Oxytocin in Translation: Manipulating the Social Brain with Pharmacology and Contextual Stimuli Pubblico

Abstract

Social behavioral neuroscience has recently achieved in animal models feats that just a decade ago were relegated to creative works of science fiction. By manipulating specific neural circuits with temporal and contextual precision, neuroscience has developed the ability to “incept” false memories, induce monogamous social bonds, and turn complex parenting behaviors on and off with the flip of a switch. These remarkable capabilities contrast starkly with the limited efficacy and decades-old paradigms of psychiatry, which still relies on purely behavioral diagnoses and chronic, brain-wide pharmacological interventions. In this dissertation, I draw from theoretical and experimental publications I authored in collaboration with Dr. Larry Young and members of his laboratory to examine the disjunction between neuroscience and psychiatry, and to illustrate a translational process by which this disjunction might be ameliorated, with a focus on oxytocin and social behavior. In Chapter 1, we describe how a circuit-level approach to studying, understanding, and manipulating the social brain might facilitate translation from neuroscience to psychiatry and enable a shift in therapeutic paradigms from behavioral pharmacology to neural rewiring. We examine a prominent failure of the behavioral pharmacology paradigm – a clinical trial that failed to improve social behavior in autism using chronic intranasal oxytocin administered independent of context – and propose an alternative paradigm utilizing pharmacologically enhanced behavioral therapy and context-dependent oxytocin administration to rewire the brain. However, this approach requires understanding how specific neural circuits are affected by particular pharmacological manipulations, so Chapter 2 describes in great detail the anatomical distribution of oxytocin receptors in the prairie vole brain and the functional implications thereof. Chapter 3 models pharmacologically enhanced behavioral therapy for social deficits and demonstrates that administering a novel pharmaceutical in a social context activates the endogenous oxytocin system and thereby selectively increases the activity of a brain area critical for social reward learning. As the therapeutic approach we advocate involves using psychological interventions to rewire the brain, in Chapter 4, I explore other psychosomatic phenomena, including the neurobiological basis of the placebo effect, translational possibilities for the salubrious properties of love, and the evolutionary origins of the increased mortality associated with widowhood.

Table of Contents

Chapter 1. Advancing 21^st-Century Psychiatry: Translational Opportunities for Circuit-Based Social Neuroscience - 1

1.1 Acknowledgment of Reproduction and Authors’ Contributions - 2

1.2 Abstract - 2

1.3 Introduction: The Gulf between Psychiatry and Neuroscience - 3

1.4 Conception of the Social Brain from Animal Research - 4

1.5 Insights from Human Research - 7

1.6 Translational Implications - 10

1.7 Refining Oxytocin Therapy for Autism: A Case Study - 13

1.8 Concluding Remarks - 17

Chapter 2. Oxytocin Receptors are Widely Distributed in the Prairie Vole Brain: Relation to Social Behavior, Genetic Polymorphisms, and the Dopamine System - 24

2.1 Acknowledgment of Reproduction and Authors’ Contributions - 25

2.2 Abstract - 25

2.3 Introduction - 26

2.4 Materials and Methods - 30

2.4.1 Subjects - 30

2.4.2 Brain sectioning - 31

2.4.3 Chromogenic RNAscope in situ hybridization for mapping Oxtr mRNA - 31

2.4.4 Oxytocin receptor autoradiography for mRNA-protein comparison - 32

2.4.5 Fluorescent RNAscope for colocalizing Oxtr mRNA within D1R- and D2R-expressing cells - 33

2.4.6 Microscopy - 33

2.4.7 Image analysis and statistics - 34

2.5 Results - 35

2.5.1 Brain-wide mapping of Oxtr mRNA - 35

2.5.2 Regions involved in social salience and memory - 36

2.5.3 Hypothalamic, thalamic, and septal regions - 36

2.5.4 Cortical regions - 37

2.5.5 Neuromodulatory areas - 37

2.5.6 Mismatch of Oxtr mRNA and OXTR protein - 38

2.5.7 Colocalization of Oxtr with Drd1 and Drd2 mRNA in the NAc - 39

2.6 Discussion - 40

2.6.1 Oxytocin receptor mRNA expression in select areas influencing behavior - 42

2.6.2 Mismatches in the localization of Oxtr mRNA and OXTR protein - 46

2.6.3 Comparing the localization of Oxtr mRNA with Drd1 and Drd2 mRNA in the NAc - 49

2.7 Conclusion and Future Directions - 51

Chapter 3. Melanocortin Agonism in a Social Context Selectively Activates Nucleus Accumbens in an Oxytocin-Dependent Manner - 73

3.1 Acknowledgment of Reproduction and Authors’ Contributions - 74

3.2 Abstract - 74

3.3 Introduction - 75

3.4 Material and Methods - 78

3.4.1 Subjects - 78

3.4.2 Peripheral MTII administration in a non-social context - 79                     

3.4.3 Peripheral MTII administration in a social context - 79

3.4.4 Central MTI administration dose-response - 80

3.4.5 Central MTII administration in a social context - 81

3.4.6 Central MTII administration in a novel context - 82

3.4.7 Perfusion and sectioning - 82

3.4.8 Fos immunohistochemistry - 82

3.4.9 Nissl staining - 83

3.4.10 Imaging - 84

3.4.11 Statistics - 85

3.5 Results - 86

3.5.1 Melanocortin receptor agonism in a non-social context - 86

3.5.2 Melanocortin receptor agonism in a social context - 87

3.5.3 Melanocortin receptor agonism in a social context with central administration - 89

3.5.4 Melanocortin receptor agonism in a novel context - 89

3.6 Discussion - 91

Chapter 4. Love, Death, and Placebos: A Foray in Psychosomatics - 113

4.1 Acknowledgment of Reproduction and Authors’ Contributions - 114

4.2 Abstract - 114

4.3 Introduction: The Case for Psychosomatics - 115

4.4 The Neurobiological Mechanisms of the Placebo Effect - 116

4.5 Harnessing the Healing Power of Love - 122

4.6 On the Origin of the Widowhood Effect - 126

4.6.1 A Novel Hypothesis - 126

4.6.2 Natural Selection for Altruistic Mortality - 129

4.6.3 The Case of Partner Loss - 132

4.6.4 Evaluating the “Altruistic Mortality Hypothesis” - 134

4.6.5 A Remarkable Implication - 137

4.7 Conclusions and Future Directions - 139

References - 143

About this Dissertation

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Biology, Neuroscience Psychology, Psychobiology Health Sciences, Mental Health
Parola chiave	Autism Prelimbic Cortex Oxytocin receptor distribution Social Neuroscience Melanotan II Oxytocin Behavioral Therapy Hippocampus Widowhood effect Paraventricular Nucleus Placebo effect Melanocortin Basolateral Amygdala Neural Circuits Psychosomatic Pharmacologically enhanced therapy Nucleus Accumbens Psychiatry
Committee Chair / Thesis Advisor	Larry Young, Emory University
Committee Members	Joseph Cubells, Emory University Shannon Gourley, Emory University Paul García, Columbia University Robert Liu, Emory University

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