Neural mechanisms of variation in pair bond formation in prairie voles Public

Abstract

The socially monogamous prairie vole (Microtus ochrogaster) forms long-term opposite-sex pair bonds, and provides a unique model to study the neural control of complex sociality. Much of the neural circuitry underlying these social bonds have been elucidated using comparative studies with non-monogamous, asocial Microtus species, and has been linked to the neuropeptides oxytocin and vasopressin, as well as dopaminergic reward systems. In addition to drastic species differences, a remarkable degree of individual variation in neuropeptide receptor expression and social behavior is observed within the prairie vole species. Here, we explored proximate mechanisms controlling individual variation in vole sociality. Using RNA interference to knockdown vasopressin V1a receptor expression, we overcome some past limitations of viral vector over-expression or pharmacological manipulations to show that subtle naturalistic-like variations in receptor expression drives within-species variation in pair bonding. Next, we show that although an individual's neuropeptide receptor expression is remarkably resilient to early adversity, variation in neuropeptide receptor expression may mediate behavioral responses to early life events. Early touch elicited immediate early gene activity in oxytocin neurons. Thus sensitivity to early social interactions may determine behavioral outcomes in adulthood. Finally, we show that neonatal treatment with melanocortin agonists, which promote adult attachment, prime oxytocin neurons, and stimulate dopamine release, lead to persistent changes in later play and bonding. Elucidation of the factors and mechanisms mediating normative social behavioral development can ultimately help to reveal potential targets for interventions for social deficits common among human psychiatric disorders.

Table of Contents

TABLE OF CONTENTS

CHAPTER 1 1

Molecular neurobiology of social bonding and social cognition 1

Abstract. 2

Introduction 3

Neuropeptidergic control of the pair bond and proximate behaviors 8

Dopaminergic regulation of monogamy 17

Social cognition, reward and the neural circuitry of social bonding 19

The link between stress, anxiety, social loss, and pair bonding 23

Within-species variability in social behavior 28

Parallels with human social cognition 41

Specific Aims of this Dissertation 44

CHAPTER 2 47

Variation in vasopressin receptor (Avpr1a) expression creates diversity in behaviors related to monogamy in prairie voles. 47

Abstract 48

Materials and Methods 51

Results 63

Discussion 69

CHAPTER 3 78

Interaction of early-life social experience and brain oxytocin receptor expression on pair bonding behavior. 78

Abstract 79

Introduction 80

Materials and Methods 83

Results 92

Discussion 98

CHAPTER 4 107

Neonatal melanocortin receptor agonist treatment activates hypothalamic peptide systems, promotes adult attachment, and reduces play fighting in prairie voles. 107

Abstract 108

Introduction 109

Materials and Methods 111

Results 123

Discussion 132

CHAPTER 5 141

General Conclusions and Future Directions 141

Summary 142

Chapter 2. Future directions. 142

Chapter 3. Future directions. 149

Chapter 4. Future directions. 154

Conclusion and Future Directions 158

APPENDIX 1 161

Identification of variables contributing to superovulation efficiency for production of transgenic prairie voles (Microtus ochrogaster). 161

ABSTRACT 162

Introduction 163

Methods 166

Results 170

Discussion 173

APPENDIX 2. 178

Melanocortin receptor agonists facilitate oxytocin-dependent social behavior 178

Abstract 179

Introduction 180

Methods 182

Results 186

Discussion 192

REFERENCES 198

FIGURES

Chapter 1.

Figure 1.1: Prairie vole model.... 5

Figure 1.2. Comparative differences in neuropeptide receptor expression and functional effects on behavior.... 11

Figure 1. 3. Neurocircuitry of pair bond formation.... 22

Figure 1.4. Intraspecies variation in neuropeptide receptor expression.... 31

Figure 1.5. Proximate and evolutionary systems mediating plasticity in social behavior.... 32

CHAPTER 2.

Figure 2.1. Design of short hairpin RNA sequences... 52

Figure 2.2. Characterization of shRNA knockdown in vitro and in vivo.... 64

Figure 2.3. Partner preference and elevated-plus maze behavior in shRNA-pvAvpr1a and scrambled injected male prairie voles.... 66

Figure 2.4. Analysis of V1aR knockdown, OTR and GFP expression in shRNA-pvAvpr1a and scrambled injected male prairie voles.... 69

CHAPTER 3.

Figure 3.1. Experimental design.... 85

Figure 3.2. Impact of early isolation on pup weight and adult behavior.... 93

Figure 3.3. Females with low NAcc OTR susceptible to early adversity.... 96

Figure 3.4. Tactile stimulation activates OT neurons in the PVN of females.... 97

CHAPTER 4.

Figure 4.1. Experimental design.... 113

Figure 4.2. Daily neonatal MTII treatment reduced weight gain and induced darkened pigmentation.... 124

Figure 4.3. Daily neonatal MTII treatment reduced male juvenile play bouts.... 125

Figure 4.4. Daily neonatal MTII facilitated adult female partner preference.... 126

Figure 4.5. MTII-induced neuropeptide activation in the PVN.... 128

Figure 4.6. Daily neonatal treatment with the specific MC4R agonist PF446687 facilitated partner preference in both sexes.... 129

Figure 4.7 Females exposed to early isolation form PP when given MT2.... 131

CHAPTER 5.

Figure 5.1 NAcc OTR knockdown in females.... 146

Figure 5.2 Ontogeny of oxytocin in prairie voles and mice... 153

Figure 5.3 MC4R agonist promote pup motivated reunion with the mother... 157

APPENDIX 1.

Figure A1.1. Impact of hormone administration and separated cohabitation on superovulatory response in the presence and absence of mating.... 171

Figure A1.2. Female age and occurrence of mating are indicators of superovulation efficiency.... 172

Figure A1.3. Impact of parentage on superovulation efficiency.... 173

APPENDIX 2.

Figure A2.1. MTII facilitates immediate and long-term partner preference in female prairie voles.... 187

Figure A2.2. MTII interacts with the OT system.... 188

Figure A2.3. MC4R mRNA is present in the PVN of the prairie vole brain.... 190

Figure A2.4. MTII activates OT-positive neurons in the paraventricular nucleus.... 191

Figure A2.5. Pf-446687 facilitates partner preference in prairie voles.... 192

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Mot-clé	early experience development social behavior oxytocin vasopressin
Committee Chair / Thesis Advisor	Young, Larry J, Emory University
Committee Members	Wilson, Mark, Emory University Gourley, Shannon L, Emory University Sanchez, Mar, Emory University Ressler, Kerry, Emory University

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