Novel approaches to enhance social cognition by stimulating central oxytocin release using a melanocortin 4 receptor agonist 公开

Kittelberger, Kara (Fall 2017)

Permanent URL: https://etd.library.emory.edu/concern/etds/0g354f20t?locale=zh
Published

Abstract

 The evolutionarily conserved neuropeptide oxytocin (OT) modulates sociocognitive functioning by coordinating activity across brain regions responsible for integrating the physiological, motivational, and associative properties of social stimuli.  Recently, there has been strong clinical interest in pharmacological targeting of the OT system as a potential treatment of social impairments in psychiatric or neurodevelopmental disorders, including autism spectrum disorder (ASD).  To date, effective manipulation of the central OT system in a behaviorally- and ecologically-relevant manner has remained elusive.  Social attachment formation in the monogamous prairie vole (Microtus ochrogaster) is an ideal model for the study of OT-dependent sociocognitive behaviors with face, construct, and predictive validity for functional human social cognition.  We propose here a novel method of enhancing OT-dependent social cognition and neuronal network processing through the use of a melanocortin 4 receptor (MC4R) agonist, Melanotan II (MTII).  Stimulation of MC4Rs enhances stimulus-evoked endogenous central OT release.  It is hypothesized that MTII could mirror the behavioral effects of direct exogenous OT, and previous studies in female prairie voles report enhancements in social attachment formation following MTII administration.  To demonstrate equivalent efficacy of this novel potential treatment in both sexes, we first successfully replicated these published findings using male subjects.  Quantitative analysis of reciprocal social interactions did not reveal any MTII-mediated positive shifts in affiliative social behaviors.  We therefore hypothesized MTII administration, and consequent elevations in central OT release, may instead modulate neuronal network processing to affect the perception of social stimuli rather than social interactive behavior itself.  In a social exposure context, but not in the homecage, MTII treatment robustly increases neuronal activation in brain regions known to mediate social reward and social motivation, the nucleus accumbens shell (NAcc shell) and prelimbic cortex (PLC).  Context-dependent increases in NAcc shell and PLC activation following MTII treatment were significantly attenuated by selective blockade of OT receptors.  These results support the hypothesis that MTII administration elevates endogenous central OT release in social contexts and positively modulates social salience processing.  Enhancing endogenous OT release with MTII could have significant clinical utility as a pharmacological adjuvant to behavioral therapies, particularly those targeting social reward or social motivation.

 

Table of Contents

 

TABLE OF CONTENTS

 

CHAPTERS                                                                                                              PAGE

 

1.  Oxytocin as a modulator of the social salience network and a target

 

      for novel drug development                                                                               1

 

            1.1.  Abstract                                                                                                 2

 

            1.2.  Introduction                                                                                          3

 

            1.3.  Oxytocin and Social Cognition                                                            4

 

                        1.3.1.  Social information detection and processing                            8

 

                        1.3.2.  Social salience                                                                          11

 

                        1.3.3.  Social motivation and social reward                                         17

 

                        1.3.4.  Social memory                                                                         20

 

                        1.3.5.  Oxytocin and modulation of the social salience network          22

 

            1.4.  Pharmacological Targeting of the Oxytocin System                          23

 

                        1.4.1.  Intranasal oxytocin                                                                   24

 

                        1.4.2.  Melanocortin 4 receptor agonists and endogenous

 

                                    central oxytocin release                                                           27

 

            1.5.  Conclusions                                                                                           28

 

            1.6.  Figures                                                                                                   31

 

2.  Behavioral effects of melanocortin 4 receptor agonists in prairie voles          32

 

            2.1.  Abstract                                                                                                 33

 

            2.2.  Introduction                                                                                          34

 

            2.3.  Methods                                                                                                 40

 

            2.4.  Results                                                                                                   45

 

            2.5.  Discussion                                                                                              49

 

            2.6.  Figures                                                                                                   53

 

3.  Melanocortin 4 receptor agonists and context-dependent neuronal

 

    activation                                                                                                               58

 

            3.1.  Abstract                                                                                                 59

 

            3.2.  Introduction                                                                                          60

 

            3.3.  Methods                                                                                                 64

 

            3.4.  Results                                                                                                   71

 

            3.5.  Discussion                                                                                              75

 

            3.6.  Figures                                                                                                   83

 

4.  General conclusions and future directions                                                        106

 

            4.1.  Conclusions                                                                                           107

 

                        4.1.1.  Project 1: Behavioral effects of a melanocortin 4

 

                                    receptor agonist in the prairie vole                                           110

 

                        4.1.2.  Project 2: Context-dependent neuronal network

 

                                    activation in response to MC4R agonism                                111

 

                        4.1.3.  General Summary                                                                    113

 

            4.2.  Future Directions                                                                                  118

 

                        4.2.1.  Social memory and ventral hippocampal CA1 region              119

 

                        4.2.2.  Contribution of direct extrahypothalamic MC4R

 

                                    stimulation                                                                               120

 

                        4.2.3.  Interactions with mesocorticolimbic dopamine

 

                                    pathway                                                                                   121

 

                        4.2.4.  Possible caveats to clinical applicability of MC4R

 

                                    agonists                                                                                   123

 

            4.3.  Final Conclusions                                                                                 125

 

5.  Appendix                                                                                                              128

 

            5.1.  Observations on conducting partner preference testing in

 

                    suboptimal conditions                                                                          128

 

            5.2.  Tables                                                                                                     136

 

6.  References                                                                                                             138

 

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