Chronic Adolescent Stress Differentially Sensitizes Neuro-Immune Reactivity in Male and Female Rats Restricted; Files Only

Bekhbat, Mandakh (Spring 2018)

Permanent URL: https://etd.library.emory.edu/concern/etds/1g05fb61q?locale=en
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Abstract

 

Adversity early in life is a reliable predictor of psychiatric disorders such as depression and anxiety which are increasingly recognized to have an immune component. However, the mechanisms by which early life adversity promotes inflammation are not yet fully defined. Using a chronic adolescent stress (CAS) model in rats, I tested the hypothesis that a history of CAS exaggerates induction of the pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) pathway in the adult rat hippocampus without impacting the peripheral immune response. I also assessed potential sex differences because it is unclear whether females, who are twice as likely to suffer from mood and anxiety disorders as males, are disproportionally affected by stress-primed inflammation. Male and female adolescent rats underwent a CAS paradigm or received no stress. Five weeks following the last stressor all rats received a single, systemic injection of either lipopolysaccharide (LPS) or vehicle to unmask possible immune-priming effects of CAS. Through a series of experiments, I demonstrated evidence of central immune sensitization in female CAS rats and both peripheral and central immune sensitization in male CAS rats. These changes were epitomized by an exaggerated NFκB-driven hippocampal transcriptome and altered glucocorticoid receptor signaling in response to LPS. Collectively, these results illustrate one mechanism via which early life adversity promotes neuroinflammation and associated behavioral deficits, and address potential sex-specific mechanisms of CAS-mediated immune priming. I conclude that chronic stress experienced during adolescence leads to enduring changes to immune reactivity in both males and females, and that the mechanism and manifestation of such alterations may be sex-specific. 

Table of Contents

 

CHAPTER 1: CHRONIC STRESS, MOOD DISORDERS, AND NFΚB.. 1

 

1.1.     Mood disorders as imbalance of stress and immune signaling. 2

 

1.2.     The neuro-immune axis and its effectors. 11

 

1.3.     NFΚB, chronic stress, and mood disorders. 14

 

1.4.     Impact of sex and the adolescent period on stress-related inflammation. 24

 

1.5.     Specific aims of this dissertation. 36

 

CHAPTER 2: CHRONIC ADOLESCENT STRESS SEX-SPECIFICALLY ALTERS CENTRAL AND PERIPHERAL NEURO-IMMUNE REACTIVITY IN RATS. 40

 

2.1.     Abstract 41

 

2.2.     Introduction. 43

 

2.3.     Methods. 46

 

2.4.     Results. 50

 

2.4.1.      CAS leads to decreased weight 50

 

2.4.2.      CAS exaggerates NFκB-related inflammatory gene expression in the hippocampus  52

 

2.4.3.      CAS enhances hippocampal IL1B mRNA expression in female rats. 53

 

2.4.4.      CAS exaggerates peripheral immune reactivity in males. 55

 

2.4.5.      CAS leads to blunted corticosterone response to LPS in males. 59

 

2.5.     Conclusions. 61

 

CHAPTER 3: CHRONIC ADOLESCENT STRESS CAUSES ENDURING ALTERATIONS TO THE ADULT NEUROIMMUNE TRANSCRIPTOME.. 66

 

3.1.     Abstract 67

 

3.2.     Introduction. 69

 

3.3.     Methods. 71

 

3.4.     Results. 76

 

3.4.1.      RNA-Seq reveals differentially expressed genes and pathways. 76

 

3.4.2.      NFκB signaling pathway is enriched to a greater extent in the hippocampus of CAS rats following LPS. 81

 

3.4.3.      CAS potentiates the induction of canonical and non-canonical NFκB pathway members in the hippocampus of male and female rats. 82

 

3.4.4.      CAS potentiates GR signaling in the hippocampus of female rats. 84

 

3.4.5.      CAS potentiates chemokine signaling in the hippocampus of male and female rats  87

 

3.5.     Discussion. 88

 

CHAPTER 4: CHRONIC ADOLESCENT STRESS LEADS TO AN ANXIETY-LIKE PHENOTYPE THAT IS ASSOCIATED WITH ALTERED IMMUNE CELL PROPERTIES. 94

 

4.1.     Abstract 95

 

4.2.     Introduction. 96

 

4.3.     Methods. 97

 

4.4.     Results. 102

 

4.4.1.      CAS leads to anxiety-like behavior in the open field in adolescence. 102

 

4.4.2.      CAS males display anxiety-like behavior during social interaction in adulthood  103

 

4.4.3.      CAS does not alter the number of total microglia in the hippocampus. 105

 

4.4.4.      CAS does not impact leukocyte infiltration or MHC-II presentation by microglia  106

 

4.4.5.      Adolescent behavior is associated with microglial number in adulthood. 110

 

4.5.     Discussion. 112

 

CHAPTER 5: CONCLUSIONS AND FUTURE DIRECTIONS. 117

 

5.1.     CAS-induced changes to NFkB-GR dynamics. 118

 

5.2.     Cellular origin of exaggerated neuro-immune reactivity in CAS rats. 120

5.3.      Sex differences in stress-induced neuro-inflammation  122

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