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Modi Dissertation 2012 Submitted To Distribution Agreement In presenting this thesis or dissertation as a partial fulfillment of the requirements for an advanced degree from Emory University, I hereby grant to Emory University and its agents the non-exclusive license to archive, make accessible, and display my thesis or dissertation in whole or in part in all forms of media, now or hereafter known, including display on the world wide web. I understand that I may select some access restrictions as part of the online submission of this thesis or dissertation. I retain all ownership rights to the copyright of the thesis or dissertation. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. Signature: ________________________ ______________________ Meera Modi Date Identifying Novel Therapeutic Strategies for Enhancing Social Cognition Using Functional Animal Models By Meera Modi Doctor of Philosophy Graduate Division of Biological and Biomedical Science Neuroscience _________________________________________ Larry Young, PhD Advisor _________________________________________ Lisa Parr, PhD Committee Member _________________________________________ Diana Robins, PhD Committee Member _________________________________________ Randy Hall, PhD Committee Member _________________________________________ Kerry J. Ressler, MD/PhD Committee Member Accepted: _________________________________________ Lisa A. Tedesco, Ph.D. Dean of the James T. Laney School of Graduate Studies ___________________ Date Identifying Novel Therapeutic Strategies for Enhancing Social Cognition Using Functional Animal Models By Meera Modi B.S./B.A., Binghamton University, 2005 Advisor: Larry Young, PhD An abstract of A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience 2012 Abstract Identifying Novel Therapeutic Strategies for Enhancing Social Cognition Using Functional Animal Models By Meera Modi Currently, there are no FDA approved drugs for the treatment of the social impairments characteristic of many psychiatric disorders, including autism and schizophrenia. One potential approach to treating social impairments is to target the neural systems that underlie functional social motivation and information processing in normative populations. Oxytocin (OT) has emerged as a central modulator of social behavior, and the OT system is being actively explored as a pharmacological target for the enhancement of social cognition clinically. However, the therapeutic potential of OT is limited by the biophysical properties of the peptide, include its poor penetration of the blood-brain barrier and its metabolic instability. Consequently, novel methods of enhancing the OT system and the social brain circuit are required to realize the pharmacological treatment of social impairments. Through my doctoral work, I have evaluated and developed novel methods of pharmacologically enhancing social cognition and characterized a functional animal model with predictive validity for prosocial therapeutics. Alternate methods of enhancing the central OT system were tested. The relative efficacy of peripheral routes of OT administration on increasing central peptide levels to evoke behavioral effects was measured in a rhesus monkey model. In prairie voles, a novel method of increasing central OT through the pharmacological stimulation of oxytocinergic neurons was tested. Peripherally administered melanocortin receptor agonists, Melanotan II and Pf-446687, are able to recapitulate the behavioral effects of central OT in this model, through an OT-dependent pathway. These findings suggest indirect stimulation of the OT system can result in a functional enhancement of social cognition. Social cognition can also be enhanced in the prairie vole model through the glutamatergic activation of the brain areas involved in the regulation of OT- dependent social behavior. Administration of the NMDA receptor partial agonist, D-cycloserine, prior to a social learning experience also facilitates social cognition through brain areas that regulate the expression of social behavior, the nucleus accumbens and the amygdala. Importantly, preliminary studies indicate that D-cycloserine reduces some of the social impairments in individuals with autism, suggesting that partner preference in the prairie vole may have predictive validity for identifying drugs that enhance the acquisition of social information. Identifying Novel Therapeutic Strategies for Enhancing Social Cognition Using Functional Animal Models By Meera Modi B.S./B.A., Binghamton University, 2005 Advisor: Larry Young, PhD A dissertation submitted to the Faculty of the James T. Laney School of Graduate Studies of Emory University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Neuroscience 2012 ACKNOWLEDGMENTS My time at Emory has been both incredibly productive and deeply rewarding because of the communities of which I have had the privilege of being a part and the individuals who have shared my journey. The Young Laboratory has been my scientific home throughout my graduate career. Within the laboratory, I received exceptional training and guidance from my mentor Larry Young, both in the actual “doing” of science and in the broader “world” of science. Dr. Young has taught me what it means to be a part of a scientific community and the benefits, and even necessity, of collaboration in the pursuit of meaningful scientific contributions. In addition, his treatment of me as a peer, from day one, compelled me to continually work my hardest to be worthy of such a distinction. I am also deeply grateful to the continuing support of my fellow students, post-docs and laboratory technicians, who have been with me through the bowels of my scientific pursuits. From Lisa McGraw, Zoe Donaldson and Todd Ahern, I have received invaluable guidance that enabled me to function competently as an independent researcher within the laboratory. I hope that as I continue to grow as a scientist, I will continue to be able count this group amongst my closest friends and colleagues. If the Young Laboratory was my home, the Neuroscience Program has been my family. The friends I have made within our program are amongst the greatest rewards of my graduate career. They have been my buffer in the sometimes-turbulent world of graduate school and are the reason I am graduating with a smile still on my face. In particular, I would like to acknowledge Vasiliki Michopoulos, Rebecca Roffman, Kate O’Toole and Alex Poplawsky for their unending support and enthusiasm. Beyond Emory, I have been privileged to be a part of two outstanding organizations, the Center for Behavioral Neuroscience and the Center for Translational Social Neuroscience (CTSN). These organizations have immersed me in the diverse and talented community of Atlanta neuroscience and have showed me first hand the synergistic power of collaboration. Through the CTSN, I may eventually see ultimate translation of much of my basic science research into a therapeutic benefit for individuals with autism. To have even the potential of a real-world impact resulting from my work is truly the ultimate reward. Financially, I have had the continuing support of Autism Speaks, which funded me personally with the awarding of a pre-doctoral fellowship and of my the majority of my research through a basic science research grant. Their continued support is indicative of their commitment to the search for biologically based treatments for the social impairments associated with autism. And lastly, I am grateful for my family that has supported my protracted education process and encouraged me to follow in the academic footsteps of my grandfather. And my husband Jay, who has enforced balance in my life and continuously reminded me there is great fun to be had outside of the ivory tower. TABLE OF CONTENTS CHAPTERS PAGE 1. The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies………………………………………………..………….......……..…1 1.1. Abstract.............................................................................................................................2 1.2. Introduction…………………………………………………………………………..…3 1.2.1. Using animal models to understand ASD…………………………….....…………..4 1.3. ASD phenotypes in genotype based models…………………………………….….….5 1.3.1. Social information processing and recognition…………………………………….5 1.3.2. Social comfort……………………………………………………………………...7 1.3.3. Anxiety……………………………………………………………………….…….8 1.3.4. Other ASD relevant phenotypes………………………………………….………...9 1.3.5. Evidence for construct validity…………………………………….……………….9 1.3.6. Oxytocin and monogenic forms of ASD…………………………….……………10 1.4. ASD Related Phenotype Based Models………………………………………………11 1.4.1. Inbred mouse models of social variability………………………………………...12 1.4.2. Social variation in microtine rodents……………………………………………...13 1.5. Therapeutic strategies for targeting the OT system…………………………………15 1.5.1. Intranasal OT………………………………………………………………………16 1.5.2. Non-peptide agonist…………………………………………………….…………17 1.5.3. Enhancing endogenous OT release………………………………………..………18 1.5.4. Oxytocinase inhibitors……………………………………………………..……...21 1.5.5. Oxytocin manipulations as adjuncts to behavioral therapies………………..…….22 1.6. Conclusions………………………………………………………………….………….23 1.7. Acknowledgments...........................................................................................................24
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