Molecular and Behavioral Effects of Infant Maltreatment across Generations in Rhesus Monkeys

Abstract

36Childhood maltreatment is among the most robust risk factors for subsequent psychiatric and 37 medical disorders, and data in humans and rodents suggest that effects of adverse childhood 38 experiences may be transmitted across generations. Recent indications for biological processes 39 underlying this transfer of experiential effects are intriguing; yet, their relevance in primates is 40 inconclusive due to limitations of current studies. In this study, we bridge research in rodent 41 models and humans with a natural non-human primate model on intergenerational effects of 42 childhood maltreatment. Using a unique, well-controlled, randomized cross-fostering design in 43 rhesus monkeys, we test the influence of ancestral maltreatment on molecular, neuroendocrine 44 and behavioral outcomes in offspring, and show that childhood maltreatment results in 45 transmission of information to the subsequent generation independent of behavioral 46 transmission. We further demonstrate differences in the offspring longitudinal DNA methylation 47 profile of the FKBP5 gene, an important regulator of the hypothalamus-pituitary-adrenal axis in 48 offspring of the maltreatment lineage compared to the control lineage. Finally, we show that 49 differences in FKBP5 methylation have functional effects on molecular, neuroendocrine and 50 behavioral outcomes in offspring of the maltreatment ancestral line, even if the infants were 51 never exposed to maltreatment nor interacted with their exposed ancestors. Although the 52 molecular mechanism underlying our observations remains unknown, our data point to a 53 potential germline-dependent effect. In summary, our data suggest that history of maltreatment 54 in primates can induce molecular and behavioral changes in a subsequent generation 55 independent of behavioral transmission that may influence risk for mental and physical diseases 56 across generations. 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 Exposure to childhood maltreatment is one the most important risk factors for a variety of 73 psychiatric disorders 1,2 . However, both human studies and animal models suggest that effects 74 of environmental experiences such as maltreatment extend beyond the affected individual, 75 influencing phenotypes in subsequent generations. This sparked a controversial discussion on 76 the prevalence of these phenomena, the underlying mechanisms and their biomedical relevance77 3-5 . Strong evidence exists for effects of environmental cues on offspring phenotypes when 78 exposed during in utero development 6-8 , or for the consequences of parental experience on 79 offspring phenotypes mediated by parental behavior 9 . More recently, experiments in rodents 80 suggested that pre-conceptional exposure to chemicals 10 , drugs 11 , nutritional abnormalities 12 81 and stress 13-15 can prompt intergenerational effects or even lead to transgenerational 82 inheritance of specific phenotypes 16 . These events seem independent of in utero perturbations 83 or behavioral transmission and point to p...

Profiling nonhuman primate germline RNA to understand the legacy of early life stress

“…Missing from our analyses is a profile of RNA in eggs of female rhesus macaques that had experienced maltreatment as infants. With literature demonstrating the transmission of behavioral and physiological legacies of infant maltreatment along maternal lineages of rhesus macaques (Drury et al, 2017; Klengel et al, 2019), understanding how the female germline responds to ELS will undoubtedly provide new clues as to how intergenerational legacies of stress perpetuate across generations.…”