Exposure to different early-life stress experiences results in differentially altered DNA methylation in the brain and immune system

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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Effects of Early-Life Stress on the Brain and Behaviors: Implications of Early Maternal Separation in Rodents

International Journal of Molecular Sciences ◽

10.3390/ijms21197212 ◽

2020 ◽

Vol 21 (19) ◽

pp. 7212

Author(s):

Mayumi Nishi

Keyword(s):

Child Abuse ◽

Hpa Axis ◽

Brain Function ◽

Life Stress ◽

Early Life ◽

Maternal Separation ◽

Early Life Stress ◽

Emotional Behavior ◽

Neural Basis ◽

The Brain

Early-life stress during the prenatal and postnatal periods affects the formation of neural networks that influence brain function throughout life. Previous studies have indicated that maternal separation (MS), a typical rodent model equivalent to early-life stress and, more specifically, to child abuse and/or neglect in humans, can modulate the hypothalamic–pituitary–adrenal (HPA) axis, affecting subsequent neuronal function and emotional behavior. However, the neural basis of the long-lasting effects of early-life stress on brain function has not been clarified. In the present review, we describe the alterations in the HPA-axis activity—focusing on serum corticosterone (CORT)—and in the end products of the HPA axis as well as on the CORT receptor in rodents. We then introduce the brain regions activated during various patterns of MS, including repeated MS and single exposure to MS at various stages before weaning, via an investigation of c-Fos expression, which is a biological marker of neuronal activity. Furthermore, we discuss the alterations in behavior and gene expression in the brains of adult mice exposed to MS. Finally, we ask whether MS repeats itself and whether intergenerational transmission of child abuse and neglect is possible.

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Early life stress induces age-dependent epigenetic changes in p11 gene expression in male mice

Scientific Reports ◽

10.1038/s41598-021-89593-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mi Kyoung Seo ◽

Jung Goo Lee ◽

Sung Woo Park

Keyword(s):

Gene Expression ◽

Dna Methylation ◽

Histone Acetylation ◽

Histone Methylation ◽

Life Stress ◽

Early Life ◽

Age Groups ◽

Early Life Stress ◽

Epigenetic Modifications ◽

Age Dependent

AbstractEarly life stress (ELS) causes long-lasting changes in gene expression through epigenetic mechanisms. However, little is known about the effects of ELS in adulthood, specifically across different age groups. In this study, the epigenetic modifications of p11 expression in adult mice subjected to ELS were investigated in different stages of adulthood. Pups experienced maternal separation (MS) for 3 h daily from postnatal day 1 to 21. At young and middle adulthood, behavioral test, hippocampal p11 expression levels, and levels of histone acetylation and methylation and DNA methylation at the hippocampal p11 promoter were measured. Middle-aged, but not young adult, MS mice exhibited increased immobility time in the forced swimming test. Concurrent with reduced hippocampal p11 levels, mice in both age groups showed a decrease in histone acetylation (AcH3) and permissive histone methylation (H3K4me3) at the p11 promoter, as well as an increase in repressive histone methylation (H3K27me3). Moreover, our results showed that the expression, AcH3 and H3Kme3 levels of p11 gene in response to MS were reduced with age. DNA methylation analysis of the p11 promoter revealed increased CpG methylation in middle-aged MS mice only. The results highlight the age-dependent deleterious effects of ELS on the epigenetic modifications of p11 transcription.

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S.01.02 The interplay between early-life stress and neuroinflammation on structure and function of the brain throughout life

European Neuropsychopharmacology ◽

10.1016/j.euroneuro.2018.11.915 ◽

2019 ◽

Vol 29 ◽

pp. S4-S5

Author(s):

A. Korosi

Keyword(s):

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Structure And Function ◽

And Function ◽

The Brain

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Lasting Differential Effects on Plasticity Induced by Prenatal Stress in Dorsal and Ventral Hippocampus

Neural Plasticity ◽

10.1155/2016/2540462 ◽

2016 ◽

Vol 2016 ◽

pp. 1-10 ◽

Cited By ~ 17

Author(s):

Gayane Grigoryan ◽

Menahem Segal

Keyword(s):

Prenatal Stress ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Brain Structures ◽

Traumatic Experience ◽

Stressful Stimulation ◽

The Brain ◽

Two Sectors ◽

Structure And Functions

Early life adversaries have a profound impact on the developing brain structure and functions that persist long after the original traumatic experience has vanished. One of the extensively studied brain structures in relation to early life stress has been the hippocampus because of its unique association with cognitive processes of the brain. While the entire hippocampus shares the same intrinsic organization, it assumes different functions in its dorsal and ventral sectors (DH and VH, resp.), based on different connectivity with other brain structures. In the present review, we summarize the differences between DH and VH and discuss functional and structural effects of prenatal stress in the two sectors, with the realization that much is yet to be explored in understanding the opposite reactivity of the DH and VH to stressful stimulation.

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