Jessica Rene' Raper - US grants

Abstract: A strong link between early life stress/adversity (ELS/ELA) and age-related disorders, such as cardiometabolic disease, cognitive and psychiatric/neurological disorders, have been established mostly based on retrospective human reports. Yet, prospective, longitudinal, studies across the life span are critical to identify biomarkers of ELA risk embedded earlier in life, during middle age to develop early intervention strategies. Animal models with short life spans (invertebrates, rodents) have significant limitations to inform about human aging and the therapeutics developed from those models have failed in clinical trials. Longitudinal nonhuman primate (NHP) studies could provide significant information on early biological and neural markers of ELA-related cognitive decline due to their long life span and gradual aging-related cognitive impairments and brain pathology similar to those in humans emerging in middle age. This proposal builds on our data linking ELA in macaques with early markers of accelerated cellular aging (accelerated DNA methylation age, shortened telomere length), inflammation, and neurocognitive alterations detectable from infancy to young adulthood. The goal is to use a prospective, longitudinal design in NHPs to identify early biomarkers/pathways and underlying mechanisms of ELA-related accelerated neural aging trajectories and cognitive decline from young adulthood to middle age. This unique population of adult female macaques with ELA (social subordination stress) are currently living in social groups at the Yerkes National Primate Research Center and were longitudinally characterized from birth through puberty as part of NIH-funded studies. These animals (High-ELA: subordinates; low-ELA: dominant) will be studied longitudinally between 7(early adulthood) and 11 (middle age) years of age. Aim 1 will examine trajectories of ELA-accelerated neural aging in brain regions that control cognitive and stress/emotional functions studied in Aim 2 (prefrontal cortex -PFC-, hippocampus -HIPP-, amygdala); it will use (a) MRI, DTI and resting state fMRI to examine myelin loss, cortical thinning and loss of long-range connectivity; (b) measures of neuropathology with MR spectroscopy (reductions in N-Acetylaspartate) and markers preceding dementia in humans (reduced amyloid ?(A?42)/tau ratio in CSF); and (c) markers of neuroinflammation and neurotoxicity (CSF levels of kynurenine pathway metabolites). Aim 2 will test whether ELA accelerates age- related deficits in stress/emotional regulation mediated by PFC-amygdala circuits (HPA axis, Human Intruder and dot-probe tasks), and cognition: attention (continuous performance task), executive function and cognitive flexibility mediated by PFC circuits (Intradimensional/Extradimensional discrimination), and spatial relational memory mediated by HIPP-PFC circuits (spatial memory span). Aim 3 will examine associations between longitudinal trajectories of neural measures (Aim 1) and cognitive outcomes (Aim 2); we will use innovative longitudinal statistical approaches developing individualized trajectory biomarkers of risk and resilience that move beyond association to establishing statistical causation. The hypothesis is that the ELA group will show early biomarkers of stress and accelerated trajectories of biological and neurocognitive aging in middle age.

PROJECT SUMMARY / ABSTRACT Intense research has focused on the neurologic effects of prenatal Zika virus (ZIKV) infection; however, the consequences of postnatal infection early in life are understudied. Infants exposed to ZIKV in utero but born without microcephaly can develop postnatal microcephaly, neurologic dysfunction, and neurodevelopmental ab- normalities, highlighting the potential of ZIKV to cause ongoing damage after birth. This damage is likely related to the exponential maturation of the brain that occurs during the first 2 years of life, particularly in temporal, prefrontal and parietal regions important for emotional, social and executive functions, including learning, atten- tion and memory. Our group has previously reported that postnatal ZIKV infection causes abnormalities in brain structure, function, and behavior in a pilot study of infant rhesus macaques (RMs) infected postnatally. Here, we propose to extend the scope and duration our prior pilot study and generate novel data regarding the impact of postnatal ZIKV infection on the developing brain. The Objective of this application is to bring new mechanistic insights into postnatal ZIKV infection to address the existing knowledge gap regarding outcomes and host-virus interactions. We will use our postnatal ZIKV-RM model to interrogate the neurobehavioral impact of ZIKV infection at different stages of postnatal brain develop- ment, with approaches that span from single cells to whole animal. This model of postnatal ZIKV exposure allows us to generate key data on the mechanisms by which ZIKV and/or the immune response to infection leads to cellular changes that ultimately result in aberrant postnatal development of limbic structures and behavioral def- icits later in life. We hypothesize that 1) ZIKV and/or the immune response to infection disproportionately affects limbic structures in the postnatally developing brain; 2) cellular changes in these limbic structures lead to aberrant neurodevelopment and abnormal behaviors; and 3) there may be a period of vulnerability to ZIKV during post- natal brain development. We will test our hypotheses in these Specific Aims: 1) Determine the spectrum of abnormal behavior and cognition following ZIKV infection of infant RMs at different stages of brain development; 2) Identify developmental trajectories of brain structure and function following postnatal ZIKV infection of infant RMs at different stages of brain development; and 3) Define the neurodevelopmental pathways and cell types impacted by postnatal ZIKV infection. This work will include RM infants infected with ZIKV at 1 or 6 months of age (equivalent to 4 and 24 month old humans) as well as age- and rearing-matched and viral mimic controls, that over their first 2 years of life will undergo a series of detailed assessments including validated tests of soci- oemotional behavior and cognition, structural and functional brain imaging, brain histology, stereology and single cell and bulk cell transcriptomics. Our results may have important public health implications for children living in ZIKV-endemic/epidemic areas as well as for travelers to these regions.