate cross-fostered (FOSTER) conditions, when one group consists of infants reared by biologically unrelated mothers. If FOSTER dyads exhibit the same relationship between early care and infant neurobehavioral development as biologically related (BIO) dyads, we can focus on environmentally mediated maternal effects. This can only be accomplished in animal models, as experimental adoption studies in humans cannot be executed for ethical reasons, and naturalistic adoption studies are confounded by the fact that adoptive parents may be selected for greater psychological and physical resources than the normal population. Rhesus macaques (Macaca mulatta) are one of the best animal models of neurobehavioral development, as they are closely related to humans, and display comparable genetic, neural, and socio-emotional complexity. Importantly, rhesus macaque mothers, like all mammalian mothers studied to date, vary in the quality of care they give to infants. The only obstacle to the effective use of macaque FOSTER dyads is that some procedures for fostering infants to rhesus macaque mothers may reduce maternal care and enhance infant stress reactivity, making them poor controls for BIO dyads. The PI proposes to determine the effects of natural variation in maternal care quality on rhesus macaque infant development while testing new FOSTER procedures to reduce the differences between FOSTER and BIO dyads. If the relationship between maternal care and infant outcomes does not differ between BIO- and FOSTER- dyads, this will represent a new platform for understanding the genetic, epigenetic, neural and experiential bases of risk and resiliency in the most translatable animal model available. PUBLIC HEALTH RELEVANCE: Human children are at greater risk for poor health following early trauma. Understanding the role of early experience in infant development is best accomplished by observing how natural variation in care relates to infant outcomes. The proposed research will do so while introducing new methods for controlling for the role of genetic relatedness between parent and offspring, an approach that is impossible to take in human research for ethical reasons. This work will be therefore conducted in one of the best translational animal models available, the rhesus macaque.

DESCRIPTION (provided by applicant): The effects of early stress can last a lifetime, affecting physical, mental, and social well-being across the lifespan. The effects of early stress may not be limited to the affected generation: trans-generational effects of early stress have been reported across species. This means that, at both the societal and individual level, the long-term health effects of early stress may be harder to alleviate than was previously understood. Identifying the mechanisms of the transgenerational effects of stress may help us understand why some stress-related traits and diseases run in families. The use of animal models to understand these transgenerational processes is critical because early life stress can be randomized and standardized in a laboratory setting. Additionally, rhesus macaques are ideal for examining the transgenerational effects of stress, as they are one of our most translatable animal models of human health and development. We have recently observed effects of fathers', but not mothers', experience of early maternal deprivation stress, or nursery rearing (NR), on infant rhesus macaque immunity and physiological stress response. Since fathers play little role in macaque postnatal development, this finding suggests that heritable factors may play a role. For many years, it would have been thought impossible that acquired changes to the genome could be passed on to offspring, because we did not know that genes could be changed in response to stress. We now know that epigenetic plasticity occurs in multiple tissues following early stress, and there is some evidence that these changes might be inherited. The proposed study will use a large sample of archived data to examine whether epigenetic factors play a role in the transgenerational health effects of NR stress in primates. Using archived samples collected from 3000 infant rhesus macaques during a standardized BioBehavioral Assessment Program available only at the California National Primate Research Center (CNPRC), we will first explore whether early NR stress epigenetically exacerbates inflammation and physiological stress response. Next, we will assess whether similar changes are observed in offspring and paternal grand-offspring of NR-exposed males. Finally, we will investigate whether NR-related epigenetic patterns are heritable via the paternal line. DNA methylation is one of the most stable epigenetic marks, so we will target promoter methylation patterns as a potential mechanism for the transgenerational effects of early stress in this study. The significance of this application is that we will use a highly translational animal model to explore how acquired stress-related health outcomes can be transmitted across generations, which may reveal new avenues for intervention to improve the health and quality of life of at-risk children and their families.

Maternal infection during pregnancy has emerged from epidemiological research as a key factor in the risk for neurodevelopmental disorders (NDD), including schizophrenia (SZ) and autism spectrum disorder (ASD). Translational animal models demonstrate that maternal immune activation (MIA) negatively affects fetal neurodevelopment and leads to the emergence of aberrant behavior later in life. Emerging evidence from rodent MIA models suggests that prenatal immune challenge induces NDD-like phenotypes not only in exposed individuals but also their descendants, suggesting that the risks of MIA may be exponentially greater than previously understood. Although epigenomic mechanisms could explain both lifetime and transgenerational effects associated with maternal infection, there are limitations in translating epigenetic findings from preclinical rodent MIA models to humans. Our research program has extended the MIA model from rodents to nonhuman primates, demonstrating that rhesus monkeys born the MIA-treated dams exhibit alterations in behavior, immune function, and neural development. Here we propose to leverage the current UC Davis Conte Center funded cohort of MIA exposed nonhuman primates to evaluate, for the first time, the effects of MIA on the primate?s epigenome. This cohort also provides an unprecedented opportunity to explore the potential transgenerational effects of MIA described in rodent models in a species more closely related to humans. We propose to examine the immune cell and germ-line epigenome in MIA-exposed and CONTROL males as they mature from adolescence into early adulthood. We will determine if these changes explain adverse neurobehavioral development in the exposed generation and also confer risk for transgenerational inheritance of MIA effects. Converging evidence from clinical and preclinical studies suggests that the epigenetic and transgenerational mechanisms explored in the proposed studies may be relevant to a number of NDDs independent of current diagnostic classifications. Thus the proposed studies may provide insight into the molecular mechanisms that link prenatal immune challenge to long-lasting brain and behavior abnormalities that are relevant to a number of human brain disorders associated with prenatal environmental insults.