Early-life stress has persistent effects on amygdala function and development in mice and humans

Abstract

Relatively little is known about neurobiological changes attributable to early-life stressors (e.g., orphanage rearing), even though they have been associated with a heightened risk for later psychopathology. Human neuroimaging and animal studies provide complementary insights into the neural basis of problem behaviors following stress, but too often are limited by dissimilar experimental designs. The current mouse study manipulates the type and timing of a stressor to parallel the early-life stress experience of orphanage rearing, controlling for genetic and environmental confounds inherent in human studies. The results provide evidence of both early and persistent alterations in amygdala circuitry and function following early-life stress. These effects are not reversed when the stressor is removed nor diminished with the development of prefrontal regulation regions. These neural and behavioral findings are similar to our human findings in children adopted from orphanages abroad in that even following removal from the orphanage, the ability to suppress attention toward potentially threatening information in favor of goal-directed behavior was diminished relative to never-institutionalized children. Together, these findings highlight how early-life stress can lead to altered brain circuitry and emotion dysregulation that may increase the risk for psychopathology.anxiety | emotion regulation | infralimbic cortex | c-fos | cross-species E arly-childhood adversity (e.g., abuse, neglect) accounts for over 30% of all anxiety disorders (1) and is associated with later emotional and behavioral dysregulation (2-6). One form of early-life stress (ELS) in humans that has received significant attention is that of orphanage rearing (7-11). It is estimated that eight million children live in orphanages worldwide. Children adopted from these orphanages provide a unique opportunity to assess the effects of ELS with a discrete timing and offset (12, 13). However, it is unclear to what extent emotional and behavioral dysregulation reported in this population is the result of the orphanage experience of disorganized care or attributable to preexisting conditions (e.g., prenatal exposure to substances, maternal malnutrition, and/or congenital disorders) (12). Moreover, we know little about the long-term effects of such early-life experiences and whether they reverse after the stressor is removed. The current study examines these issues using a rodent model of ELS (14, 15) and an outcome measure that uniquely parallels human paradigms to test for immediate and long-term effects of stress across development while controlling for preexisting environmental and genetic factors.To date, most animal studies of stress have either focused on the effects of adult stress or on how early stress impacts later adult brain and behavior. The findings have been mixed depending on the type and timing of the stressor and the specific task and age of testing. Adult-restraint stress leads to reversible decreases in dendritic arborization and volume in...

Social Origins of Developmental Risk for Mental and Physical Illness

“…To address this, an alternative limited-bedding paradigm was initially developed in rats (Gilles et al, 1996), obviating the requirement for overt separation of pups and dams typically used in rodent ELS models . This paradigm induces inconsistent and fragmented maternal care (Heun-Johnson and Levitt, 2016), which has since been validated and adopted for use with mice by multiple laboratories Wang et al, 2011Wang et al, , 2013Gunn et al, 2013;Malter Cohen et al, 2013;Liao et al, 2014;Kohl et al, 2015;Naninck et al, 2015;Yang et al, 2015;Arp et al, 2016;Bath et al, 2016Bath et al, , 2017Liu et al, 2016;McIlwrick et al, 2016McIlwrick et al, , 2017Yam et al, 2017). The paradigm provides an ethologically relevant framework for addressing heritability of risk-, sex-, and developmentally dependent influences that determine outcomes following ELS.…”

Hygiene and Other Early Childhood Influences on the Subsequent Function of the Immune System

“…Moreover perinatal maternal anxiety affects early development of the hippocampus (Qiu et al, 2013), and a history of childhood trauma is manifested as a smaller hippocampal volume in women with major depression (Vythilingam et al, 2002). Early-life stress also induces persistent alterations in amygdala circuitry and function in mice and humans (Malter Cohen et al, 2013).…”

Toward Understanding How Early-Life Stress Reprograms Cognitive and Emotional Brain Networks

“…Accordingly, the central nervous system is equipped with several sensing mechanisms to identify stress, as well as processes to respond to stressful signals and be modified by them. Cognitive brain networks, including those centered on the hippocampus and prefrontal cortex regions involved in emotional processes, such as amygdala and the nucleus accumbens, as well as network involved in social behaviors, appear to be particularly vulnerable to the effects of stress (Kim and Diamond, 2002;Joëls and Baram, 2009;Lupien et al, 2009;Malter Cohen et al, 2013;Sandi and Haller, 2015). Important parameters that govern the effects of stress on brain functions include the context and nature of the stress (Zoladz and Diamond, 2008;Joëls and Baram, 2009;McEwen and Gianaros, 2011;Schwabe et al, 2011).…”