Neural mechanisms of variation in pair bond formation in prairie voles Pubblico
Barrett, Catherine Eileen (2014)
Published
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
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