Early life stress, FK506 binding protein 5 gene (FKBP5) methylation, and inhibition-related prefrontal function: A prospective longitudinal study

AbstractIndividuals who have experienced high levels of childhood stress are at increased risk for a wide range of behavioral problems that persist into adulthood, yet the neurobiological and molecular mechanisms underlying these associations remain poorly understood. Many of the difficulties observed in stress-exposed children involve problems with learning and inhibitory control. This experiment was designed to test individuals' ability to learn to inhibit responding during a laboratory task. To do so, we measured stress exposure among a community sample of school-aged children, and then followed these children for a decade. Those from the highest and lowest quintiles of childhood stress exposure were invited to return to our laboratory as young adults. At that time, we reassessed their life stress exposure, acquired functional magnetic resonance imaging data during an inhibitory control task, and assayed these individuals' levels of methylation in the FK506 binding protein 5 (FKBP5) gene. We found that individuals who experienced high levels of stress in childhood showed less differentiation in the dorsolateral prefrontal cortex between error and correct trials during inhibition. This effect was associated only with childhood stress exposure and not by current levels of stress in adulthood. In addition, FKBP5 methylation mediated the association between early life stress and inhibition-related prefrontal activity. These findings are discussed in terms of using multiple levels of analyses to understand the ways in which adversity in early development may affect adult behavioral adaptation.

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Abstract 17: Early Life Stress Sensitizes The Angiotensin II-elicited Hypertensive Response

Hypertension ◽

10.1161/hyp.76.suppl_1.17 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Baojian Xue ◽

Terry Beltz ◽

Fang Guo ◽

David M Pollock ◽

Jennifer S Pollock ◽

...

Keyword(s):

Mrna Expression ◽

Proinflammatory Cytokines ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Male Rats ◽

Sprague Dawley ◽

Cns Inflammation ◽

Wide Range ◽

The Brain

Separation of neonatal rodent pups from their mothers has been used as a model to study the effects of early life stress (ELS) on behavioral and physiological responses in adults. Using an Induction-Delay-Expression experimental paradigm, our previous studies demonstrate that a wide range of stressors administered during an induction period produces hypertensive response sensitization (HTRS) in response to a subsequent pro-hypertensive stimulus. HTRS is accompanied by activation of the brain renin-angiotensin system (RAS) and CNS inflammation. The present study investigated whether ELS induces HTRS and changes in brain-related underlying mechanisms. Rat neonates from Sprague-Dawley breeders were subjected to ELS by separating them each morning from their mothers for 3 h on postnatal days 2 to 14. Pups from non-handled litters formed control groups. At 10 weeks of age, male rats were used to evaluate blood pressure and autonomic function using telemetric probes and pharmacological methods. In addition, in separate control and ELS groups, the lamina terminalis (LT) structures and the hypothalamic paraventricular nucleus (PVN) were analyzed for mRNA expression of RAS components and proinflammatory cytokines. Adult ELS rats as compared to non-separated controls exhibited 1) HTRS during expression testing using 2 week ANG II infusions (120 ng/kg/min s.c.; ELS animals, Δ45.5±4.5 mmHg vs. controls, Δ22.4±3.1 mmHg); 2) a greater reduction in mean arterial pressure following ganglionic blockade (hexamethonium, 30 mg/kg, ip), 3) increased sympathetic drive to the heart (atenolol, 8 mg/kg, ip), 4) decreased vagal tone (atropine, 8 mg/kg, ip), and 5) increased mRNA expression of several components of the brain RAS and proinflammatory cytokines in the LT and PVN. These results suggest that maternal ELS may predispose individuals to hypertension that is mediated by upregulation of the brain RAS and proinflammatory cytokines and increased sympathetic drive to the cardiovascular system.

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The Dual Impact of Early and Concurrent Life Stress on Adults’ Diurnal Cortisol Patterns: A Prospective Study

Psychological Science ◽

10.1177/0956797619833664 ◽

2019 ◽

Vol 30 (5) ◽

pp. 739-747 ◽

Cited By ~ 14

Author(s):

Ethan S. Young ◽

Allison K. Farrell ◽

Elizabeth A. Carlson ◽

Michelle M. Englund ◽

Gregory E. Miller ◽

...

Keyword(s):

Life Stress ◽

High Stress ◽

Early Life Stress ◽

Stress Exposure ◽

Childhood Stress ◽

Major Life ◽

Diurnal Cortisol ◽

A Prospective Study ◽

Cumulative Model

Major life stress often produces a flat diurnal cortisol slope, an indicator of potential long-term health problems. Exposure to stress early in childhood or the accumulation of stress across the life span may be responsible for this pattern. However, the relative impact of life stress at different life stages on diurnal cortisol is unknown. Using a longitudinal sample of adults followed from birth, we examined three models of the effect of stress exposure on diurnal cortisol: the cumulative model, the biological-embedding model, and the sensitization model. As its name implies, the cumulative model focuses on cumulative life stress. In contrast, the biological-embedding model implicates early childhood stress, and the sensitization model posits that current life stress interacts with early life stress to produce flat diurnal cortisol slopes. Our analyses are consistent with the sensitization model, as they indicate that the combination of high stress exposure early in life and high current stress predict flat diurnal cortisol slopes. These novel findings advance understanding of diurnal cortisol patterns and point to avenues for intervention.

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P.220 FKBP51 loss in glutamatergic forebrain neurons and early life stress exposure shape anxiety and cognition in female mice

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2019.12.046 ◽

2020 ◽

Vol 31 ◽

pp. S33-S34

Author(s):

L. Van Doeselaar ◽

C. Engelhardt ◽

J. Bordes ◽

L. Brix ◽

J. Deussing ◽

...

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Stress Exposure ◽

Female Mice ◽

Forebrain Neurons

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Incentive effect on inhibitory control in adolescents with early-life stress: An antisaccade study

Child Abuse & Neglect ◽

10.1016/j.chiabu.2011.10.010 ◽

2012 ◽

Vol 36 (3) ◽

pp. 217-225 ◽

Cited By ~ 30

Author(s):

Sven C. Mueller ◽

Michael G. Hardin ◽

Katherine Korelitz ◽

Teresa Daniele ◽

Jessica Bemis ◽

...

Keyword(s):

Inhibitory Control ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Incentive Effect

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The adaptive and maladaptive continuum of stress responses – a hippocampal perspective

Reviews in the Neurosciences ◽

10.1515/revneuro-2014-0083 ◽

2015 ◽

Vol 26 (4) ◽

Cited By ~ 17

Author(s):

Deepika Suri ◽

Vidita A. Vaidya

Keyword(s):

Stress Responses ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Negative Consequences ◽

Functional Responses ◽

Physiological Level ◽

Early Stress ◽

Wide Range ◽

Potential Factors

AbstractExposure to stressors elicits a spectrum of responses that span from potentially adaptive to maladaptive consequences at the structural, cellular and physiological level. These responses are particularly pronounced in the hippocampus where they also appear to influence hippocampal-dependent cognitive function and emotionality. The factors that influence the nature of stress-evoked consequences include the chronicity, severity, predictability and controllability of the stressors. In addition to adult-onset stress, early life stress also elicits a wide range of structural and functional responses, which often exhibit life-long persistence. However, the outcome of early stress exposure is often contingent on the environment experienced in adulthood, and could either aid in stress coping or could serve to enhance susceptibility to the negative consequences of adult stress. This review comprehensively examines the consequences of adult and early life stressors on the hippocampus, with a focus on their effects on neurogenesis, neuronal survival, structural and synaptic plasticity and hippocampal-dependent behaviors. Further, we discuss potential factors that may tip stress-evoked consequences from being potentially adaptive to largely maladaptive.

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Adolescent Stress Increases Adult Ethanol Self-administration and Alters Ventral Tegmental Area GABA Signaling

10.1101/715607 ◽

2019 ◽

Author(s):

David A Connor ◽

Ruthie E Wittenberg ◽

Jillian Drogin ◽

Allison Mak ◽

John A Dani

Keyword(s):

Life Stress ◽

Early Life ◽

Alcohol Use Disorders ◽

Early Life Stress ◽

Male Rats ◽

Stress Exposure ◽

Self Administration ◽

Adolescent Stress ◽

Gaba Signaling

AbstractAlcohol use disorders (AUDs) continue to be a significant public health problem. Early life stress and adversity have long-lasting effects on a wide range of behaviors, including responses to drugs of abuse. Epidemiological evidence indicates that exposure to early life stress contributes to alcohol use disorders and, while it is known that stress and alcohol both act on overlapping mesolimbic circuitry, the cellular mechanisms underlying the relationship between stress and alcohol intake are not well understood. Previous work has demonstrated that acute stress increases ethanol intake mediated by changes in GABA signaling within the ventral tegmental area (VTA). Here we investigated if adolescent stress exposure might elicit long-term, persistent increases in ethanol self-administration associated with altered VTA GABA signaling. To this end, we exposed adolescent postnatal day (PND) 28 male rats to 14 days of chronic variable stress (CVS) and then examined operant ethanol self-administration begun at least 30 days later. We found that adolescent stress exposure resulted in significantly increased ethanol self-administration in adulthood. In contrast, adult (PND 82) male rats exposed to the same CVS protocol did not display increased ethanol self-administration that was begun 30 days later. Furthermore, we found that adolescent stress exposure resulted in enhancement of ethanol-induced GABA signaling onto VTA dopamine neurons and impairments in VTA GABA chloride homeostasis. The results indicate that adolescence is a period vulnerable to stress, which produces long-term changes in VTA GABA signaling associated with increased ethanol self-administration behavior.

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Early life stress exposure associated with reduced polyunsaturated-containing lipids in low-income children

Pediatric Research ◽

10.1038/s41390-020-0989-0 ◽

2020 ◽

Author(s):

Jennifer L. LaBarre ◽

Alison L. Miller ◽

Katherine W. Bauer ◽

Charles F. Burant ◽

Julie C. Lumeng

Keyword(s):

Low Income ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Stress Exposure ◽

Low Income Children

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Early-Life Stress Reduces DNA Methylation of the Pomc Gene in Male Mice

Endocrinology ◽

10.1210/en.2013-1868 ◽

2014 ◽

Vol 155 (5) ◽

pp. 1751-1762 ◽

Cited By ~ 81

Author(s):

Yonghe Wu ◽

Alexandre V. Patchev ◽

Guillaume Daniel ◽

Osborne F.X. Almeida ◽

Dietmar Spengler

Keyword(s):

Dna Methylation ◽

Life Stress ◽

Early Life ◽

Binding Protein ◽

Early Life Stress ◽

Neuroendocrine Cells ◽

Mrna Levels ◽

Male Mice ◽

Pomc Mrna ◽

Pomc Gene

Early-life stress (ELS) increases the vulnerability thresholds for stress-related diseases such as major depression and anxiety by inducing alterations in the structure and function of neural circuits and endocrine pathways. We previously demonstrated the contribution of epigenetic mechanisms to the long-term programming of the hypothalamo-pituitary-adrenal axis activity following ELS exposure in male mice. Here, ELS comprising daily separation of pups from their dams on postnatal days 1–10 was observed to up-regulate the expression of the pituitary proopiomelanocortin (Pomc) gene; POMC serves as a prohormone for ACTH, a key mediator of the adrenocortical response to stress. Detailed analysis revealed that the increase in Pomc mRNA levels results from a reduction in DNA methylation at a critical regulatory region of the Pomc gene; interestingly, this change occurs with some delay after ELS and persists for up to 1 year. Using a Pomc-expressing pituitary cell line (AtT20), we confirmed a role for DNA methylation in restraining Pomc expression under resting conditions: specifically, we show that CpG site-specific methylation of the Pomc promoter represses Pomc mRNA transcription. Further, we show high-affinity binding of methyl-CpG binding protein-2 to the distal promoter of Pomc, suggesting that methyl-CpG binding protein-2 acts in association with the chromatin modifiers histone deacetylase 2 and DNA methyltransferase 1 to repress Pomc gene expression. Collectively, these experiments contribute to our understanding of the mechanisms through which environmental cues are translated into stable changes (“cellular memory”) in neuroendocrine cells.

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