Differential impact of chronic adolescent stress on the glucocorticoid receptor in adult male and female rats Público
Rowson, Sydney (Summer 2018)
Abstract
Chronic stress exposure is an important risk factor in the development of disease, and the consequences of exposure to chronic stress may differ in males and females. Furthermore, adolescents undergo extensive neural and neuroendocrine maturation and may be particularly vulnerable to the disruptive effects of chronic stress exposure. A rat model of chronic adolescent stress (CAS) exposure has been useful in studying the sex-specific consequences of CAS. Previously, female, but not male, rats exposed to CAS were found to exhibit enhanced depressive-like behaviors in adolescence. Interestingly, these sex-specific behavioral effects persisted to adulthood. While sex-specific alterations in regulation of the glucocorticoid receptor (GR) exist in adolescence, whether molecular consequences of CAS persist into adulthood is not known. Because the GR is integral in regulation of the stress response and has been implicated in the sex-specific effects of CAS, the studies in this dissertation assessed the extent to which CAS exposure alters regulation and activity of the GR in adult rats in a sex-specific manner. Adult female rats with a history of CAS exposure exhibited reduced nuclear GR localization following exposure to an acute stressor (Chapter 2), consistent with observations in adolescents, indicating that the effects of CAS on GR localization persist in the hippocampus. Adult females exposed to CAS also exhibited increased basal gene expression of Fkbp5, a co-chaperone of the GR that reduces its translocation efficiency, and increased interactions with FKBP5 following acute stressor exposure (Chapter 3). Furthermore, CAS altered global transcription in the adult hippocampus differently in males and females, and females had predicted increased activity of the GR following acute stressor exposure (Chapter 4). Together, these data indicate that CAS alters adult regulation and activity of the GR into adulthood, months removed from stressor exposure. Furthermore, the prolonged effects of CAS are sex-specific. These studies establish that there are long-term consequences of exposure to stressors in adolescence on hippocampal regulation of the GR in adulthood.
Table of Contents
Chapter 1: Introduction: The glucocorticoid receptor in chronic stress and disease...1
Consequences of chronic stress...1
Mechanisms involved in the stress response: HPA axis...4
The glucocorticoid receptor in adolescent stress...8
Mechanisms of glucocorticoid receptor regulation...10
Summary and Conclusions...17
Chapter 2: Chronic adolescent stress alters adult hippocampal localization of the glucocorticoid receptor...19
Introduction...19
Methods...21
Results...27
Discussion...34
Chapter 3: Chronic adolescent stress alters FKBP5 interaction with the glucocorticoid receptor...38
Introduction...38
Methods...40
Results...45
Discussion...53
Chapter 4: Transcriptional effects of chronic adolescent stress in the hippocampus are prolonged and sex-specific...58
Introduction...58
Methods and Materials...60
Results...65
Discussion...77
Chapter 5: General Discussion...83
Introduction...83
CAS alters hippocampal GR regulation in a sex-specific manner...84
Global Impact of CAS: Insights from RNA sequencing...86
Potential mechanisms contributing to altered GR-FKBP5 interactions...88
Potential for a role of ESR1...92
Estrogen receptor and FKBP5...93
Sex and CAS Effects...94
FKBP5 targeted therapeutics: Implications for neuropsychiatric disease...95
Potential effects of CAS in additional brain regions...99
Consequences of altered GR: Implications for cognitive behaviors...100
Conclusions...103
References...105
Appendix I: Locomotor sensitization to cocaine in adolescent and adult female Wistar
rats...132
Introduction...132
Methods...133
Results...137
Discussion...141
Appendix I References...146
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