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Galanin Mediates the Resilence Afforded by Exercise: Behavioral

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Galanin Mediates the Resilence Afforded by Exercise: Behavioral GALANIN MEDIATES THE RESILENCE AFFORDED BY EXERCISE: BEHAVIORAL, NEUROCHEMICAL, AND NEUROANATOMICAL EVIDENCE by NATALE ROSE SCIOLINO (Under the Direction of Philip Holmes) ABSTRACT Exercise is effective treatment for symptoms of mental disorders such as anxiety and substance abuse. However, the neural mechanisms that support these benefits are only beginning to be identified and dissected. Our laboratory has repeatedly shown that exercise increases levels of the peptide galanin in the locus coeruleus (LC). The effects of galanin share many qualities with those of exercise. Both manipulations are protective against the behavioral impact of stress and cocaine in rodent models of mental disease. We hypothesized that the behavioral protection provided by exercise is mediated by galanin, and similarly that galanin receptor agonists would protect against stress- and drug-induced perturbation of behavior. We also predicted that exercise or administration of a galanin agonist would block neural markers of stress or cocaine in the frontal cortex, a region particularly vulnerable to these challenges. Male Sprague Dawley rats were used in all experiments, and a subset underwent stereotaxic brain cannulation for drug delivery (ICV) and/or in vivo microdialysis (intra-frontal cortex). Rats were assigned to sedentary or exercise conditions and then exposed to stress or cocaine as detailed in the experiments. We measured behavior in tests of anxiety, including the elevated plus maze, open field, and shock probe defensive burying test. We measured galanin levels after exercise using in situ hybridization and ELISA. We also performed in vivo microdialysis and Golgi- impregnation in the frontal cortex. The results showed that exercise increased galanin levels in the locus coeruleus. Exercise and administration of a galanin receptor agonist (galnon or galanin) protected against the behavioral impacts of stress and cocaine. These manipulations also blunted the stress- and cocaine- induced increase in dopamine in the frontal cortex. Further, exercise protected against the loss of dendritic spines after stress. The behavioral protection induced by exercise was mimicked by repeated intracranial galanin administration, and blocked by repeated administration of the galanin receptor antagonist M40. Collectively, our data implicate an important role for galanin in behavioral resilience. Exercise, like galanin therapy, may protect against the aberrant neural plasticity seen in comorbid disorders like anxiety and drug addiction. INDEX WORDS: Anxiety; brain; cocaine; cortex; dendritic spines; dopamine; environmental enrichment; exercise; galanin; galnon; locus coeruleus; mPFC; neuroplasticity; resilience; stress; GALANIN MEDIATES THE RESILENCE AFFORDED BY EXERCISE: BEHAVIORAL, NEUROCHEMICAL, AND NEUROANATOMICAL EVIDENCE by NATALE ROSE SCIOLINO BS, SUNY at Buffalo, 2008 MS, University of Georgia, 2009 A Dissertation Submitted to the Graduate Faculty of The University of Georgia in Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY ATHENS, GEORGIA 2014 © 2014 Natale Rose Sciolino All Rights Reserved GALANIN MEDIATES THE RESILENCE AFFORDED BY EXERCISE: BEHAVIORAL, NEUROCHEMICAL, AND NEUROANATOMICAL EVIDENCE by NATALE ROSE SCIOLINO Major Professor: Philip V. Holmes Committee: Rodney K. Dishman Gaylen L. Edwards Electronic Version Approved: Maureen Grasso Dean of the Graduate School The University of Georgia May 2014 DEDICATION This work is dedicated to Jean DiPirro and Brendan Walsh for your endless support, kindness, and belief in me. At the root of things, this work is also dedicated to Nunzia and Benedetto Sciolino. iv ACKNOWLEDGEMENTS I would like to acknowledge my advisor Philip Holmes for providing me with guidance, and encouraging me to develop intellectual independence. I also owe great thanks to Gaylen Edwards and Rodney Dishman for instruction throughout my training, especially the support provided as committee members. This work was supported by DA027535A from the National Institute on Drug Abuse (NIDA), which was awarded to Philip Holmes and our collaborator David Weinshenker. Natale Sciolino was also supported by a NIDA Diversity supplement to DA027535, ARCS Fellowship, UGA Dissertation Completion award, and travel funds provided by the Neuroscience Program in the Biomedical and Health Science Institute. This work would not be possible without such research funding and support. v TABLE OF CONTENTS Page ACKNOWLEDGEMENTS ........................................................................................................... v LIST OF TABLES ....................................................................................................................... ix LIST OF FIGURES ..................................................................................................................... x CHAPTER 1 GENERAL INTRODUCTION…. ................................................................................. 1 2 LITERATURE REVIEW. EXERCISE OFFERS ANIOLYTIC-POTENTIAL: A ROLE FOR STRESS AND BRAIN NORADRENERGIC-GALANINERGIC MECHANISMS………………………………………………………………...............…....3 Abstract ...............................................................................................................4 Anxiety and its treatment ...................................................................................... 5 Tests and models of anxiety in rodents…………………………………………. ...... .7 Effects of wheel running on anxiety-like behavior and fear learning ..................... 9 Effects of wheel running on neurotransmission in regions controlling stress and anxiety .............................................................................................................. .26 Final Remarks .................................................................................................... 33 References ........................................................................................................ 50 3 VOLUNTARY EXERCISE OFFERS ANXIOLYTIC POTENTIAL AND AMPLIFIES GALANIN GENE EXPRESSSION IN THE LOCUS COERULEUS OF THE RAT ........................................................................................................... 79 Abstract ............................................................................................................. 80 Introduction ........................................................................................................ 81 Materials and methods ....................................................................................... 83 vi Results ............................................................................................................... 91 Discussion ......................................................................................................... 95 Conclusions ..................................................................................................... 100 References ...................................................................................................... 112 4 THE GALANIN RECEPTOR AGONIST GALNON ATTENUATES COCAINE- INDUCED REINSTATEMENT AND DOPAMINE OVERFLOW IN THE FRONTAL CORTEX ............................................................................................................... 124 Abstract ........................................................................................................... 125 Introduction ...................................................................................................... 126 Materials and Methods ..................................................................................... 127 Results ............................................................................................................. 134 Discussion……………….. ................................................................................ 138 Conclusions ..................................................................................................... 142 References ...................................................................................................... 153 5 GALANIN MEDIATES THE NEURAL AND BEHAVIORAL STRESS RESILIENCE AFFORDED BY EXERCISE .................................................................................. 159 Abstract ........................................................................................................... 160 Introduction ...................................................................................................... 161 Materials and Methods ..................................................................................... 162 Results ............................................................................................................. 168 Discussion ....................................................................................................... 173 References ...................................................................................................... 192 6 GENERAL CONCLUSIONS .................................................................................. 198 vii LIST OF TABLES Page Table 2.1: Summary of the effects of wheel running on baseline responding in tests of anxiety ......... ……………………………………………………………………………..…. 34 Table 2.2: Summary of the effects of wheel running on stress-evoked responding in tests of anxiety ......................................................................................................................3 6 Table 2.3: Summary of the effects of wheel running on fear learning .......................................
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