Energetic Stress: The reciprocal relationship between energy availability and the stress response Open Access

Shreckengost, Constance Scott Harrell (2015)

Permanent URL: https://etd.library.emory.edu/concern/etds/2r36tz29m?locale=en
Published

Abstract

Cerebral structure and function are intrinsically dependent on the brain's ability to avail itself of energy. In turn, perturbations to energy availability alter cerebral structure and function. The stress response, mediated through the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system, shifts energy allocation to maximize availability to structures of most need. Under chronic stress, these shifts in energy availability can become maladaptive. HPA axis dysfunction related to chronic stress is linked to disorders including obesity, diabetes, and cardiovascular disease. As these epidemics of obesity and metabolic syndrome continue to expand, investigating the reciprocal relationship between energy availability and the stress response is imperative to addressing the neuropsychiatric implications of these conditions. In Part One of this dissertation, I examine the environmental and hormonal influences on markers of cerebral metabolism, namely, glucose transporters. I demonstrate that psychosocial and inflammatory stressors modulate cerebral glucose transporter expression in a region- and sex-dependent manner. Ovarian steroids regulate regional expression of these same transporters, which may be relevant to sex differences in the stress response. In Part Two, after reviewing the diverse contributors to cerebral metabolism, I shift focus to examine how a dietary influence on energy availability - i.e., a high-fructose diet - alters the stress response. I present evidence of the effects of this diet on metabolic, hormonal, and behavioral outcomes, indicating that high-fructose diet initiated during adolescence promotes a negative metabolic phenotype as well as depressive- and anxiety-like behavior. Periadolescent high-fructose diet also remodels the hypothalamic transcriptome, with a particular impact on POMC processing and additional effects on inflammatory and dopaminergic pathways. In addition, high-fructose diet remodels cerebral vasculature without affecting behavioral outcomes after cerebral ischemia. Taken together, the evidence presented indicates that exposure to stressors including psychosocial stress, inflammatory stress, and physical injury shift brain and behavior to alter energy availability. On the other hand, changes in energy availability, elicited through a high-fructose diet, can alter the stress response. Thus, this dissertation demonstrates that the reciprocal relationship between energy availability and the stress response is far-reaching, affecting the immune system, the endocrine system, limbic circuitry, and cerebral vasculature.

Table of Contents

TABLE OF CONTENTS

GENERAL INTRODUCTION…………………………………………………………..…………………...1

1. Energetic stress: Disruptions to energy homeostasis alter the stress response…………….……..2

1.0 Abstract - 2

1.1 Introduction - 3

1.2 Overview of the hypothalamic role in regulating energy and the stress response - 4

1.2.1 The hypothalamus as a regulator of energy homeostasis - 5

1.2.2 Relationship between metabolism and stress-induced activation of the HPA axis -6

1.3 Influence of energy homeostasis on the stress response -7

1.3.1 Dietary imbalance disrupts HPA axis signaling - 8

1.3.2 Disrupted energy homeostasis impairs central glucocorticoid signaling - 10

1.3.3 Disruption of energy homeostasis alters glucocorticoid signaling in peripheral tissues - 12

1.3.4 Disruptions to energy homeostasis induce hyperactivity of the sympathetic nervous system - 13

1.3.5 Change in energy homeostasis disrupts signaling of neuroendocrine and neuropeptide factors that interact with the HPA axis - 15

1.3.6 Disruptions to energy homeostasis alter the HPA axis response to inflammatory stimuli - 17

1.3.7 Disruptions of energy homeostasis modulate the gut-brain axis to dysregulated the HPA axis - 19

1.4 Discussion - 23

PART ONE………………………………………………………………………………………….27

2. Psychosocial and Inflammatory Stressors Modulate Regional Glucose Transporter Expression in a Sexually-Dimorphic Manner………………………………………………………………..35

2.1 Abstract - 35

2.1 Introduction - 36

2.2 Materials and Methods - 39

2.2.1 Animals - 39

2.2.2 Experimental Design - 40

2.2.3 Mixed Modality Chronic Stress - 41

2.2.4 Vaginal Lavage - 41

2.2.5 Quantitative RT-PCR - 42

2.2.6 Statistical Analysis - 43

2.3 Results - 43

2.3.1 Hypothalamic GLUT1 and GLUT4 mRNA abundance increases with age and is sexually dimorphic - 43

2.3.2 Hippocampal mRNA Abundance of GLUT3, GLUT4, and GLUT5 decreases with age in males and females - 44

2.3.3 Neither sex nor age impact mRNA abundance of GLUTs in the amygdala or prefrontal cortex - 44

2.3.4 Chronic stress reduces weight gain - 44

2.3.5 Chronic stress interacts with stress and age to alter hypothalamic GLUT mRNA abundance - 45

2.3.6 Chronic stress interacts with stress and age to increase hippocampal GLUT mRNA abundance - 45

2.3.7 Chronic stress interacts with stress and age to increase GLUT mRNA abundance in the male amygdala - 46

2.3.8 Chronic stress does not alter GLUT mRNA abundance in the prefrontal cortex - 46

2.3.9 Effects of adolescent chronic stress on hippocampal GLUT mRNA abundance persist into adulthood in a sexually dimorphic manner - 47

2.3.10 Adolescent chronic stress blunts the male increase in hippocampal GLUT mRNA abundance after LPS - 47

2.4 Discussion - 48

3. Estrous cycle and ovariectomy influence regional expression of cerebral glucose transporter isoforms…63

3.0 Abstract - 63

3.1 Introduction - 63

3.2 Materials and Methods - 66

3.2.1 Animal Husbandry - 66

3.2.2 Cycle Staging - 66

3.2.3 Plasma Hormone Analysis - 67

3.2.4 Ovariectomy - 67

3.2.5 Quantitative RT-PCR - 68

3.2.6 Statistical Analysis - 69

3.3 Results - 69

3.3.1 Estrous cycle stage was established from vaginal lavage and confirmed with uterine weights and hormone concentrations - 69

3.3.2 The hippocampus and hypothalamus demonstrate a greater relative abundance of GLUT mRNA than the prefrontal cortex - 70

3.3.3 The hippocampus and prefrontal cortex demonstrate greater cycle-dependent variation in gene expression for GLUTs than the hypothalamus - 71

3.3.4 Expression of GLUT1, 3, and 8 in the hippocampus is directly influenced by ovarian hormones - 71

3.4 Discussion - 71

INTERLUDE…………………………………………………………………………………..84

4. Contributors to cerebral energy metabolism……………………………………………………85

4.0 Abstract - 85

4.1 Review

PART TWO…………………………………………………………………………………………78

5. High-fructose diet initiated during adolescent development influences metabolism, behavior, and the HPA axis in male rats…………………………………………………………………………92

5.0 Abstract - 92

5.1 Introduction - 93

5.2 Materials and Methods - 94

5.2.1 Animal Husbandry - 94

5.2.2 Diet and Metabolic Measurement - 95

5.2.3 Fat Pad Collection - 97

5.2.4 Mixed Modality Stress - 97

5.2.5 Glucose Tolerance Test - 98

5.2.6 Insulin Analysis - 99

5.2.7 Behavioral Testing - 99

5.2.8 Corticosterone Analysis - 100

5.2.9 Whole Transcriptome RNA sequencing - 100

5.2.10 Pathway Analysis - 101

5.2.11 Quantitative RT-PCR - 102

5.2.12 Statistical Analysis - 104

5.3 Results - 104

5.3.1 Periadolescent high-fructose diet increases caloric efficiency, fasting glucose, and visceral fat pad mass - 104

5.3.2 Periadolescent high-fructose diet and stress alter weight gain and fasting glucose - 105

5.3.3 Periadolescent high-fructose diet alters gene expression of hippocampal glucose transporter-1 after a glucose challenge or acute stress - 106

5.3.4 Periadolescent high-fructose feeding does not alter gene expression of glucocorticoid signaling factors - 107

5.3.5 Periadolescent high-fructose diet increases anxiety-like behaviors -107

5.3.6 Periadolescent high-fructose diet increases depressive-like behaviors - 108

5.3.7 Periadolescent high-fructose diet interacts with acute stress to alter plasma corticosterone - 109

5.3.8 Periadolescent high-fructose diet remodels the hypothalamic transcriptome with greatest impact on POMC processing - 109

5.3.9 High-fructose diet upregulates hypothalamic expression of Pomc and Crfr1 when consumed during periadolescence but only Pomc when consumed during adulthood - 110

5.4 Discussion - 111

6. High-fructose diet initiated during adolescent development increases expression of innate immune factors in male rats …………………………………………………………………140

6.0 Abstract - 140

6.1 Introduction - 141

6.2 Materials and Methods - 143

6.2.1 Animal Husbandry - 143

6.2.2 Diet - 144

6.2.3 Whole Transcriptome RNA-sequencing - 144

6.2.4 Pathway Analysis - 145

6.2.5 Quantitative RT-PCR - 146

6.2.6 Immunoblotting - 147

6.2.7 Statistical Analysis - 148

6.3 Results - 148

6.3.1 High-fructose diet consumption remodels hypothalamic gene expression - 149

6.3.2 Hypothalamic immune response and inflammatory pathways are significantly enriched with transcripts altered by fructose consumption - 149

6.3.3 Hypothalamic expression of classical, lectin-induced, and alternative complement pathways are significantly enriched with transcripts altered by fructose consumption - 149

6.3.4 Rats fed a high-fructose diet during adolescent development have increased expression of complement components C4b and Cfb - 149

6.3.5 Rats fed a high-fructose diet only in adulthood do not show increased hypothalamic expression of complement components C4b and Cfb - 150

6.3.6 Increased expression of complement components C4b and Cfb extends from the hypothalamus to the hippocampus in rats fed a high-fructose diet during periadolescence but not adulthood - 150

6.3.7 Synaptophysin and post-synaptic density 95 are not differentially expressed in the hippocampus of periadolescent fructose-fed rats - 151

6.3.8 Expression of complement factors predicts expression of synaptic markers in the hippocampus - 151

6.4 Discussion - 152

7. High-fructose diet initiated during adolescent development alters hypothalamic expression of mRNA related to dopamine synthesis and signaling without affecting protein expression in male rats………………………………………………………………………………………….…172

7.0 Abstract - 172

7.1 Materials and Methods - 175

7.1.1 Animal Husbandry - 176

7.1.2 Diet - 176

7.1.3 Whole-transcriptome RNA sequencing - 176

7.1.4 Pathway analysis - 177

7.1.5 Prolactin Analysis - 178

7.1.6 Immunoblotting - 178

7.1.7 Statistical Analysis - 179

7.2 Results - 180

7.2.1 Fructose and chow diets determine clustering of the hypothalamic transcriptome - 180

7.2.2 Periadolescent fructose-feeding alters expression of genes in dopamine signaling pathways - 180

7.2.3 Plasma prolactin is not significantly altered in either periadolescent or adult fructose-fed rats - 181

7.2.4 Plasma prolactin predicts dopamine transporter, tyrosine hydroxylase, and vesicular monoamine transporter-2 gene expression in RNA-sequencing - 181

7.2.5 Tyrosine hydroxylase, vesicular monoamine transporter-2, and dopamine transporter expression were unaffected by fructose-feeding in the dorsal striatum of both periadolescent and adult rats - 182

7.2.6 Periadolescent fructose-feeding did not alter tyrosine hydroxylase or vesicular monoamine transporter-2 protein expression in the hypothalamus, nucleus accumbens, and ventral tegmental area - 182

7.3 Discussion - 183

8. High-fructose diet initiated during adolescent development promotes cerebrovascular remodeling but does not alter behavioral outcomes after middle cerebral artery occlusion in male rats ……………………199

8.0 Abstract - 199

8.1 Introduction - 199

8.2 Materials and Methods - 202

8.2.1 Animal Husbandry - 202

8.2.2 Diet - 202

8.2.3 Metabolic Assessments - 203

8.2.4 Corticosterone analysis - 204

8.2.5 Quantitative RT-PCR - 204

8.2.6 Blood-brain-barrier Permeability - 205

8.2.7 Vascular Length - 206

8.2.8 Surgery - 207

8.2.9 Neurologic Behavior Assessment - 207

8.2.10 Affective Behavior Assessment - 209

8.2.11 Lesion Volume Assessment - 210

8.2.12 Statistical Analysis - 211

8.3 Results - 211

8.3.1 Fructose alters basal metabolism and decreases weight loss after surgery - 211

8.3.2 Fructose increases hippocampal gene expression of Vegfa - 212

8.3.3 Fructose increases vascular density in CA1 of the hippocampus - 212

8.3.4 Fructose does not alter blood-brain-barrier permeability - 212

8.3.5 Fructose and acute stress increase corticosterone irrespective of surgery - 212

8.3.6 Fructose does not exacerbate MCAO-induced impairments in neurologic behavior - 213

8.3.7 Fructose promotes anxiety-like behavior in both sham and MCAO-affected animals - 214

8.3.8 Greater lesion volume correlates with an active coping strategy in the forced swim test - 215

8.3.9 Fructose does not change lesion volume after MCAO - 184

8.4 Discussion - 215

GENERAL DISCUSSION……………………………………………………………………………..234

9. Energetic Stress: Expensive effects on body and brain……………………………………….235

9.0 Abstract - 235

9.1 Introduction - 235

9.2 Stress effects on a marker of cerebral energy metabolism - 238

9.2.1 Psychosocial and inflammatory stress change expression of cerebral glucose transporters in a region-, age-, and sex- specific manner - 238

9.2.2 Ovarian hormones modulate expression of cerebral glucose transporters in a region- and isoform- specific manner - 240

9.2.3 Future directions in stress effects on GLUT - 241

9.3 Effects of shifting energy homeostasis on the stress response - 242

9.3.1 Fructose as an energetic stressor - 242

9.3.2 Metabolic & behavioral effects of a high-fructose diet - 245

9.3.3 Effects of fructose on the hypothalamic transcriptome - 246

9.3.4 Energy homeostasis and HPA axis effects on outcomes after ischemic injury - 249

9.3.5 Future directions in the study of the effects of a high-fructose diet on the stress response - 250

9.4 Conclusion - 250

REFERENCES………………………………………………………………………….254

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