Reading Week 7

Maternal Stress Induces Epigenetic Signatures of Psychiatric and Neurological Diseases in the Offspring

Authors and Affiliations

  • Fabiola C. R. Zucchi (1,2), Youli Yao (1,3), Isaac D. Ward (1), Yaroslav Ilnytskyy (3), David M. Olson (4), Karen Benzies (5), Igor Kovalchuk (3), Olga Kovalchuk (3), Gerlinde A. S. Metz (1*)

  1. Department of Neuroscience, University of Lethbridge, Lethbridge, Alberta, Canada

  2. Department of Biological Sciences, University of Mato Grosso State, Caceres, Mato Grosso, Brazil

  3. Department of Biological Sciences, University of Lethbridge, Lethbridge, Alberta, Canada

  4. Departments of Obstetrics and Gynecology, Pediatrics and Physiology, University of Alberta, Edmonton, Alberta, Canada

  5. Faculty of Nursing, University of Calgary, Calgary, Alberta, Canada

Abstract

  • Gestational State: Vulnerable period for maternal and fetal health.

  • Influence of Stress: Stress during gestation impacts maternal mental health and offspring brain development.

  • Key Findings: Fetal transcriptome responds to prenatal stress and is associated with epigenetic signatures of psychiatric and neurological diseases.

  • Methodology: Assessment focused on maternal behavior, microRNA (miRNA) profiles, and transcriptomic changes in offspring brains.

Introduction

  • Vulnerability of Gestational State:

    • Significant impact on maternal and fetal health.

    • Distress during pregnancy has long-term consequences on offspring's brain function and behavior.

  • Effects of Gestational Stress:

    • Alters postpartum maternal care, influencing offspring development.

    • Impacts maternal behavior, HPA axis function, and susceptibility to psychiatric conditions like depression, bipolar disorder, and schizophrenia.

  • Epigenetic Influences:

    • Stress potentially leads to transgenerational epigenetic programming.

    • MicroRNA expression regulated epigenetically allows adjustments in gene expression without altering DNA sequences.

    • Dysregulation seen in various psychiatric and neurological disorders.

  • Mechanistic Proposal:

    • Link between gestational stress and epigenetic reprogramming in maternal and offspring brains via miRNA modulation.

Materials and Methods

  1. Experimental Design:

    • Female Long-Evans rats were subjected to stress from gestational days 12 to 18 and assessed against non-stressed controls.

  2. Animal Subjects:

    • Caged 21 timed-pregnant nulliparous female rats prepared for study.

  3. Ethics Statement:

    • Adherence to animal care guidelines approved by the University of Lethbridge Animal Welfare Committee.

  4. Stress Procedures:

    • Stressors: Restraint (20 min), forced swimming (5 min) from gestational days 12 to 18.

  5. Behavior Analysis:

    • Scoring focused on tail chasing behavior to gauge maternal preparedness pre-delivery.

  6. Tissue Collection:

    • Postpartum collection of maternal and offspring brain tissue for analysis post-euthanasia.

  7. Gene Expression Analysis:

    • Utilized qRT-PCR and miRNA microarrays for data on gene expression changes.

  8. Statistical Analysis:

    • Used software for behavioral data and microarray results assessed via t-test and ANOVA; significance set at p < 0.05.

Results

Maternal Behavior and Epigenetic Changes

  • Significant reduction in tail chasing behavior among stressed dams compared to controls (F(1,13) = 5.35, p < 0.05).

  • 342 miRNAs showed differential expression due to stress, with 195 downregulated and 147 upregulated.

    • Specific downregulated miRNAs: miR-329, miR-380, miR-20a, let-7c, miR-23b, miR-181, miR-186.

    • Upregulated miRNA: miR-24-1.

Offspring miRNAome and Transcriptome

  • 336 miRNAs were differentially expressed in offspring brains: 205 upregulated and 131 downregulated.

  • Notable miRNA changes included:

    • Upregulated: miR-23a, miR-129-2, let-7f, miR-98, miR-9, miR-216-5p, miR-667.

    • Downregulated: miR-361, miR-425, miR-345-5p, miR-103, miR-151, miR-219-2-3p.

  • 39 genes were significantly downregulated, affecting DNA methylation, neurodevelopment, apoptosis, neurotransmission, and immune responses.

    • Certain genes like Ptplb (targeted by miR-103) showed inverse relationships.

Discussion

Consequences of Prenatal Stress

  • Maternal stress is implicated in altered brain development and associations with cognitive decline in later life.

  • Upregulation of miR-103 might contribute to increased vulnerability to cognitive decline and promotes neuropathological effects in adults.

  • miR-219 regulatory impact suggests involvement in processes associated with schizophrenia and bipolar disorder.

  • Prenatal stress influences immune function through changes in miRNA signatures relevant for conditions like multiple sclerosis, depression, and anxiety.

Epigenetic Persistence

  • Early

The study aimed to investigate how stress during gestation impacts maternal mental health and offspring brain development, specifically focusing on the fetal transcriptome's response to prenatal stress and its association with epigenetic signatures of psychiatric and neurological diseases. It proposed a link between gestational stress and epigenetic reprogramming in maternal and offspring brains via microRNA (miRNA) modulation.

The study was inspired by existing knowledge indicating that distress during pregnancy has long-term consequences on offspring's brain function and behavior. Previous findings also suggested that gestational stress alters postpartum maternal care, impacts maternal behavior, HPA axis function, and increases susceptibility to psychiatric conditions like depression, bipolar disorder, and schizophrenia. Furthermore, the understanding that stress can lead to transgenerational epigenetic programming, and that microRNA dysregulation is observed in various psychiatric and neurological disorders, fueled the investigation into the mechanistic link between gestational stress and epigenetic reprogramming via miRNA modulation.

The main findings of the study were:

  • Fetal Transcriptome Response: The fetal transcriptome responds to prenatal stress and is associated with epigenetic signatures of psychiatric and neurological diseases.

  • Maternal Behavior and Epigenetic Changes: Stressed dams showed a significant reduction in tail chasing behavior compared to controls. Additionally, 342 microRNAs (miRNAs) in maternal brains showed differential expression due to stress, with 195 downregulated and 147 upregulated (e.g., downregulated miR-329, miR-380, miR-20a, and upregulated miR-24-1).

  • Offspring miRNAome and Transcriptome Changes: In offspring brains, 336 miRNAs were differentially expressed (205 upregulated and 131 downregulated). Notable changes included upregulated miR-23a, miR-129-2, and downregulated miR-361, miR-425, miR-103, and miR-219-2-3p. Furthermore, 39 genes were significantly downregulated, impacting processes such as DNA methylation, neurodevelopment, apoptosis, neurotransmission, and immune responses, with some showing an inverse relationship with certain miRNAs (e.g., Ptplb targeted by miR-103).

This study is about how stress experienced by a mother during pregnancy can affect her unborn baby's brain development and potentially lead to epigenetic changes (changes in how genes are expressed without altering the DNA itself) that are linked to psychiatric and neurological conditions later in life. Researchers looked at how maternal stress impacts maternal behavior and, more specifically, the changes in tiny molecules called microRNAs (miRNAs) in the brains of both the mother and the offspring, which can alter gene expression.

The study found a few key things:

  1. Baby's Genes React to Stress: The genes in the unborn babies' brains changed in response to the mother's stress. These changes were linked to marks on the genes that are associated with mental health and brain disorders.

  2. Mothers' Behavior and Gene Regulators Changed: Stressed mothers were less active (specifically, they showed less tail chasing behavior) compared to mothers who weren't stressed. Also, their brains showed changes in tiny molecules called microRNAs (miRNAs), which help control how genes work. Some miRNAs went up, and some went down.

  3. Babies' Brains Showed Gene Regulator Changes: In the babies' brains, many of these small microRNA molecules also changed. Some went up, and some went down. In addition, about 39 genes became less active. These less active genes are important for things like brain development, the immune system, and how brain cells communicate. Sometimes, when a certain microRNA changed, its target gene showed an opposite change, meaning the microRNA was likely influencing that gene.