Genetic Variation of the Oxytocin System and Social Behavior of Adult Female Rhesus Macaques Open Access

Abstract

Affiliative behavior, which underlies the formation and maintenance of social bonds, is a vital component of human mental health. This behavior varies on a spectrum across typical individuals and deficits are observed in those with autism spectrum disorder (ASD), schizophrenia, and adverse early life experiences. Decades of human genetic research have established that most complex traits are highly heritable. Thus, investigating the genetic contributions to individual variation in these socio-behavioral traits and the neural mechanisms that precede them is important for understanding how affiliative bonds are either maintained, supported, or disrupted. The neurohormone oxytocin (OXT) and its receptor OXTR as well as the genes that encode them have established history of shaping social behavior in a variety of mammals. As such, in this dissertation I examine the genetic and epigenetic variation of these oxytocin-related genes and measure their effect on various social traits of adult female rhesus macaques. I quantify the predictive value of 13 genetic variants in OXTR as well as the methylation patterns at CPG sites in both OXT and OXTR.  I do not find evidence of robust influence of any of these markers on behavioral outcomes or OXT in cerebrospinal fluid. These findings support the conclusion that has emerged in human genetic studies of complex traits, which is that individual markers have negligibly small effects. To reliably detect effects of small sizes, genetic association studies would need to be carried out in much larger sample sizes. While the rhesus macaque model has a social and neuroanatomical similarity to humans with high translational value, to maximize the validity of genetic association findings from non-human primate (NHP) research, funding agencies and NHP centers should optimize experimental designs for maximum statistical power.

Table of Contents

CHAPTER 1. INTRODUCTION.......................................................................................... 1

1.1 The importance of studying social behavior.......................................................... 2

1.2 Environmental and genetic influences on complex social behavior................... 3

1.3 A brief history of oxytocin....................................................................................... 5

1.4 Manipulations of the OXT system............................................................................. 7

1.5 Variation in the OXT system...................................................................................... 8

1.5.1 Genetic variation of the OXT system............................................................ 9

1.5.2 Epigenetic variation of the OXT system..................................................... 11

1.6 Why use NHPs for studying social behavior?...................................................... 13

1.7 NHPs and OXTR distributions................................................................................. 14

1.8 Rhesus macaques and OXT....................................................................................... 19

1.8.1 Experience and OXT....................................................................................... 20

1.8.2 Exogenous OXT and rhesus.......................................................................... 20

1.8.3. Rhesus OXTR behavioral genetics............................................................. 23

1.9 Translational relevance......................................................................................... 24

1.9.1 ASD and OXT genetics................................................................................... 27

1.9.2 Intranasal oxytocin....................................................................................... 28

1.10 Overall goals and hypotheses............................................................................. 29

CHAPTER 2. HERITABILITY AND RELATIONSHIP OF OXYTOCIN RECEPTOR GENE VARIANTS WITH SOCIAL BEHAVIOR AND CENTRAL OXYTOCIN IN COLONY-REARED ADULT FEMALE RHESUS MACAQUES           31

Acknowledgment of Reproduction.............................................................................. 32

2.1 Abstract..................................................................................................................... 32

2.2 Introduction.............................................................................................................. 33

2.3 Materials and Methods............................................................................................ 35

2.3.1 Subjects and Housing.................................................................................... 35

2.3.2 Behavioral Data Collection......................................................................... 35

2.3.3 CSF and Blood Samples................................................................................. 35

2.3.4 Covariates....................................................................................................... 36

2.3.5 SNP Selection................................................................................................. 36

2.3.6 Genotyping...................................................................................................... 37

2.3.7 Statistical Analysis....................................................................................... 37

2.4 Results....................................................................................................................... 39

2.4.1 Heritability Estimates................................................................................... 39

2.4.2. SNP Associations.......................................................................................... 39

2.4.3 Associations between OXT CSF and Behavior........................................... 39

2.5 Discussion.................................................................................................................. 39

CHAPTER 3. METHYLATION OF OXT AND OXTR GENES, CENTRAL OXYTOCIN LEVELS, AND SOCIAL BEHAVIOR IN FEMALE MACAQUES...................................................................................................................... 49

Acknowledgment of Reproduction.............................................................................. 50

3.1 Abstract..................................................................................................................... 50

3.2 Introduction.............................................................................................................. 51

3.3 Materials and Methods............................................................................................ 54

3.3.1 Subjects and Housing.................................................................................... 54

3.3.2 Behavioral Data Collection......................................................................... 55

3.3.3 Physiological Data Collection and Analysis............................................. 56

3.3.4 Epigenetic Analysis........................................................................................ 57

3.3.5. Statistical Analysis...................................................................................... 59

3.4 Results....................................................................................................................... 60

3.4.1 Characteristics of Behavioral and Physiological Measures................. 60

3.4.2 DNAm of OXT and OXTR................................................................................. 61

3.4.3 Methylation and OXT in CSF......................................................................... 62

3.5 Discussion.................................................................................................................. 63

3.5.1 Relevance to human studies......................................................................... 65

3.5.2 Is peripheral methylation of OXTR a relevant marker?.......................... 66

3.5.3 This is an exploratory study with many comparisons............................... 67

3.5.4 Conclusion...................................................................................................... 69

CHAPTER 4. GENERAL DISCUSSION........................................................................... 83

Summary of findings....................................................................................................... 84

Weak behavioral associations of OXT and OXTR variants in rhesus...................... 87

Moving forward with behavioral genetic NHP studies............................................. 90

REFERENCES.................................................................................................................. 95

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Subfield / Discipline	Neuroscience
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience
Keyword	rhesus macaques oxytocin
Committee Chair / Thesis Advisor	Larry J. Young, Emory University Mar M. Sanchez, Emory University
Committee Members	Mark E. Wilson, Emory University Adrian V. Jaeggi, Emory University Alicia K. Smith, Emory University

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