Genetic Diversity in Oxytocin Receptor Sequence, Neural Expression, and Social Behavior Open Access

Abstract

Oxytocin (OXT) is a neuropeptide with conserved functions in reproductive physiology and social cognition through signalling with a single receptor, OXTR. OXTR expression occurs in diverse distributions within the brain and influences species-typical behavior. The socially monogamous prairie vole has high OXTR density in the nucleus accumbens (NAcc) compared to non-monogamous vole species. OXT and dopamine signalling converge in the prairie vole NAcc, enabling social attachments to distinct individuals. OXTR diversity in the NAcc also contributes to individual variation in prairie vole social behavior. Thus, regulatory elements (cis-REs) that influence transcription of the oxtr gene or synthesis of OXTR must be susceptible to variation. This dissertation examines the hypothesis that transcription of the prairie vole oxtr is modulated by polymorphic cis-REs. I found that a molecular signature of polymorphic cis-RE activity, allelic imbalance, occurs robustly and specifically in the NAcc. The single nucleotide polymorphism (SNP) marker used for allelic imbalance, NT204321, predicts OXTR density in the NAcc. NT204321 genotype groups also exhibit differences in mRNA levels in the NAcc and mRNA and OXTR binding are correlated in the NAcc. NT204321 also predicts individual differences in prairie vole social attachment. I next attempted to identify putative locations of cis-REs using next-generation sequencing and found approximately 3,000 SNPs within the oxtr locus. I discovered that SNPs in the prairie vole oxtr are in strong linkage disequilibrium (LD) with each other. One of these SNPs, which is located in the single intron, outperforms NT204321 as a marker of NAcc OXTR density, explaining 75% or more density variation in three separate replicates. Future studies using the intron SNP will investigate gene by environment interactions and probe more deeply into the mechanisms influence oxtr regulation.

Table of Contents

CHAPTER 1. 1

GENERAL INTRODUCTION. 1

INTRODUCTION. 2

OXYTOCIN, VASOPRESSSIN AND SOCIAL BEHAVIOR. 3

NEUROHYPOPHYSEAL PEPTIDE GENE STRUCTURE, EVOLUTION AND CONSERVED FUNCTION. 5

CONSERVATION IN NEURAL EXPRESSION. 7

OXYTOCIN AND VASOPRESSIN IN THE VERTEBRATE BRAIN. 8

OXT AND AVP RECEPTORS. 10

PRAIRIE VOLES AND PAIR BONDING. 12

OXT AND AVP INFLUENCE PAIR BONDING. 14

SPECIES DIFFERENCES IN SOCIAL BEHAVIOR ARE PATTERNED BY RECEPTOR DIVERSITY. 16

NEUROPEPTIDE RECEPTOR EXPRESSION CONTRIBUTES TO INDIVIDUAL DIFFERENCES IN BEHAVIOR. 20

HOW DIVERSITY IN RECEPTOR EXPRESSION IS ACHIEVED. 24

TRANSLATIONAL IMPLICATIONS FOR OXTR AND AVPR1A. 28

OPPORTUNITIES FOR DISCOVERY. 33

CHAPTER 2. 35

GENETIC VARIATION IN THE OXYTOCIN RECEPTOR CONTRIBUTES TO INDIVIDUAL DIVERSITY IN BRAIN RECEPTOR DISTRIBUTION AND SOCIAL ATTACHMENT IN MONOGAMOUS PRAIRIE VOLES. 35

ABSTRACT. 36

INTRODUCTION. 37

RESULTS. 41

Variation in OXTR density across brain regions. 41

Allelic imbalance occurs selectively in the dorsal and ventral striatum. 42

NT204321 is associated with OXTR density. 45

NT204321 genotype predicts individual differences in social behaviors. 49

DISCUSSION. 52

METHODS. 57

Animals. 57

Sanger sequencing and polymorphism discovery. 57

Allelic imbalance. 58

Genotyping. 60

Ultrasonic vocalizations. 60

Partner preference test. 61

Oxytocin receptor autoradiography. 63

In situ hybridization. 64

Statistical analysis. 65

CHAPTER 3. 67

DISSECTION OF THE PRAIRIE VOLE OXYTOCIN RECEPTOR GENE TO IDENTIFY ROBUST MARKERS OF BRAIN REGION SPECIFIC TRANSCRIPTIONAL VARIATION. 67

ABSTRACT. 68

INTRODUCTION. 69

RESULTS. 73

A genetic marker of cis-RE activity selectively predicts OXTR density variation in the NAcc. 73

Sample selection and sequencing for polymorphism discovery in the prairie vole oxtr gene. 74

Association analyses. 77

DISCUSSION. 82

METHODS. 84

Long-range PCRs for target enrichment of 70kb surrounding oxtr. 84

Amplicon library preparation. 85

Amplicon sequencing analysis. 86

Genotyping. 86

Statistical analysis. 87

CHAPTER 4. 88

CONCLUDING REMARKS. 88

SUMMARY OF FINDINGS. 89

FUTURE DIRECTIONS. 93

OXTR in neural networks. 93

REFERENCES. 98

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, Genetics Biology, Neuroscience
Keyword	Oxytocin Social behavior Gene expression
Committee Chair / Thesis Advisor	Young, Larry J, Emory University
Committee Members	Cubells, Joseph F, Emory University Weinshenker, David, Emory University Bassell, Gary, Emory University Rainnie, Donald, Emory University

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